A versatile one-pot synthesis of fused polycyclic imidazole-naphthoquinone derivatives through imidazole-4,5-quinodimethane generation followed by Diels-Alder cycloaddition

Article abstract of DOI:10.1055/s-2007-986656

An efficient procedure for the trapping of an imidazole-4,5-quinodimethane intermediate 3 with quinones in boiling toluene and in the presence of 18-crown-6 is described. In all cases the fully aromatized imidazole- naphthoquinone derivatives were isolate

Full text of DOI:10.1055/s-2007-986656

2596
LETTER
A Versatile One-Pot Synthesis of Fused Polycyclic Imidazole-naphthoquinone
Derivatives through Imidazole-4,5-quinodimethane Generation Followed by
Diels–Alder Cycloaddition
O
ne-Pot Synthesi
o
s
of Fused
P
n
olycyclic Im
s
idazole-na
t
phthoq
a
uinone
D
er
n
ivatives tinos Neochoritis, Julia Stephanidou-Stephanatou, Constantinos A. Tsoleridis*
Department of Chemistry, Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Fax +30(2310)997679; E-mail: tsolerid@chem.auth.gr
Received 18 July 2007
this study we envisaged that Diels–Alder trapping of an
Abstract: An efficient procedure for the trapping of an imidazole-
imidazole o-QDM with quinones could offer a successful
4,5-quinodimethane intermediate 3 with quinones in boiling toluene
pathway. Moreover, very few reactions between o-
and in the presence of 18-crown-6 is described. In all cases the fully
aromatized imidazole-naphthoquinone derivatives were isolated as
QDMs19 (especially heterocyclic o-QDMs20) and quino-
the main reaction products in satisfactory yields. However, in the nes as dienophiles, leading to quinone derivatives fused to
case of benzo- and naphthoquinone, aromatized products were also
a biologically active heterocyclic ring, have been studied.
isolated, in which the bromine in the 2-imidazole position was
replaced by hydrogen, whereas in the case of the asymmetrical 2-
Our synthetic approach is depicted in Scheme 1. The
tetrabromoimidazole derivative 2, prepared in 60% yield
by bromination of 1, was used as an o-QDM precursor.18
Due to the instability of 2 to column chromatography, it
was not purified but was treated directly with sodium
iodide in boiling toluene for 3–4 hours in the presence of
18-crown-6 to afford the imidazole o-QDM 3, which was
reacted in situ with quinones. From the reaction with the
symmetrical benzoquinone the initially formed Diels–
Alder cycloadduct was not isolated but, under the reaction
conditions, underwent subsequent oxidation to give the
aromatized product 4 in 38% yield.21 A small amount (6%
yield) of a second, aromatized product 5, in which the
bromine in the 2-imidazole position was replaced by hy-
drogen was also isolated (Scheme 1). An analogous result
was obtained from the reaction of 3 with naphthoquinone,
where the fully aromatized tetracyclic product 6 was
isolated in only 10% yield. However, a second fully aro-
matized tetracyclic product 7 was isolated in 41% yield22
along with a third product, namely the non-aromatized
Diels–Alder derivative 8 in 5% yield. In the last two prod-
ucts, 7 and 8, again the imidazole 2-position bromine
atom was replaced by hydrogen. Next, the asymmetrical
quinones, 2-phenylbenzoquinone and 5,8-quinoline dione
were used. In both cases inseparable mixtures of the regio-
isomeric aromatized compounds 10a,b (3:1) and 11a,b
(4:1) were isolated in 43% and 32% overall yield, respec-
tively. Along similar lines, 3 reacted with triptyceno-
quinone to give only the aromatized polycyclic
cycloadduct 9 in 35% yield.
phenylbenzoquinone and 5,8-quinoline dione inseparable regioiso-
meric mixtures were formed.
Key words: crown ether, Diels–Alder reactions, imidazole o-qui-
nodimethanes, fused imidazolenaphthoquinones, one-pot reaction
The heterocyclic analogues of o-quinodimethanes (o-
QDMs) are of considerable interest both from a theoreti-
cal point of view and for their potential in organic synthe-
sis as useful dienes.1 Their utilization for the annulations
of aromatic systems has now acquired practical im-
portance and has been exploited in efficient synthesis of a
wide range of polycyclic natural products.2
On the other hand, quinones occupy an important place
among the different classes of antitumor agents. The bio-
logical processes involved with the antitumor activity of
quinones are DNA intercalation, bioreductive alkylation
of biomolecules, and generation of oxy radicals through
redox cycling.3–7 Heterocycle-fused quinones, containing
nitrogen, are known to possess antibacterial,8 antifungal,9
and cytotoxic activities.10 The clinical significance of this
class of compounds has stimulated the synthesis of new
lead compounds retaining the ‘core’ quinone chromo-
phore.11 In addition, it is well known that imidazole-based
heterocyclic molecules play important role in various bio-
chemical processes.12 The imidazolyl moiety is being
used as a building block in developing new drugs,12b,13 but
also has wide-ranging applications in organometallic
catalysis,14 asymmetric catalysis,16 and coordination
chemistry.15 There are several reports of the synthesis and
functionalization of the imidazole moiety.17
The structural assignments of all isolated products were
established by analysis of their NMR spectra (1H, 13C,
DEPT, COSY H–H, NOESY H–H, HETCOR C–H, and
COLOC C–H). The COLOC correlations measured for
compound 7 are depicted in Figure 1.
As a part of our research program on heterocyclic o-
QDMs, we studied recently the synthesis and Diels–Alder
reactions of an imidazole o-QDM.18 In continuation of
In conclusion, an efficient route for the in situ reaction of
the imidazole o-QDM 3 with quinones, yielding fully
aromatized polycyclic benzimidazole derivatives as the
main products in satisfactory yields in one-pot reactions
has been described. Because of the extended coplanarity
SYNLETT 2007, No. 16, pp 2596–2598
0
1
.1
0
.2
0
0
7
Advanced online publication: 12.09.2007
DOI: 10.1055/s-2007-986656; Art ID: D21807ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Fused Polycyclic Imidazole-naphthoquinone Derivatives
2597
7
6
8
5
O
O
O
O
8a
4a
Me
Me
CH2Br
+
BrH2C
9
4
9a
3a
6 equiv NBS
N
N
N
N
N
N
N
N
N
N
N
N
Ar
Ar
Ar
CCl4, hν
reflux, 1 h
2
Me
Me
Me
Me
Br
Br
H
1
2
4
38%
5 6%
O
NaI, toluene
18-crown-6
O
3 h
8
7
9
6
H2C
CH2
5
O 10
O
O
O
N
N
N
O
O
Ar
+
O
O
11
4
Me
3a
Br
4 h
3 h
N
N
N
N
N
N
Ar
Ar
3
2
Me
Me
X
H
6
7
X = Br 10%
X = H 41%
8
5%
Ar = C6H4(4-Br)
N
O
O
O
Ph
3 h
3 h
Ph
O
Ph
N
N
8
5
O
O
O
O
O
O
O
O
O
O
+
+
9
4
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Ar
Ar
Ar
Ar
Ar
2
Me
Me
Me
Me
Me
Br
35%
Br
Br
10b
Br
11a
Br
9
10a
43%
32%
11b
Scheme 1 Bromination of compound 1, preparation and Diels–Alder trapping of o-QDM 3 in a one-pot reaction in boiling toluene with
various quinones
by other desirable substituents. Further applications,
especially with asymmetrically substituted quinones are
being studied.
H
8
H
7
6
H
O
H
H
O
H
9
5a
5
References and Notes
4
11
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H3C
N
N
N
1
2
H
H
H
Br
Figure 1 Diagnostic COLOC correlations between protons and
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Synlett 2007, No. 16, 2596–2598 © Thieme Stuttgart · New York

2598
C. Neochoritis et al.
LETTER
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Selected Data for Compound 4: Mp 125–127 °C. IR (mull)
n
max = 1666, 1604 cm–1. 1H NMR22 (300 MHz, CDCl3): d =
3.570 (s, 3 H, NMe), 6.418 (m, J = 9.1, 2.6 Hz, 2 H, C-2¢,
C-6¢), 6.982 (d, J = 10.4 Hz, 1 H, C-7 or C-6), 7.014 (d,
J = 10.4 Hz, 1 H, C-6 or C-7), 7.365 (m, J = 9.1, 2.6 Hz, 2 H,
C-3¢, C-5¢), 7.900 (d, J = 0.5 Hz, 1 H, C-9), 8.43 (d, J = 0.5
Hz, 1 H, C-4). 13C NMR (75 MHz, CDCl3): d = 40.3 (NMe),
108.6 (C-9), 114.2 (C-4¢), 114.4 (C-2¢, C-6¢), 116.2 (C-2),
119.6 (C-4), 128.6 (C-8a), 132.6 (C-3¢, C-5¢), 136.4 (C-4a),
137.1 (C-9a), 138.9 (C-7), 139.4 (C-6), 144.4 (C-1¢), 145.6
(C-3a), 184.2 (C-5), 184.5 (C-8). Anal. Calcd (%) for
C18H11Br2N3O2 (461.11): C, 46.89; H, 2.40; N 9.11. Found:
C, 46.79; H, 2.52; N 8.94.
Selected Data for Compound 7: Mp 235–237 °C. 1H
NMR22 (300 MHz, CDCl3): d = 3.590 (s, 3 H, NMe), 6.504
(m, J = 9.1, 2.6 Hz, 2 H, C-2¢, C-6¢), 7.372 (m, J = 9.1, 2.6
Hz, 2 H, C-3¢, C-5¢), 7.796 (m, J = 7.9, 7.6, 2.2 Hz, 1 H, C-8
or C-7), 7.817 (m, J = 7.9, 7.6, 2.2 Hz, 1 H, C-7 or C-8), 8.18
(d, J = 0.5 Hz, 1 H, C-11), 8.307 (m, J = 7.9, 2.2, 0.5 Hz, 1
H, C-9 or C-6), 8.34 (s, 1 H, C-2), 8.366 (m, J = 7.9, 2.2, 0.5
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Hz, 1 H, C-6 or C-9), 8.82 (d, J = 0.5 Hz, 1 H, C-4). 13
C
NMR (75 MHz, CDCl3): d = 41.9 (NMe), 109.9 (C-11),
114.6 (C-4¢), 115.2 (C-2¢, C-6¢), 121.6 (C-4), 127.4 and
127.5 (C-9 and C-6), 129.9 (C-4a), 130.2 (C-10a), 132.5 and
133.8 (C-5a and C-9a), 132.6 (C-3¢, C-5¢), 134.0 and 134.2
(C-7 and C-8), 135.5 (C-11a), 145.3 (C-3a), 147.1 (C-1¢),
147.4 (C-2), 182.7 (C-5), 183.0 (C-10). MS (EI, 70 eV): m/z
(%) = 431/433 (72) [M+], 416/417 (10) [M – CH3]+, 352 (7),
281 (43), 207 (100). Anal. Calcd (%) for C22H14BrN3O2
(432.27): C, 61.13; H, 3.26; N 9.72. Found: C, 61.25; H,
3.17; N, 9.65.
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protons have been confirmed after simulation with program
SpinWorks, version 2.2.0, available from ftp://
davinci.chem.umanitoba.ca.
Synlett 2007, No. 16, 2596–2598 © Thieme Stuttgart · New York