Synthesis and electrochemical evaluation of substituted imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine scaffolds

Article abstract of DOI:10.1016/j.tet.2012.04.030

Substituted 4-(2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazoles were prepared from 5-amino-1-aryl-4-cyanoformimidoylimidazoles and cyanoacetamide, under mild experimental conditions. The pyrrolyl-imidazoles were cyclized to the corresponding 7,8-dihydroimidazo[4

Full text of DOI:10.1016/j.tet.2012.04.030

Tetrahedron 68 (2012) 4628e4634
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journal homepage: www.elsevier.com/locate/tet
Synthesis and electrochemical evaluation of substituted imidazo[4,5-d]pyrrolo
[3,2-f][1,3] diazepine scaffolds
*
Magdi E.A. Zaki, A. Paula Bettencourt, Francisco M. Fernandes, M. Fernanda Proenc¸ a
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Substituted 4-(2,5-dihydro-1H-pyrrol-3-yl)-1H-imidazoles were prepared from 5-amino-1-aryl-4-
cyanoformimidoylimidazoles and cyanoacetamide, under mild experimental conditions. The pyrrolyl-
imidazoles were cyclized to the corresponding 7,8-dihydroimidazo[4,5-b]pyrrolo[3,4-d]pyridines by re-
flux in ethanol, with catalysis by DBU. The same pyrrolyl-imidazoles were reacted with orthoesters, at
room temperature and in the presence of sulfuric acid, to generate 3,7-dihydro-8H-imidazo[4,5-d]pyr-
rolo[3,2-f]diazepines in very good yield. Electrochemical studies of the imidazo[4,5-d]pyrrolo[3,2-f][1,3]
diazepine derivatives were carried out. The reduction potential of 7-ethyl-3-(4-methoxyphenyl)-8-oxo-
7,8-dihydro-3H-imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-carbonitrile was in the adequate range for
presenting bioreduction properties.
Received 25 January 2012
Received in revised form 5 April 2012
Accepted 6 April 2012
Available online 20 April 2012
Keywords:
Cyanoformimidoyl imidazole
Cyanoacetamide
Imidazo-pyrrolodiazepine
Cyclic voltammetry
Reduction potential
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
suggests that this new tricyclic systems may also present angio-
genic activity.
The imidazole ring is present in the structure of several bio-
active natural products1 and of a broad range of medicinally useful
agents.2 The synthesis of substituted imidazoles has been widely
reported in the literature3 and varying the position and nature of
the substituents allowed the preparation of a variety of derivatives.
The synthesis of 4/5-heterylimidazoles, although less common, has
also been described. According to the literature reports, it is usually
difficult to use the available cross-coupling methods to link the
imidazole to the heterocyclic ring. The best approach is still to
construct the heterocyclic unit from an appropriate substituent in
the imidazole moiety, or to build the imidazole ring from conve-
nient precursors, already incorporating the heterocycle. The syn-
thesis of 4-pyridinyl4 and 4-pyrimidinyl4,5 imidazoles has been
reported, and also of imidazoles where the heterocycle is linked to
a linear chain in the 4 or 5 position.6 Recently, Hosmane7 et al.
reported the use of 4,40-biimidazole, prepared by a synthetic ap-
proach previously developed in our research group, as a new pre-
cursor for the 5:7:5-fused biimidazolediazepine ring system. These
compounds showed potent anti-cancer properties8 and the analogy
with the pyrrolo imidazodiazepine scaffold reported in this work
In general, electron transfer (ET) and oxidative stress have been
increasingly implicated in the action of drugs, in particular as anti-
infective and anti-cancer agents.9 Many bioactive substances, or
their metabolites, incorporate ET groups, so electrochemistry can
provide valuable insight concerning the mode of action of drugs.
Significantly, a large number of physiologically active substances
possess redox potential values greater than about ꢀ0.5 V versus NHE
(ꢀ0.744 V vs SCE), in the physiological active range. They can accept
electrons from biological donors or suffer metabolic changes, pro-
vidingeasilyreduced derivatives.9,10 Theredox potentials shiftgreatly
in aprotic media compared to water and are normally more negative
(for reductions) than those measured inwater. Therefore thevalues of
redox potential of physiologically active substances in aprotic media
are usually higher than ꢀ1.10 V versus SCE.10
A few studies11e13 established a relationship between the re-
duction potential of anti-cancer agents and their cytotoxicity
against several tumor cell lines e the more delocalized the elec-
tronic system, implying higher reduction potentials, the greater the
cytotoxic activity.
These results suggest that a preliminary screening of the po-
tential anti-cancer activity of synthetic compounds can be made
using their reduction potential. With this aim the electrochemical
behavior of the imidazo[4,5-d]pyrrolo[3,2-f]diazepine derivatives
was studied and DMSO was used as solvent in order to mimic the
hydrophobic cell environment.
* Corresponding author. E-mail address: fproenca@quimica.uminho.pt
(M. Fernanda Proenc¸ a).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.04.030

M.E.A. Zaki et al. / Tetrahedron 68 (2012) 4628e4634
4629
2. Results and discussion
2.1. Synthesis
displaced as product 3 precipitates from solution (Scheme 2). The
formation of compound 3 requires the elimination of ammonia from
intermediate 7, leading to structure 8. Compound 8 was never iso-
lated nor identified, as it promptly evolved to the 4-pyrrolyl-imid-
azole 3 by intramolecular cyclization. The ammonia generated
during the reaction could be responsible for the cyclization step, as
previous work showed that, for similar structures bearing a cyano
and a carbamoyl group on adjacent alkene carbon atoms, a pyrrole
ring was always formed upon addition of base.18 Acetic acid or tri-
fluoroacetic acid were added tothe reaction mixture (Table 1, entries
1 and 3) in order to trap ammonia as the reaction proceeded, but
compound 3 was again the only product isolated in moderate yield.
The structure of compound 3 was supported mainly by 1H and
In our research group, 5-amino-4-cyanoformimidoyl imidazoles
1 have been used as versatile precursors for the synthesis of fused
heterocycles incorporating the imidazole unit.14 The reaction of
imidazoles 1 with carbon acids (malononitrile,15 methyl cyanoa-
cetate,16 benzoylacetonitrile, and phenylsulfonylacetonitrile17) in-
dicated that the addition occurred selectively to the carbon atom of
the cyanoformimidoyl substituent. Ammonia or HCN were elimi-
nated from the adduct, depending on whether the reaction was
carried out in the absence or in the presence of DBU, respectively.
Intramolecular cyclization led to the formation of highly
substituted imidazo[4,5-b]pyridines, isolated in excellent yield.
This work reports the reaction of 5-amino-4-cyanoformimidoyl
imidazole 1 with cyanoacetamide 2 (1.5e2 molar equiv) using eth-
anol/acetonitrile or ethanol/DMF as solvent (Scheme 1, Table 1, en-
tries 1e4). The use of solvent mixtures was critical for the formation
of product 3. Imidazole 1 was soluble in acetonitrile (1a, 1c) or DMF
(1b, 1d) and ethanol was essential for the reaction as in its absence
no evolution was detected. The 4-pyrrolylimidazole 3 was the only
isolated product that graduallyprecipitated from a deep redsolution
and was filtered after 3e10 days at room temperature. To rationalize
the reactivity of cyanoacetamide in this Knoevenagel-type con-
densation, imidazole 1a was combined with 2 molar equiv of cya-
noacetamide in DMSO-d6 and the reaction was followed by H1 NMR.
After 10 days at 20 ꢁC, the signals for the product were completely
absent in the spectrum. The reagents were then combined in deu-
terated methanol using 3 molar equiv of cyanoacetamide and the
reaction was followed by 1H NMR over a 24 h period. A signal at
13C NMR data. The signal for the CeH proton in the
region and the corresponding carbon around 138 ppm were
considered indicative of the presence of a substituted imidazole
ring. The two signals around 10.2 and 9.3 ppm were assigned to
the imino and pyrrolo protons and broad singlet in the
9.35e9.64 ppm region, integrating for two protons, was associ-
ated to the amino group.
d
7.7ꢀ7.8 ppm
d
d
d
a
d
This value was considered unusually high, when compared with
the chemical shift of the amino group in an analogous structure 9
(around
d 7.2 ppm) (Fig. 1). The electron-withdrawing effect of the
substituent on C-4 of both compounds must be comparable, as the
chemical shift for the imidazole proton on C-2 has the same value
for 3 and 9 (d 7.7 ppm). The striking difference in the chemical shift
of the amino substituent on C-5 can only be explained by the vi-
cinity of the imino double bond. Considering that the pyrrole
substituent is slightly twisted in relation to the plane of the imid-
azole ring, the protons of the amino group can be experiencing the
deshielding anisotropic effect of the
p bond, pushing the chemical
d
3.58 ppm, assigned to the methylene group of cyanoacetamide,
shift of these protons to an unexpected low field. The imino and
was present in the spectrum as a triplet (J¼2.7 Hz), evidencing long
carbonyl carbon atoms were associated with the two signals
around d 168 ppm and d 160 ppm and a single peak at d 115.9,
range coupling with the two amide protons.
assigned to the cyano group, further confirms the presence of the
cyclic pyrrole substituent. In the infrared spectrum, the carbonyl
stretching vibration corresponds to an intense band between 1710
and 1729 cmꢀ1. According to the literature18 this high value, com-
pared with what was expected for the carbonyl group of the con-
jugated linear amide, is typical of the pyrrolone structure.
The functional groups present in the pyrrolyl-imidazole 3
prompted us to induce intramolecular cyclization. The reaction
occurred when a suspension of 3aec in ethanol was refluxed in the
presence of a catalytic amount of DBU (Scheme 1, Table 1, entries
5e7). The deep red suspension was converted to a dark green so-
lution, with formation of a greenish-yellow precipitate identified as
the 7,8-dihydroimidazo[4,5-b]pyrrolo[3,4-d]pyridin-6(3H)-one 4.
The synthesis of a similar structure (isolated in 7% yield) was pre-
viously reported in the literature, and the pyrrole ring was gener-
ated upon cyclization of an amide and ester functions in positions 6
and 7 of a substituted imidazo-pyridone.19
Compound 3 was also reacted with 5 equiv of orthoesters
(orthoformate, orthoacetate, orthopropionate, and orthobenzoate)
in acetonitrile and in the presence of acid catalysis. Cyclization
occurred between the imidate carbon and the imino nitrogen,
generating the fused diazepine ring of compounds 5aeg (Scheme 1,
Table 1, entries 8e14). When compound 3b was combined with an
excess of triethyl orthoformate and the mixture was refluxed in
DMF for 2 h, the same diazepine moiety was generated, but the
NeH proton on the pyrrole unit was replaced by the ethyl group
leading to compound 6. The use of triethyl orthoformate as an
alkylating reagent was reported in a previous work,20 when 1,2,4-
benzothiadiazine 1,1-dioxide and triethyl orthoformate were
heated at 150 ꢁC for 3 h. In this work, the alkylation was also due to
the large excess of orthoformate present in the reaction mixture
and not caused by ethanol, released during the synthesis. This was
Ar
NH2
NH
O
N
NC
+
NH2
N
NC
2
1a, Ar= 4-CH3C6H4
b, Ar= 4-CH3OC6H4
c, Ar= 4-FC6H4
d, Ar= 4-NCC6H4
Ar
Ar
NH2
3a
N
5
NH2
O
N
N
N
EtOH, DBU
Reflux
NH
NH
6
N
7a
NH
NC
3a-d
HN
4a-c
O
RC(OC2H5)3, H+(cat.)
CH3CN/DMF, rt
HC(OC2H5)3
excess
DMF, reflux
Ar
N
Ar
R
N
5
3a
8a
N
N
N
2
N
8
7
N
N
NH
N
NC
5a-g
NC
9
O
O
6
Scheme 1. Synthesis of compounds 3e6.
The CeH signal for product 3a (d 7.58 ppm) was visible in the
spectrum after 10 min at roomtemperature and a single product was
slowly formed as only 8% of 3a was generated after 24 h at 20 ꢁC. The
low rate of reaction may result from the formation of an equilibrium
mixture between the reagents and adduct 7, which is slowly

4630
M.E.A. Zaki et al. / Tetrahedron 68 (2012) 4628e4634
Table 1
Yield and reaction conditions for the synthesis of compounds 3e5
Entry
Ar
R
Reaction conditions
Product (Y%)
1
4-H3CC6H4
d
d
d
d
d
d
d
d
1aþ2 (2 equiv), EtOH/MeCN (3:1), 3 d, rt
1aþ2 (2 equiv), EtOH/MeCN (3:1), AcOH (40
1bþ2 (1.5 equiv), EtOH/DMF (2:1), 5 d, rt
1cþ2 (2 equiv), EtOH/MeCN (4:1), 5 d, rt
3a (91%)
3a (70%)
3b (83%)
3c (77%)
3c (65%)
3d (94%)
4a (81%)
4b (91%)
4c (89%)
5a (83%)
5b (88%)
5c (85%)
5d (65%)
5e (82%)
5f (82%)
5g (82%)
m
L, 0.7 mmol), 5 h, rt
2
3
4-H3COC6H4
4-FC6H4
1cþ2 (2 equiv), EtOH/MeCN (3:1), TFA (10
1dþ2 (1.5 equiv), EtOH/DMF (2:1), 10 d, rt
3a, EtOH, DBU (cat.), 2 h, reflux
mL, 0.13 mmol), 5 h, rt
4
5
6
7
8
9
10
11
12
13
14
4-NCC6H4
4-H3CC6H4
4-H3COC6H4
4-FC6H4
4-H3CC6H4
4-H3COC6H4
4-FC6H4
4-NCC6H4
4-H3CC6H4
4-H3CC6H4
4-H3CC6H4
3b, EtOH, DBU (cat.), 2 h, reflux
3c, EtOH, DBU (cat.), 2 h, reflux
H
H
H
H
Me
Et
Ph
3a, HC(OEt)3 (5 equiv), MeCN, H2SO4 (cat), 5 min, rt
3b, HC(OEt)3 (5 equiv), MeCN, H2SO4 (cat), 20 min, rt
3c, HC(OEt)3 (5 equiv), MeCN, H2SO4 (cat), 10 min, rt
3d, HC(OEt)3 (5 equiv), MeCN, H2SO4 (cat), 30 min, rt
3a, MeC(OEt)3 (5 equiv), MeCN, H2SO4 (cat), 6 d, rt
3a, EtC(OEt)3 (5 equiv), MeCN, H2SO4 (cat), 2 h, rt
3a, PhC(OEt)3 (5 equiv), MeCN, H2SO4 (cat), 6 d, rt
compounds 5) and that of the corresponding carbon (around
H
Ar
O
O
NH2
NH
+ H+
- H+
d
145 ppm for compounds 4 and d 147 ppm for compounds 5). In the
N
N
+
13C NMR of compounds 4, the signals for the pyrrole carbon atoms
are broad and could not be identified in 4a and 4c. This suggests
extensive tautomerism of the NeH protons associated with this
ring. The presence of the diazepine ring in compounds 5 was
carefully confirmed through the 3-bonds HeC correlation of the
NC
NC
NH2
NH2
2
NC
1a, Ar= 4-CH3C6H4
b, Ar= 4-CH3OC6H4
c, Ar= 4-FC6H4
d, Ar= 4-NCC6H4
proton on C-5 (around
pyrrole ring (C-7, around
(around
compound 4a23 showed that C2eH (
of an imino ( 251.6 ppm) and an amino (
atom. The proton C5eH ( 8.51 ppm) in compound 5a interacted
with two different imino nitrogen atoms ( 255.9 ppm and
d
8.5 ppm) with the imino carbon in the
d
160 ppm) and the imidazole carbon C-3a
Ar
Ar
Ar
d
145 ppm). The HeN correlation spectrum (HMBC) of
8.97 ppm) was in the vicinity
184.9 ppm) nitrogen
NH2
NH2
N
NH2
NH2
N
N
- NH3
d
NH
CN
NH2
N
d
d
N
N
NH
H
d
NC
H2N
CN
O
NC
NC
d
O
O
d
263.7 ppm). This data was in good agreement with the values
8
3a-d
7
reported in the literature for the 15N NMR of substituted purine
derivatives.24
Scheme 2. A plausible mechanism for the formation of 4-pyrrolyl-imidazoles 3.
2.2. Electrochemistry
MeO
MeO
H
In order to get information regarding the potential bioactivity of
the imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine derivatives, their
electrochemical properties were analyzed by cyclic voltammetry.
Cyclic voltammograms of compounds 5aef and 6 were recorded in
DMSO containing 0.10 M tetrabutylammonium tetrafluoroborate
(nBu4NBF4) as supporting electrolyte at different scan rates
(0.020e0.400 V sꢀ1), using a glassy carbon electrode, at room
temperature under argon atmosphere. The relevant electro-
chemical data for all compounds are summarized in Table 2, where
the potentials are registered against saturated calomel electrode
(SCE).
δ
δ
δ
δ
9.4
7.2
148.3
148.4
4
NH2
4
5
NH2
N
N
N
N
2
2
δ
δ
δ 7.7
δ
NH
NH
O
7.7
H
137.6
138.5
CN
OEt
5
NC
NC
3b
O
9
Fig. 1. 1H and 13C NMR values for compound 3b and 9.
confirmed by refluxing a solution of compound 5b in DMF and
triethyl orthoformate for 2 h. Product 6 was isolated in 66% yield
after removal of the solvent and addition of ethanol. When the
same experimental procedure was reproduced, using DMF and
ethanol, the starting material 5b was recovered in 70% yield. To our
knowledge, there is no previous record for the synthesis or isolation
of this type of fused tricyclic structure. Substituted imidazo-
diazepines are well known compounds since the discovery of
pentostatin, a potent inhibitor of adenosine deaminase used in the
treatment of leukemia.21 The severe toxicity, poor oral absorption,
and rapid metabolism of this compound, resulted in an eager
search for analogous structures with reduced side effects.22
With the exception of compound 6, that presented a more
complex cyclic voltammogram, the electrochemical behavior of all
Table 2
Cyclic voltammetric data for reduction of compounds 5aef, 6 at a Glassy Carbon
Electrode obtained at a scan rate of 0.10 V sꢀ1. A 1.0 mM solution of each compound
in DMSO containing 0.10 M nBu4NBF4 was used. Potentials are given versus SCE
Compound
Ep (I0c)/V
Ep (Ic)/V
Ep (IIc)/V
5a
5b
5c
5d
5e
5f
6
d
ꢀ1.484
ꢀ1.478
ꢀ1.441
ꢀ1.417
ꢀ1.517
ꢀ1.502
ꢀ1.470
ꢀ2.107
ꢀ2.108
ꢀ2.001
ꢀ2.013
ꢀ2.140
ꢀ2.032
ꢀ2.290
d
d
The fused tricyclic structure of compounds 4 and 5 was sup-
ported by NMR correlation techniques. The extended aromatic
system was confirmed by the chemical shift of the CeH imidazole
d
d
d
ꢀ0.744
proton (
d
8.6ꢀ8.7 ppm for compounds 4 and
d
8.9ꢀ9.0 ppm for

M.E.A. Zaki et al. / Tetrahedron 68 (2012) 4628e4634
4631
compounds was similar, suggesting an analogous reduction
Ar
R
Ar
Ar
R
R
N
N
N
mechanism. The voltammograms obtained for compound 5b, typ-
ical of the whole series, and for compound 6 are presented in Fig. 2.
Reduction of compounds 5aef occurred in two voltammetric
waves. The first one appears as a reversible wave (labeled Ic and Ia,
Fig. 2a), whereas the second reduction wave can be considered ir-
reversible (labeled IIc). The first reduction peak potentials of the
compounds range from ꢀ1.417 V up to ꢀ1.517 versus SCE and the
second peak covers a wider range (140 mV) and varies from
ꢀ2.001 V to ꢀ2.140 versus SCE. Peak currents obtained for both
electrochemical processes of all the compounds increase linearly
with the square root of the scan rate, suggesting diffusion-
controlled processes.
N
N
N
N
N
N
+e-
-e-
N
N
N
NH
NH
NH
NC
NC
NC
O
O
O
-e-
+e-
Ar
Ar
N
H
N
R
R
Ar
R
N
N
N
N
N
N
NH
NH
+2H
N
N
N
NH
OH
NH
NC
NC
NC
O
H
O
Scheme 3. Proposed mechanism for the redox process of imidazo[4,5-d]pyrrolo[3,2-f]
[1,3] diazepines 5aef.
then suffers a second electron transfer, at a more negative potential
(wave IIc, Fig. 2a), generating a dianion that seems to be unstable
under these conditions. It can be protonated by residual water from
the solvent or from a nearby molecule of the fused tricyclic com-
pound, with an acidic proton on the lactam nitrogen. Protonation
can occur on the oxygen atom and on one of the nitrogen atoms of
the diazepine ring leading to different products. The substituents
may affect the stability of the compound and/or the kinetics of the
chemical reaction.
The cyclic voltammogram of compound 6 (Fig. 2b) presents two
major peaks (Table 2). The first peak, at ꢀ0.744 V versus SCE, cor-
responds to a reversible process (I0c and I0a) and the second one, at
ꢀ1.470 V versus SCE (Ic and Ia) can be considered a quasi-reversible
process.25 The replacement of a hydrogen atom (compound 5b) by
an ethyl group (compound 6) at the lactam nitrogen generates
a compound, that is, more easily reduced. The only structural dif-
ference between compounds 6 and 5b is the presence of an ethyl
group instead of the hydrogen atom and this must be responsible
for the observed differences in peak potentials.
The amide moiety in compound 5b allows the formation of
a stable dimer, through two intermolecular hydrogen bonds.
Compound 6 can only exist as the monomeric species. The more
negative reduction potential obtained for compound 5b can be
assigned to this stabilization. The reduction of compound 6 is
easier, and occurs at a less negative reduction potential. This ob-
servation is in agreement with a similar situation reported in the
literature and sustained by theoretical calculations.26 Further work
is currently being developed on the synthesis and electrochemical
analysis of different N-substituted imidazo-pyrrolodiazepines in
order to support this mechanistic proposal.
Fig. 2. Cyclic voltammograms of a 1.0 mM solution of (a) compound 5b and (b)
compound 6, in DMSO containing 0.1 M nBu4NBF4, at a glassy carbon electrode; scan
rate of 0.10 V sꢀ1
.
The first peak of the voltammograms (Ic and Ia) corresponds to
a reversible Nernstian one electron transfer (Ep(Ic) is independent of
the scan rate and Ip(Ia)/Ip(Ic) equals 1).25 The data for the second
reductionpeak suggests thatthe second electron transferisfollowed
byother processes (Ep(IIc) varies with scan rate and an anodic peak is
absent in the reverse scan).25 Moreover, on the reverse scan, a small
oxidation wave (IIIa) at ca. ꢀ0.8 V versus SCE was observed. This
wave vanished when the potential scan was reversed after the first
reduction peak, indicating that it corresponds to the oxidation of
a product formed on the second reductionprocess. The height of this
peak is different for each compound suggesting that the amount of
product formed is probably related to the rate of the chemical re-
action coupled to the second electron transfer.
Based on previous studies regarding reduction of quinones in
non aqueous media11 we propose a reduction mechanism that in-
volves the carbonyl group of the lactam ring (Scheme 3).
The first electron uptake (wave Ic, Fig. 2a) leads to a stable
radical anion, that is, highly stabilized on the seven-membered
ring, in particular on the second nitrogen atom. The radical anion
Previous studies27 identified correlations between redox po-
tentials of organic molecules and Hammett substituent constants.
These correlations are associated to the fact that electrochemical
processes involve addition or removal of electrons from an organic
framework and therefore should be related with the ability of
substituents to withdraw or donate electrons to that framework.27
In this work, a quantitative measure of the effect of the aryl sub-
stituent on the imidazole ring over the electrochemical reduction of
compounds 5aed was also established. The first reduction peak
potentials obtained by cyclic voltammetry were plotted versus the
Hammett-constants considering inductive/field effect,28 as shown
by Fig. 3. The peak reduction potentials vary linearly with
Hammett-constant (r¼0.97) according to the equation:
Ep ¼ 0:991sind ꢀ 1:58
This correlation suggests that the reduction potentials of com-
pounds 5 are affected primarily by the inductive effect of the aryl

4632
M.E.A. Zaki et al. / Tetrahedron 68 (2012) 4628e4634
300 MHz for 1H and 75 MHz for 13C or at 400 MHz for 1H and
100 MHz for 13C, including the 1He13C correlation spectra (HMQC
and HMBC). Deuterated DMSO was used as solvent. The chemical
shifts are expressed in
d (parts per million) and the coupling con-
stants (J) in hertz (Hz). IR spectra were recorded on a FT-IR using
Nujol mulls and NaCl cells. The reactions were monitored by thin
layer chromatography (TLC) using silica gel. The melting points
were determined on
uncorrected.
a melting point apparatus and are
Electrochemical measurements were made in methyl sulfoxide
(DMSO, extra dry, 99.7%) used without further purification. Tetra-n-
butylammonium tetrafluoroborate (nBu4NBF4, 98%) kept for 24 h in
a vacuum oven at 70e80 ꢁC to remove traces of water was used as
supporting electrolyte. A conventional two-compartment three-
electrode glass cell, a glassy carbon working electrode (3 mm di-
ameter), together with a platinum counter-electrode were used.
The pseudo-reference electrode consisted of a silver wire immersed
in DMSO containing nBu4NBF4 (0.1 M) and the ferrocene/ferroce-
nium cation couple was used as internal standard. All potentials
presented are referenced to the saturated calomel electrode (SCE).
Solutions of the tested compounds (1 mM) in DMSO containing
0.1 M of nBu4NBF4 were prepared just before electrochemical ex-
periments. Prior to the measurements, solutions were bubbled
with argon to eliminate dissolved oxygen and the working elec-
Fig. 3. Correlation of first reduction peak potential, Ep (Ic), of compounds 5aed ob-
tained by cyclic voltammetry with the calculated sind Hammett-constants28 of the aryl
substituent.
trode was cleaned with an aqueous suspension of 0.05 mm alumina
on a polishing pad, rinsed and wiped dry. The cyclic voltammo-
grams were recorded at scan rates in the range 0.020e0.400 V sꢀ1
using various starting and switching potentials.
substituent on the imidazole moiety and, as expected, the in-
troduction of electron-withdrawing substituents facilitates the
reduction.
In summary, the peak potential of the synthesized compounds
(Table 2) partially reflects the influence of substituents R and Ar on
their redox properties.
4.2. General procedure for the synthesis of 4-[5-amino-1-
(aryl)-1H-imidazol-4-yl]-5-imino-2-oxo-2,5-dihydro-1H-
pyrrole-3-carbonitrile 3
Method A: A solution of 5-amino-1-aryl-4-(cyanoformimidoyl)
imidazole 1aed (0.80e1.80 mmol) in EtOH (10e20 mL) and MeCN
(3e6 mL) or DMF (3e5 mL) was combined with cyanoacetamide
(1.5e2.0 molar equiv) and the mixture was stirred at room tem-
perature for 3e10 days. A red solid suspension separated from
a deep red solution and was filtered and washed with Et2O and
EtOH. Structure 3 was assigned to the products on the basis of el-
emental analysis, 1H NMR and 13C NMR spectroscopy.
(A) The replacement of a hydrogen atom on the C2 of the dia-
zepine ring by an ethyl or methyl group (compounds 5a, 5f, and 5e)
leads to a decrease in the reduction potential, therefore making it
more difficult to reduce.
(B) Electron-withdrawing groups (Ar¼4-NCPh, 4-FPh) on the
imidazole ring facilitate the reduction of compounds (higher re-
duction potential) whereas electron-donating groups (Ar¼4-H3CPh,
4-H3COPh) have the reverse effect (Fig. 3). This may be the result of
extended stabilization of the radical anion on the aryl substituent.
The first reduction peak potential can be used as a descriptor of
the ease of reduction of these compounds that can be ranked as
follows: 6>5d>5c>5b>5a>5f>5e.
Method B: A solution of 5-amino-1-(4-methylphenyl)-4-(cya-
noformimidoyl)imidazole 1a or 1c (0.80 mmol) in EtOH (10 mL)
and MeCN (3 mL) was combined with cyanoacetamide (2.0 molar
equiv) and (40
mL, 0.7 mmol) of acetic acid (for 1a) or (10 mL,
0.13 mmol) of trifluoroacetic acid (for 1c). The mixture was stirred
at room temperature for 19 h (1a) or 5 h (1c). A red solid suspension
separated from a deep red solution and was filtered and washed
with Et2O and EtOH. The isolated product was identified as 3a (70%)
or 3c (65%).
3. Conclusion
Easilyaccessible pyrrolyl-imidazoles3 wereusedas precursors of
fused imidazo-pyrrolo-pyridines 4 and imidazo-pyrrolo-diazepines
5. These compounds, which are not easily prepared by other
methods, were generated under mild reaction conditions and iso-
lated in very good yields. Considering that redox potentials provide
information on the feasibility of electron transfer in vivo and that
physiologically active substances should possess a redox potential in
the range ꢀ0.7eꢀ1.1 V versus SCE in aprotic media,10 compound 6
may be a promising anti-cancer agent, analogous to 5:7:5-fused
diimidazodiazepine recently recognized as highly active.
4.2.1. [5-Amino-1-(4-methylphenyl)-1H-imidazol-4-yl]-5-imino-2-
oxo-2,5-dihydro-1H-pyrrole-3-carbonitrile (3a). Red solid (215 mg,
0.73 mmol, 91%). Mp 271e273 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
10.24 (s, 1H), 9.37 (s, 2H), 9.34 (s, 1H), 7.74 (s, 1H), 7.38 (s, 5H), 2.39
(s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
167.5, 160.0, 147.9, 147.2,
138.9, 138.2, 130.8, 130.5, 125.7, 115.9, 115.0, 85.7, 20.7; IR (Nujol
mull) 3322, 3237, 2216, 1724, 1633, 1578. Anal. Calcd for
C15H12N6O.0.1H2O: C, 61.26; H, 4.18; N, 28.58, found: C, 60.95; H,
4.32; N, 28.54.
4. Experimental section
4.1. General
4.2.2. 4-[5-Amino-1-(4-methoxyphenyl)-1H-imidazol-4-yl]-5-
imino-2-oxo-2,5-dihydro-1H-pyrrole-3-carbonitrile (3b). Red solid
(210 mg, 0.67 mmol, 84%). Mp 267e268 ꢁC; 1H NMR (300 MHz,
All compounds were fully characterized by elemental analysis
and spectroscopic data. The NMR spectra were recorded at
DMSO-d6) d 10.22 (s, 1H), 9.35 (s, 2H), 9.31 (s, 1H), 7.71 (s, 1H), 7.43
(d, J¼9.0 Hz, 2H), 7.13 (d, J¼9.0 Hz, 2H), 3.82 (s, 3H); 13C NMR

M.E.A. Zaki et al. / Tetrahedron 68 (2012) 4628e4634
4633
(75 MHz, DMSO-d6)
d
168.0, 160.0, 159.7, 148.3, 147.2, 138.5, 127.6,
C14H9N6OF.0.1H2O: C, 56.40; H, 3.11; N, 28.20, found: C, 56.31; H,
126.0, 116.0, 115.2, 114.9, 85.5, 55.6; IR (Nujol mull) 3357, 3235,
2215, 1729, 1706, 1629, 1608, 1578. Anal. Calcd for
C15H12N6O2.0.2H2O: C, 57.76; H, 4.00; N, 26.94, found: C, 57.62; H,
4.12; N, 26.69.
3.48; N, 27.81.
4.4. General procedure for the synthesis of 3-(4-aryl)-8-oxo-
7,8-dihydro-3H-imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-
carbonitrile 5aed
4.2.3. 4-[5-Amino-1-(4-fluorophenyl)-1H-imidazol-4-yl]-5-imino-2-
oxo-2,5-dihydro-1H-pyrrole-3-carbonitrile (3c). Red solid (185 mg,
0.62 mmol, 77%). Mp 274e276 ꢁC; 1H NMR (300 MHz, DMSO-d6)
Triethyl orthoformate (1.70 mmol) was added to a solution of
3aed (0.34 mmol) in MeCN (5 mL). Sulfuric acid (5 mL) was added
and the reaction mixture was stirred at rt for 5e20 min. The solid
was filtered and washed with Et2O and EtOH. Structure 5 was
assigned to the products on the basis of elemental analysis, 1H NMR
and 13C NMR spectroscopy.
d
10.24 (s, 1H), 9.38 (br s, 3H), 7.76 (s, 1H), 7.59 (dd, J1¼9.0 Hz,
J2¼4.8 Hz, 2H), 7.45 (t, J¼8.7 Hz, 2H); 13C NMR (75 MHz, DMSO-d6)
d
168.0, 162.2 (d, J¼244.88 Hz), 160.0, 148.1, 147.2, 138.2, 128.7 (d,
J¼9.15 Hz), 127.8 (d, J¼3.15 Hz), 116.9 (d, J¼23.18 Hz), 115.9, 114.8,
85.8; IR (Nujol mull) 3310, 3253, 2211, 2188, 1710, 1628, 1590. Anal.
Calcd for C14H9N6OF.0.33 DMF: C, 56.24; H, 3.52; N, 27.73, found: C,
55.85; H, 3.50; N, 28.13.
4.4.1. 3-(4-Methylphenyl)-8-oxo-7,8-dihydro-3H-imidazo[4,5-d]pyr-
rolo[3,2-f][1,3] diazepine-9-carbonitrile (5a). Orange solid (85 mg,
0.28 mmol, 83%). Mp >350 ꢁC; 1H NMR (400 MHz, DMSO-d6)
4.2.4. 4-[5-Amino-1-(4-cyanophenyl)-1H-imidazol-4-yl]-5-imino-2-
d
12.80 (br, 1H), 8.98 (s, 1H), 8.52 (s, 1H), 7.56 (d, J¼8.1 Hz, 2H), 7.42
oxo-2,5-dihydro-1H-pyrrole-3-carbonitrile (3d). Red solid (190 mg,
(d, J¼8.1 Hz, 2H), 2.41 (s, 3H); 13C NMR (100 MHz, DMSO-d6)
0.63 mmol, 79%). Mp >350 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d
9.64
(br s, 4H), 8.11 (d, J¼8.7 Hz, 2H), 7.85 (s, 1H), 7.76 (d, J¼8.7 Hz, 2H);
13C NMR (75 MHz, DMSO-d6)
167.9, 159.9, 147.4, 147.3, 137.51,
d
168.3, 160.3, 150.0, 147.2, 146.2, 138.9, 138.1, 131.2, 129.8, 129.3,
126.0, 113.7, 85.8, 20.7; IR (Nujol mull) 2220, 1704, 1630, 1592 cmꢀ1
.
d
Anal. Calcd for C16H10N6O.0.1H2O: C, 63.20; H, 3.38; N, 27.64, found:
C, 63.03; H, 3.71; N, 27.59.
137.48, 134.2, 126.8, 118.1, 115.7, 114.9, 111.6, 86.6; IR (Nujol mull)
3246, 3220, 2230, 2204, 1715, 1662, 1589. Anal. Calcd for C15H9N7O
DMF. 0.25H2O: C, 56.76; H, 4.37; N, 29.42, found: C, 56.55; H, 4.08;
N, 29.57.
4.4.2. 3-(4-Methoxyphenyl)-8-oxo-7,8-dihydro-3H-imidazo[4,5-d]
pyrrolo[3,2-f][1,3] diazepine-9-carbonitrile (5b). Yellow solid
(95 mg, 0.30 mmol, 88%). Mp >350 ꢁC; 1H NMR (300 MHz, DMSO-
4.3. General procedure for the synthesis of 5-amino-8-imino-
3-(aryl)-7,8-dihydroimidazo[4,5-b]pyrrolo[3,4-d]pyridin-
6(3H)-one 4
d6)
d
12.80 (s, 1H), 8.97 (s, 1H), 8.53 (s, 1H), 7.60 (d, J¼9.0 Hz, 2H),
7.16 (d, J¼9.0 Hz, 2H), 3.85 (s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
168.4, 160.3, 159.7, 150.0, 147.9, 146.3, 138.1, 129.2, 127.6, 126.5,
114.5, 113.7, 85.7, 55.6; IR (Nujol mull) 2218, 1704, 1630, 1592 cmꢀ1
.
A solution of 3aec (0.89 mmol) in EtOH (10 mL) with a catalytic
amount of DBU was refluxed for 2 h. A turbidity gradually de-
veloped leading eventually to a greenish-yellow solid, which was
filtered and washed with Et2O and EtOH. Structure 4 was assigned
Anal. Calcd for C16H10N6O2: C, 60.38; H, 3.17; N, 26.40, found: C,
59.89; H, 3.36; N, 26.49.
4.4.3. 3-(4-Fluorophenyl)-8-oxo-7,8-dihydro-3H-imidazo[4,5-d]pyr-
rolo[3,2-f][1,3] diazepine-9-carbonitrile (5c). Yellow solid (88 mg,
0.29 mmol, 85%). Mp >350 ꢁC; 1H NMR (300 MHz, DMSO-d6)
to the products on the basis of elemental analysis, 1H NMR and 13
NMR spectroscopy.
C
d
12.84 (s, 1H), 9.01 (s, 1H), 8.54 (s, 1H), 7.76 (dd, J1¼8.7 Hz,
4.3.1. 5-Amino-8-imino-3-(4-methylphenyl)-7,8-dihydroimidazo
[4,5-b]pyrrolo[3,4-d]pyridin-6(3H)-one (4a). Greenish-yellow solid
(210 mg, 0.72 mmol, 81%). Mp >350 ꢁC; 1H NMR (300 MHz, DMSO-
J2¼4.8 Hz, 2H), 7.50 (t, J¼8.7 Hz, 2H), 13C NMR (75 MHz, DMSO-d6)
d
168.3, 162.1 (d, J¼245.0 Hz), 160.5, 150.1, 147.7, 146.2, 138.1, 130.06
(d, J¼3.0 Hz), 129.2, 128.6 (d, J¼9.0 Hz), 116.3 (d, J¼23.0 Hz), 113.6,
86.0; IR (Nujol mull) 2227, 1731, 1630, 1589 cmꢀ1. Anal. Calcd for
C15H7N6OF: C, 58.83; H, 2.30; N, 27.44, found: C, 58.65; H, 2.45; N,
27.32.
d6)
d
10.68 (br, 1H), 9.12 (br, 1H), 8.66 (s, 1H), 7.69 (d, J¼9.0 Hz, 2H),
7.37 (d, J¼9.0 Hz, 2H), 6.79 (br, 2H), 2.39 (s, 3H); 13C NMR (75 MHz,
DMSO-d6)
d 160.8, 152.8, 150.9, 144.9, 137.4, 132.4, 131.2 (br), 129.8,
123.8, 122.5, 20.6; IR (Nujol mull) 3279, 3155, 1714, 1661 cmꢀ1. Anal.
Calcd for C15H12N6O.0.6 C2H5OH: C, 60.82; H, 4.91; N, 26.27, found:
C, 60.59; H, 4.95; N, 26.17.
4.4.4. 3-(4-Cyanophenyl)-8-oxo-7,8-dihydro-3H-imidazo[4,5-d]pyr-
rolo[3,2-f][1,3] diazepine-9-carbonitrile (5d). Yellow solid (95 mg,
0.30 mmol, 89%). Mp >350 ꢁC; 1H NMR (300 MHz, DMSO-d6)
4.3.2. 5-Amino-8-imino-3-(4-methoxyphenyl)-7,8-dihydroimidazo
[4,5-b]pyrrolo[3,4-d]pyridin-6(3H)-one (4b). Greenish-yellow solid
(250 mg, 0.81 mmol, 91%). Mp >350 ꢁC; 1H NMR (400 MHz, DMSO-
d
12.90 (br s, 1H), 9.10 (s, 1H), 8.56 (s, 1H), 8.16 (d, J¼9.0 Hz), 7.98 (d,
J¼9.0 Hz, 2H), 13C NMR (100 MHz, DMSO-d6)
d 168.3, 160.6, 150.4,
147.3, 145.8, 138.1, 137.5, 133.6, 129.5, 127.0, 118.2, 113.6, 111.7, 86.4;
IR (Nujol mull) 2227, 1731, 1630, 1589 cmꢀ1. Anal. Calcd for
C16H7N7O: C, 61.34; H, 2.25; N, 31.30, found: C, 61.27; H, 2.56; N,
30.97.
d6)
d
10.5e9.0 (br s, 2H), 8.60 (s, 1H), 7.69 (d, J¼9.0 Hz, 2H), 7.13 (d,
J¼9.0 Hz, 2H), 6.78 (s, 2H), 3.82 (s, 3H); 13C NMR (100 MHz, DMSO-
d6)
d 171.6, 160.5, 158.7, 152.8, 151.1, 145.1, 131.3, 127.7, 125.7, 122.4,
114.5, 103.2, 55.5; IR (Nujol mull) 2262, 2190, 2140, 1660, 1640,
1595, 1569 cmꢀ1. Anal. Calcd for C15H12N6O2: C, 58.44; H, 3.92; N,
27.26, found: C, 58.27; H, 4.06; N, 27.02.
4.5. Synthesis of 5-alkyl/aryl-3-(4-methylphenyl)-8-oxo-7,8-
dihydro-3H-imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-
carbonitrile (5eeg)
4.3.3. 5-Amino-3-(4-fluorophenyl)-8-imino-7,8-dihydroimidazo[4,5-
b]pyrrolo[3,4-d]pyridin-6(3H)-one (4c). Yellow solid (233 mg,
0.79 mmol, 89%). Mp 334e335 ꢁC; 1H NMR (300 MHz, DMSO-d6)
The appropriate orthoester (1.70 mmol) was added to a solution
d
10.62 (br s, 1H), 9.14 (br s, 1H), 8.68 (s, 1H), 7.87 (dd, J1¼9.0 Hz,
of 3a (0.34 mmol) in MeCN (5 mL). Sulfuric acid (5 mL) was added
J2¼4.8 Hz, 2H), 7.44 (t, J¼9.0 Hz, 2H), 6.82 (br s, 2H); 13C NMR
and the mixture was stirred at rt for 2 h e 6 days. The solid was
filtered and washed with Et2O and EtOH. Structure 5eeg was
assigned to the product on the basis of elemental analysis, 1H NMR
and 13C NMR spectroscopy.
(75 MHz, DMSO-d6)
d
161.2 (d, J¼243.5 Hz), 152.9, 150.9, 144.9,
131.3, 126.3 (d, J¼8.63 Hz), 122.4, 116.3 (d, J¼22.88 Hz); IR (Nujol
mull) 3339, 3216, 1716, 1664 cmꢀ1
.
Anal. Calcd for

4634
M.E.A. Zaki et al. / Tetrahedron 68 (2012) 4628e4634
4.5.1. 5-Methyl-3-(4-methylphenyl)-8-oxo-7,8-dihydro-3H-imidazo
[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-carbonitrile (5e). Orange solid
(70 mg, 0.22 mmol, 65%). Mp >350 ꢁC; 1H NMR (300 MHz, DMSO-
References and notes
1. For a recent review, see: Lin, Z. Nat. Prod. Rep. 2006, 23, 464e496.
2. Luca, L. D. Curr. Med. Chem. 2006, 13, 1e23.
3. (a) Grimmett, M. R. In Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed.;
Pergamon: Oxford, 1984; Vol. 5, pp 345e372; (b) Grimmett, M. R. In Compre-
hensive Heterocyclic Chemistry II; Shinkai, I., Ed.; Pergamon: Oxford, 1996; Vol.
3, pp 77e220.
4. Boehm, J. C.; Bower, M. J.; Gallagher, T. F.; Kassis, S.; Johnson, S. R.; Adams, J. L.
Bioorg. Med. Chem. Lett. 2001, 11, 1123e1126.
5. (a) Seley, K. L.; Zhang, L.; Hagos, A. Org. Lett. 2001, 3, 3209e3210; (b) Seley, K. L.;
Zhang, L.; Hagos, A.; Quirk, S. J. Org. Chem. 2002, 67, 3365e3373; (c) Seley, K. L.;
Salim, S.; Zhang, L. Org. Lett. 2005, 7, 63e66.
d6)
d
12.53 (br, 1H), 8.87 (s, 1H), 7.56 (d, J¼8.4 Hz, 2H), 7.41 (d,
J¼8.4 Hz, 2H), 2.60 (s, 3H), 2.41(s, 3H); 13C NMR (75 MHz, DMSO-d6)
d
168.4, 160.7, 159.0, 147.1, 145.5, 138.7, 137.7, 131.4, 129.7, 128.3,
125.8, 113.8, 84.9, 30.3, 20.7; IR (Nujol mull) 2225, 1735, 1662, 1601,
1556 cmꢀ1. Anal. Calcd for C17H12N6O.0.1H2O: C, 64.18; H, 3.83; N,
26.42, found: C, 64.01; H, 3.98; N, 26.32.
4.5.2. 5-Ethyl-3-(4-methylphenyl)-8-oxo-7,8-dihydro-3H-imidazo
[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-carbonitrile (5f). Orange solid
(90 mg, 0.28 mmol, 82%); mp 336e337 ꢁC; 1H NMR (300 MHz,
6. Lin, Z. Nat. Prod. Rep. 2005, 22, 196e229.
7. Kumar, R.; Ujjinamatada, R. K.; Hosmane, R. S. Org. Lett. 2008, 10,
4681e4684.
8. (a) Hosmane R.S.; Raman V.; Kumar R.; Patent WO/2010/039187, International
application PCT/US 2009/005273. (b) Kondaskar, A.; Kondaskar, S.; Kumar, R.;
Fishbein, J. C.; Muvarak, N.; Lapidus, R. G.; Sadowska, M.; Edelman, M. J.; Bol,
G. M.; Vesuna, F.; Raman, V.; Hosmane, R. S. ACS Med. Chem. Lett 2011, 2,
252e256.
DMSO-d6)
(d, J¼8.4 Hz, 2H), 2.88 (q, J¼7.2 Hz, 2H), 2.41 (s, 3H), 1.17 (t, J¼7.2 Hz,
3H); 13C NMR (75 MHz, DMSO-d6)
168.4, 164.2, 159.1, 146.9, 145.4,
d
12.51 (br s, 1H), 8.93 (s, 1H), 7.60 (d, J¼8.4 Hz, 2H), 7.41
d
138.5, 138.5, 131.4, 129.6, 128.2, 125.6, 113.8, 85.1, 35.7, 20.7, 12.1; IR
(Nujol mull) 2224, 1731, 1641, 1613, 1592 cmꢀ1. Anal. Calcd for
C18H14N6O: C, 65.44; H, 4.27; N, 25.44, found: C, 65.10; H, 4.33; N,
25.53.
9. (a) Kovacic, P.; Osuna, J. A., Jr. Curr. Pharm. Des. 2000, 6, 277e309; (b) Kovacic, P.
Med. Hypotheses 2007, 69, 510e516.
10. Hillard, E. A.; Abreu, F. C.; Ferreira, D. C. M.; Jaouen, G.; Goulart, M. O. F.; Am-
atore, C. Chem. Commun. 2008, 2612e2628.
ꢀ
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11. Jimenez-Alonso, S.; Guasch, J.; Estevez-Braun, A.; Ratera, I.; Veciana, J.; Ravelo,
A. G. J. Org. Chem. 2011, 76, 1634e1643.
12. Inbaraj, J. J.; Krishna, M. C.; Gandhidasan, R.; Murugesan, R. Biochim. Biophys.
Acta 1999, 1472, 462e470.
4.5.3. 3-(4-Methylphenyl)-8-oxo-5-phenyl-7,8-dihydro-3H-imidazo
[4,5-d]pyrrolo[3,2-f][1,3]diazepine-9-carbonitrile (5g). Orange solid
(110 mg, 0.28 mmol, 83%); mp 332e334 ꢁC; 1H NMR (300 MHz,
13. Paula, F. S.; Cioletti, A. G.; Silva Filho, J. F.; Santana, A. E. G.; Santos, A. F.; Goulart,
M. O. F.; Vallaro, M.; Fruttero, R. J. Electroanal. Chem. 2003, 544, 25e34.
14. (a) Alves, M. J.; Booth, B. L.; Freitas, A. P.; Proenc¸ a, M. F. J. Chem. Soc., Perkin Trans.
1 1992, 913e917; (b) Booth, B. L.; Dias, A. M.; Proenc¸ a, M. F. J. Chem. Soc., Perkin
Trans. 1 1992, 2119e2126; (c) Alves, M. J.; Booth, B. L.; Proenc¸ a, M. F. J. Heter-
ocycl. Chem. 1994, 31, 345e350; (d) Booth, B. L.; Coster, R. D.; Proenc¸ a, M. F.
Synthesis 1988, 389e391; (e) Alves, M. J.; Carvalho, M. A.; Proenc¸ a, M. F.; Booth,
B. L.; Pritchard, R. G. J. Heterocycl. Chem. 1997, 34, 739e743; (f) Al-Azmi, A.;
Booth, B. L.; Carpenter, R. A.; Carvalho, A.; Marrelec, E.; Pritchard, R. G.; Proenc¸ a,
M. F. J. Chem. Soc., Perkin Trans. 1 2001, 2532e2537; (g) Booth, B. L.; Cabral, I. M.;
Dias, A. M.; Freitas, A. P.; Matos-Beja, A. M.; Proenc¸ a, M. F.; Ramos-Silva, M. J.
Chem. Soc., Perkin Trans. 1 2001, 1241e1251; (h) Dias, A. M.; Cabral, I.; Proenc¸ a,
M. F.; Booth, B. L. J. Org. Chem. 2002, 67, 5546e5552; (i) Carvalho, M. A.; Esteves,
T. M.; Proenc¸ a, M. F.; Booth, B. L. Org. Biomol. Chem. 2004, 2, 1019e1024; (j)
DMSO-d6)
d
12.68 (s, 1H), 9.00 (s, 1H), 8.26 (dd, J1¼7.5 Hz, J2¼2.1 Hz,
2H), 7.67 (d, J¼8.1 Hz, 2H), 7.50e7.30 (m, 5H), 2.45 (s, 3H); 13C NMR
(75 MHz, DMSO-d6)
d 168.4, 159.4, 154.6, 147.7, 145.6, 138.7, 138.5,
137.9, 131.6, 131.4, 129.8, 129.2, 129.0, 128.7, 125.7, 113.9, 85.5, 20.8;
IR (Nujol mull) 2228, 1727, 1633, 1590 cmꢀ1. Anal. Calcd for
C22H14N6O. H2O, 0.2 NH3: C, 66.09; H, 4.19; N, 21.72, found: C, 66.11;
H, 4.06; N, 21.79.
4.6. Synthesis of 7-ethyl-3-(4-methoxyphenyl)-8-oxo-7,8-
dihydro-3H-imidazo[4,5-d]pyrrolo[3,2-f][1,3] diazepine-9-
carbonitrile (6)
ꢀ
Carvalho, M. A.; Zaki, M. E. A.; Alvares, Y.; Proenc¸ a, M. F.; Booth, B. L. Org. Biomol.
Chem. 2004, 2, 2340e2345; (k) Alves, M. J.; Carvalho, M. A.; Carvalho, S.; Dias,
A. M.; Fernandes, F. H.; Proenc¸ a, M. F. Eur. J. Org. Chem. 2007, 4881e4887.
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Triethyl orthoformate (1 mL) was added to a solution of 3b
(0.26 mmol) in dimethylformamide (3 mL). The mixture was
refluxed for 2 h and the solvent was removed under reduced
pressure. Addition of ethanol led to a cream solid, which was fil-
tered and washed with diethyl ether and ethanol. The isolated
product was identified as 6. Cream solid (75 mg, 0.22 mmol, 84%);
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mp 258e260 ꢁC; 1H NMR (300 MHz, DMSO-d6)
d 9.01 (s, 1H), 8.66
(s,1H), 7.61 (d, J¼9.0 Hz, 2H), 7.17 (d, J¼9.0 Hz, 2H), 4.03 (q, J¼7.2 Hz,
2H), 3.85 (s, 3H), 1.23 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6)
d
166.7, 159.7, 157.3, 149.5, 148.2, 146.5, 137.9, 129.5, 127.6, 126.4,
114.6, 113.7, 84.0, 55.6, 34.9, 13.3; IR (Nujol mull) 2217, 1716, 1625,
1523 cmꢀ1. Anal. Calcd for C18H14N6O2. 0.4H2O: C, 61.15; H, 4.22.
Found: C, 61.43; H, 4.29.
22. For representative examples see: (a) Showalter, H. D.; Putt, S. R. Tetrahedron
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Acknowledgements
The authors gratefully acknowledge the financial support by the
ˇ
23. The 1He15N HMBC spectrum of compound 5a (20 mg) at natural abundance,
~
University of Minho and Fundac¸ ao para a Ciencia e Tecnologia
dissolved in DMSO-d6 (600 mL), was recorded at 40.55 MHz and at a tempera-
through the Portuguese NMR network (RNRMN), the Project F-
COMP-01-0124-FEDER-022716 (ref. FCT PEst-C/QUI/UI0686/2011)
FEDER-COMPETE and the post-doc grant awarded to Dr. M.Z.
(SFRH/BPD/27029/2006).
ture of 20 ꢁC. The HMBC experiment was optimized for 10 Hz (1.5 s delay) long
range coupling.
ꢀ
ꢀ
24. Marek, R.; Brus, J.; Tousek, J.; Kovacs, L.; Hockova, D. Magn. Reson. Chem. 2002,
40, 353e360.
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tions, 2nd ed.; Wiley: New York, NY, 2001.
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Quantum Chem. 2012, , doi:10.1002/qua. 24055
Supplementary data
27. (a) Alston, J. Y.; Fry, A. J. Electrochim. Acta 2004, 49, 455e459; (b) Aguilar-
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2012.04.030. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
ꢀ
Martínez, M.; Bautista-Martínez, J. A.; Macías-Ruvalcaba, N.; Gonzalez, I.; To-
var, E.; Alizal, T. M.; Collera, T. O.; Cuevas, G. J. Org. Chem. 2001, 66,
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28. ACD/Labs software, version 8.0 for Microsoft Windows, licence No. 33377.