Novel tetracyclic imidazole derivatives: Synthesis, dynamic NMR study, and anti-inflammatory evaluation

Article abstract of DOI:10.1002/jhet.376

A series of tetracyclic imidazole derivatives 9a-9v and 10a-10h are prepared by multistep route starting from the known tricyclic diketones 2a-2d. Intermediary dibenzooxepin[4,5-d]imidazoles (3a, 3c) and dibenzothiepin[4,5-d] imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds 5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formylated at C(2) to afford 7a-7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets of isomeric ω-dimethylaminoalkyl derivatives 9a-9v. N-deprotection of 9i-9v led to the compounds 10a-10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be ～11.5 and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their anti-inflammatory activity.

Full text of DOI:10.1002/jhet.376

640
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic
NMR Study, and Anti-Inflammatory Evaluation
Vol 47
ˇ
Renata Rupcic,* Marina Modric, Antun Hutinec, Ana Cikos, Barbara Stanic,
ˇ ´
´
´ ˇ ´
Milan Mesic, Dijana Pesic, and Mladen Mercep
ˇ
´
´
´
GlaxoSmithKline Research Centre Zagreb, Prilaz baruna Filipovica 29, Zagreb HR-10000, Croatia
*E-mail: renata.q.rupcic@gsk.com
Received September 23, 2009
DOI 10.1002/jhet.376
Published online 3 May 2010 in Wiley InterScience (www.interscience.wiley.com).
A series of tetracyclic imidazole derivatives 9a–9v and 10a–10h are prepared by multistep route start-
ing from the known tricyclic diketones 2a–2d. Intermediary dibenzooxepin[4,5-d]imidazoles (3a, 3c)
and dibenzothiepin[4,5-d]imidazoles (3b, 3d) are N-protected to 4e, 4f and to the isomeric compounds
5a, 5b and 6a, 6b. The isomeric compounds 5 and 6 are separated. Compounds 4, 5, and 6 are formy-
lated at C(2) to afford 7a–7j. In the last steps, aldehyde group is reduced, then alkylated to the two sets
of isomeric x-dimethylaminoalkyl derivatives 9a–9v. N-deprotection of 9i–9v led to the compounds
10a–10h. Assignment of the syn/anti structure to 5a and 6a was supported by 1D selective ROESY
NMR spectra, whereas conformational mobility for the selected representatives 8a and 8b is studied by
dynamic NMR. Activation energies (energy barriers for interconversion) are determined to be ꢀ11.5
and 16.2 kcal/mol, respectively. A series of derivatives 9 and 10 were tested in vitro for their anti-
inflammatory activity.
J. Heterocyclic Chem., 47, 640 (2010).
INTRODUCTION
polysaccharide (LPS) induced TNF-a production in
human peripheral blood mononuclear cells (hPBMCs)
that encouraged us to extend our effort on other five
membered heterocyclic systems [5,6].
In our continuing efforts toward the development of
disease modifying treatments for rheumatoid arthritis
(RA), we are targeting inhibition of overproduction of
tumor necrosis factor alpha cytokine (TNF-a) that is
recognized as a key cytokine in RA progression. A
small molecule inhibitor of TNF-a would be a novel
potent anti-inflammatory drug having this distinguished
mechanism of action. In the frame of our project aimed
toward synthesis, structure determination of tetracyclic
imidazoles, and screening of their activity on the
selected biological targets, we entered the study of a
large series of dibenzo-oxepin- and dibenzo-thiepin im-
idazole derivatives. In our previous articles we have
reported on the synthesis, properties, and preliminary bi-
ological results of oxa-, aza-, and thia-dibenzoazulenes,
characterized by the annulated furane I [2], pyrrole II,
III [3], and thiophene IV, V [4] ring (Fig. 1). Prelimi-
nary results have revealed activity of these polycyclic
systems in the in vitro anti-inflammatory test in lipo-
Generally, structural complexity of this specific class
of recently studied non-steroidal anti-inflammatory com-
pounds increases from diaryl-substituted heterocycles
general formulae VI, to polycondensed heterocyclic
structures VII. Representatives of the former are vici-
naly substituted polycyclic aryl/pyridine-4-yls, potent
inhibitors of p38 MAP kinase (p38) [7,8], while 2-sub-
stituted-4,5-diarylimidazoles VIII are claimed as in vivo
anti-inflammatory active structures (Fig. 2) [9–14].
Moreover, polycondensed heterocycles with non-aro-
matic dibenzoazulene core and annelated 5-membered het-
erocycles are repeatedly claimed as anti-inflammatory
active compounds. Among them are 2-substituted-1H-phe-
nanthro[9,10-d]imidazoles IX [15], 2-substituted diben-
zo[2,3:6,7]thiepino[4,5-d]imidazoles X [16–20], 2-substi-
tuted dibenzo[2,3:6,7]oxepino[4,5-d]imidazoles, and their
corresponding sulfoxides and sulfones XI (Fig. 3) [21].
C
V
2010 HeteroCorporation

May 2010
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,
and Anti-Inflammatory Evaluation
641
Figure 1. Previously described oxa-, aza-, and thia-dibenzoazulenes.
Figure 2. Non-steroidal heterocyclic anti-inflammatory compounds.
Figure 3. Polycondensed heterocycles with non-aromatic dibenzoazulene core.
Process for preparation of 2-formylimidazole acetals
is also claimed [22], as well as 4,5-disubstituted imidaz-
ole derivatives and their use in CSBP/PK/p38 kinase
mediated diseases [13]. First synthesis of tetracyclic,
polycondensed imidazoles, presented by the formulae X,
was reported by Lombardino [17], based on the general
imidazole synthesis of Davidson et al. [23]. The same
author claimed that a wide range of polycyclic com-
pounds have anti-inflammatory and some other activities
[16,18–20]. This method has been recently improved
using microwave irradiation [24,25].
was introduced at the imidazole ring to improve
physicochemical properties of this series of compounds
(Fig. 4).
RESULTS AND DISCUSSION
Chemistry. Tetracyclic imidazoles 3a–3d were pre-
pared starting from the known 11H-dibenzo[b,f]oxepin-
10-ones 1a, 1c or 11H-dibenzo[b,f]thiepin-10-ones 1b,
1d, cyclic ketones characterized by activated methylene
group in the a-position to carbonyl group [16–20]. This
group was oxidized by selenium dioxide to give a-dike-
tones 2a–2d. Synthesis of imidazoles 3a–3d was com-
pleted by condensation of dicarbonyl compounds 2a–2d
with paraformaldehyde and ammonium acetate in acetic
acid, according to Davidson et al., Scheme 1 [23].
N-Alkylated compounds 4a–4f were obtained from
3a, 3b using a modified method by Wolkenberg et al.
[25], on treatment with sodium hydride in tetrahydrofu-
ran at 0ꢁC followed by alkylation at elevated tempera-
tures, Scheme 2 [26].
We have extended our effort to the imidazo-deriva-
tives general formulae XII, wherein an extra basic unit
We have used 2-trimethylsilyl-ethoxymethyl (SEM)
as effective protecting group for imidazole N(1) atom
Figure 4. Novel tetracyclic imidazole derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ
R. Rupcic, M. Modric, A. Hutinec, A. Cikos, B. Stanic, M. Mesic, D. Pesic, and M. Mercep
ˇ ´
´
ˇ
´
´
ˇ ´
´
642
Vol 47
Scheme 1
Scheme 2
any clue on exact position of the side-chain on N(1)
atom of imidazole. Straightforward determination
required combined use of 2D NMR techniques and 1D
selective ROESY spectrum, as exemplified for the com-
pounds 5a and 6a (Fig. 5).
Correlation peaks from COSY, HMBC, HMQC, and
2D TPPI NOESY spectra afforded ambiguous informa-
tion due to the overlap of key signals, so final solution
for this problem came from the analysis of the selective
1D ROESY spectrum. Selective excitation was applied
to methylenic protons of NACH2AO unit at 5.356 and
5.372 ppm. NOE interactions were expected between
methylenic protons of NACH2AO group and ortho-pro-
tons in the vicinal aromatic ring, HB for 5a and HA for
6a, which are close enough to engage in dipolar interac-
tion through space, (Fig. 6).
which was introduced using (2-trimethylsilyl)-ethoxy-
methyl chloride (SEMCl) [27].
Protons HA and HB in both 5a and 6a have very close
chemical shifts at the applied magnetic field, and are
unequivocally assigned on the basis of their coupling
patterns. Thus, HA is coupled with ortho- and meta-pro-
ton giving dd at 7.84 ppm, whereas HB is coupled only
with meta-situated proton giving doublet at 7.86 ppm.
On selective excitation of methylenic protons of
NACH2AO unit in 6a doublet of HB proton disap-
peared, while resonance lines for proton HA remained,
revealing its vicinity to the methylenic group, and thus
syn (cis) orientation of the side chain on N(1) of imidaz-
ole ring to the aromatic ring that has no chlorine in
meta-position to the annulated heterocycle.
In the polycondensed imidazole derivatives 3a, 3b (Y
¼ H) two tautomeric forms are equivalent and, there-
fore, single isomers 4a–4f are obtained on alkylation.
However, N(1)-alkylation of 3c, 3d affords structural
isomers 5 and 6, Scheme 3.
N-Trimethylsylil-ethoxymethylated compounds 5a, 6a
and 5b, 6b were separated by purification on silica gel
SPE cartridge using step gradient system for elution
with ethyl acetate/n-hexane. In both cases, regioisomers
5a, 6a and 5b, 6b are obtained in ꢀ1:1 ratio, revealing
minor effect of electron-withdrawing chlorine in the
meta-position of the aromatic ring. 1D NMR spectra of
compounds in the isomeric series 5 and 6 did not give
Scheme 3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,
and Anti-Inflammatory Evaluation
643
membered ring play an important role in biological ac-
tivity of non-aromatic polycyclic compounds. Illustrative
example represents octoclothepin 14 (Fig. 7), centrochi-
ral, and planar-chiral compound with dibenzo-thiepine
tricyclic core, wherein two conformers with inversed 7-
membered ring are diastereotopic. An early study of (S)-
14 (Fig. 7), neuroleptic compound that binds on dopa-
mine D-2 receptor [30], has revealed that stable confor-
mation of (S)-14, which is responsible for the dopamine
D-2 receptor antagonism, is significantly different from
the one observed in the crystal [31].
Figure 5. Regioisomeres determined by 2D NMR techniques and 1D
selective ROESY spectrum.
On the other hand, conformational mobility of diben-
zothiepines with sulfide 1b and sulfoxide 15 unit in the
bridge, was studied by dynamic NMR [32]. Huge differ-
ence in the activation energies for ring-inversion was
observed; 9.3 kcal/mol for 1b and 23 kcal/mol for 15,
revealing that at ambient temperature only the later may
be separated into stable conformers (Fig. 8).
Having this result in hands, ulterior synthetic steps
have been performed on the separated isomers with
known structure. From 4, 5, and 6 are obtained C(2) for-
mylated derivatives 7 on generation of carbanion at C(2)
of imidazole ring by n-butyllithium/tetrahydrofuran at
ꢂ78ꢁC, followed by treatment with DMF at r.t., Scheme
4 [9,28].
For many condensed non-aromatic heterocycles with
one heteroatom in the 7-membered ring correlation
between conformational properties and biological activ-
ities are studied. Detailed study of N-acylbenzazepines
with interesting pharmacological properties [33], by
dynamic NMR is an instructive case [34–36]. For dihy-
drobenz/b/azepines thermodynamic parameters for con-
formation equilibria are determined by dynamic NMR
[37,38].
Reduction of 7a–7h with sodium borohydride at r.t.
afforded benzylic alcohols 8a–8h. From 7i and 7j under
the same conditions are obtained 8i and 8j. Both sets of
hydroxymethyl imidazole derivatives are converted to
dialkylaminoalkyl ethers 9a–9v on treatment with x-
chloroalkyl-dimethylamines under phase transfer condi-
tions in the presence of benzyltriethylammonium chlo-
ride (BTEAC), Scheme 5 [4,29].
Products 10a–10h are obtained on cleavage of 2-(tri-
methylsilyl)ethoxymethyl group with 0.5M hydrochloric
acid/methanol, Scheme 6 [9].
In view of the importance of conformational mobility
of non-aromatic polycondensed heterocycles, we have
determined difference in conformational mobility of the
two representatives of oxepines and thiepines, com-
pounds 8a and 8b, respectively. They are selected due
Conformational properties of representative oxepin
(8a) and thiepin (8b) tetracycles. Conformational mo-
bility and preferred conformation in solution of the 7-
Figure 6. Comparison between aromatic region of 1H (a) and 1D selective ROESY (b) spectra of 6a.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Scheme 4
to their well resolved peaks for methylenic protons HA,
HB, present in the 5-member chelate ring
C(2)ACHAHBAOAHꢃꢃꢃN(3) formed by hydrogen bond
to N(3) atom, formulae 8a, 8b (Fig. 9).
On the basis of the reported results, we expected no-
table difference of the energy for conformational inver-
sion for these two compounds. To our satisfaction,
dynamic NMR study has revealed two different temper-
ature intervals for the collapse of the AB(X) system into
A2 system of the methylenic protons. Series of proton
NMR spectra acquired in temperature range where the
coalescence of proton signals occurs are shown in the
Figures 10 and 11.
Activation energies (energy barriers for interconver-
sion) for compounds 8a and 8b are determined and
results are presented in Table 1.
Biology. Among many discovered biological targets
in the past 30 years, TNF-a, interleukin 1 (IL-1), p38,
and COX-2 enzyme belong to the group of the most
studied and the most relevant mediators of
Scheme 5

May 2010
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,
and Anti-Inflammatory Evaluation
645
Scheme 6
Figure 7. Octoclothepin and its (S)-conformer.
Figure 9. Methylenic protons HA and HB in the 5-membered chelate
ring.
over-expression of TNF-a cytokine has been impli-
cated in a number of serious inflammatory disorders.
Consequently, agents that inhibit the production of
TNF-a can decrease levels of inflammatory response,
and thereby reduce inflammation and prevent further
tissue destruction.
Figure 8. Dibenzothiepines with sulfide and sulfoxide unit in the
bridge.
From medicinal chemistry point of view, connecting
previous knowledge about anti-inflammatory properties
of some compounds with today’s understanding of im-
portant key players in inflammation mechanism could
provide rational approach to the lead molecules that
may be further optimized for better activity and
inflammation [39]. Overproduction inhibition of these
cytokines which are responsible for inflammation has
been proposed as a disease modifying approach
towards the treatment of inflammatory disorders. The
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ
R. Rupcic, M. Modric, A. Hutinec, A. Cikos, B. Stanic, M. Mesic, D. Pesic, and M. Mercep
ˇ ´
´
ˇ
´
´
ˇ ´
´
646
Vol 47
Table 1
Activation energies for compounds 8a and 8b.
Compound
8a
8b
Solvent
Acetone-d6 DMSO-d6
Starting temperature (ꢁC)
Ending temperature (ꢁC)
Coalescence temperature TC (ꢁC)
Separation between signals Dm (Hz)
Coupling constant JA,B (Hz)
Rate constant at the
25
ꢂ60
ꢂ40
25
80
50
17.3
4.9
2
13.1
80.9
13.1
72.1
coalescence temzperature kC (Hz)
Gibbs energy DGC (kcal/mol)
11.5
16.2
z Activated complex, transition state.
Compounds possessing alkoxymethylene linker (ether)
at position C(2) on imidazole ring showed potency to in-
hibit TNF-a production in vitro in low micromolar
range with IC50 values for the most potent compounds
in the range of 1–3 lM.
According to obtained results dibenzo-oxepin- and
dibenzo-thiepin imidazole derivatives were recognized
as a novel class of tetracyclic compounds with anti-
inflammatory activity through specific inhibition of
TNF-a secretion.
Figure 10. 1H NMR spectra of 8a acquired in acetone-d6 in the tem-
perature intervals from 25ꢁC to ꢂ60ꢁC (coalescence range for the HA
and HB protons signals).
EXPERIMENTAL
Chemistry. Commercial reagents were used as received
without additional purification. All used chemicals and sol-
vents were p.a. purity. Differential scanning calorimetry data
were collected on a Mettler Toledo differential scanning calo-
rimeter 822e/500 using Mettler Toledo STARe software. Sam-
ples about 5 mg were weighed into Al-pans (40 lL) with
pierced cover. Dry nitrogen was used as purge gas (purge: 50
mL/min). The heating rate of 10ꢁC/min over the range 25–
300ꢁC was used. The instrument was calibrated using certified
indium and zinc. IR spectra were recorded as potassium bro-
mide (KBr) pastilles or as a film on a sodium chloride plate,
on a Nicolet Magna IR 760 FT IR-spectrophotometer, and on
a Bruker Vertex 70 as ATR (ZnSe) powder or film cast from
DCM solution. One- and two-dimensional NMR spectra were
recorded on Bruker Avance DPX 300 (300 MHz), Bruker
Avance DRX 500 (500 MHz), and Bruker Avance III 600
(600 MHz) spectrometers. Deuterated dimethylsulfoxide
(DMSO-d6) and deuterated chloroform (CDCl3) were used as
solvents and tetramethylsilan (TMS) as an internal standard.
Purity of the compounds was obtained on a Waters HPLC-UV/
MS Autopurification System with a Micromass ZQ and a
Waters 996 Photodiode Array Detector, and on Varian Chrom-
pack CP-3800 Gas Chromatograph with a Varian Chrompack
Saturn 2000 MS/MS detector. HRMS data were acquired using
Q-TOF 2 Waters system. Thin layer chromatography (TLC)
was run on Merck Silica gel 60 F254 plates, spots detected
with UV light at 254 and/or 365 nm. Proportions of solvents
used for TLC are by volume.
Figure 11. 1H NMR spectra of 8b acquired in DMSO-d6 in the tem-
perature intervals from 25ꢁC to 60ꢁC (coalescence range for the HA
and HB protons signals).
selectivity profile and desirable pharmacokinetic proper-
ties. Along this line we have continued our project of
the synthesis of tetracyclic target structures and their
testing on inhibition of LPS stimulated TNF-a produc-
tion. In vitro biological tests are performed on some
intermediates and all tetracyclic compounds 9 and 10 to
test their ability to inhibit TNF-a production in LPS-
activated hPBMC assay [5,6].
Products were purified using Solid Phase Extraction (SPE)
columns on an automated SPE purification system (FlashMas-
ter II).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,
and Anti-Inflammatory Evaluation
647
2H), 7.37 (br. s., 2H), 7.55 (d, J ¼ 7.02 Hz, 1H), 7.76 (d, J ¼
6.71 Hz, 1H), 7.96 (s, 1H), 12.92 ppm (br. s., 1H); 13C NMR
(126 MHz, DMSO-d6): d 121.48, 122.63, 126.44, 127.08,
127.36, 132.06, 136.66, 155.30 ppm; HRMS: m/z calcd. for
C15H11N2O: 235.0871 [MþH]þ, found 235.0865.
General procedure for reaction of ketones 1 with sele-
nium dioxide (preparation of compounds 2). To the suspen-
sion of selenium dioxide (1.74 g, 15.70 mmol) in glacial acetic
acid (10 mL) was added a solution of ketone 1 (14.3 mmol) in
glacial acetic acid (30 mL). The suspension was heated for 2 h
at 100ꢁC and undissolved material filtered off. The filtrate was
diluted with water (50 mL) and extracted with dichlorome-
thane (2 ꢄ 50 mL). Organic extracts were washed with water
(3 ꢄ 50 mL), and saturated sodium hydrogencarbonate (3 ꢄ
50 mL), dried over anhydrous sodium sulfate, concentrated,
and then precipitated from n-hexane/dichloromethane to give
compound 2.
1H-Dibenzo[2,3:6,7]thiepino[4,5-d]imidazole (3b). Obtained
from 2b as a yellow solid: Yield 75%; mp 263.23ꢁC; IR
1
(KBr): 2815, 2641, 1511, 1478, 953, 758, 651 cmꢂ1; H NMR
(500 MHz, DMSO-d6): d 7.37 (t, J ¼ 7.17 Hz, 2H), 7.44 (t, J
¼ 7.32 Hz, 2H), 7.59 (br. s., 3H), 7.81 (br. s., 1H), 7.99 (s,
1H), 12.92 ppm (br. s., 1H); 13C NMR (75 MHz, DMSO-d6):
d 136.85, 133.60, 132.60, 132.17, 131.63, 130.90, 128.75,
128.35, 127.65, 126.85 ppm; HRMS: m/z calcd. for
C15H11N2S: 251.0638 [MþH]þ, found 251.0630.
Dibenzo[b,f]oxepin-10,11-dione (2a). Obtained from 1a as
a yellow solid: Yield 85%; mp 116.68ꢁC; IR (KBr): 1670,
1
1600, 1469, 1447, 1281, 1220, 926, 771 cmꢂ1; H NMR (500
11-Chloro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazole
(3c). Obtained from 2c as a beige amorphous solid: Yield
MHz, CDCl3): d 7.35 (td, J ¼ 7.55, 1.07 Hz, 2H), 7.42–7.43
(m, 1H), 7.43–7.45 (m, 1H), 7.64–7.68 (m, 2H), 7.99 (d, J ¼
1.83 Hz, 1H), 8.00 ppm (d, J ¼ 1.83 Hz, 1H); 13C NMR (126
MHz, CDCl3): d 121.60, 125.50, 126.11, 131.71, 135.83,
156.65, 186.31 ppm; MS: m/z 225.00 [MþH]þ.
84%; IR (KBr): 3113, 14785, 953, 758, 651 cmꢂ1 1H NMR
;
(600 MHz, DMSO-d6): d 7.29 (dt, J ¼ 7.76, 3.97 Hz, 1H),
7.33–7.45 (m, 4H), 7.66 (br. s., 2H), 8.00 (s, 1H), 13.00 ppm
(br. s., 1H), 13C NMR (151 MHz, DMSO-d6): d 153.81,
152.60, 137.92, 129.36, 125.58, 123.37 ppm; HRMS: m/z
calcd. for C15H10ClN2O: 269.0482 [MþH]þ, found 269.0468.
11-Chloro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazole
(3d). Obtained from 2d as a yellow solid: Yield 68%; mp
Dibenzo[b,f]thiepin-10,11-dione (2b). Obtained from 1b as
a yellow solid: Yield 80%; mp 122.69ꢁC; IR (KBr): 1675,
1
1581, 1435, 1280, 1258, 1219, 916, 760 cmꢂ1; H NMR (500
MHz, CDCl3): d 7.31–7.37 (m, 4H), 7.51 (dd, J ¼ 7.63, 1.53
Hz, 2H), 7.69 ppm (dd, J ¼ 7.17, 1.98 Hz, 2H); 13C NMR (75
MHz, CDCl3): d 129.23, 131.26, 132.09, 132.98, 134.55,
139.35, 190.62 ppm; MS: m/z 240.09 [MþH]þ.
241.28ꢁC; IR (KBr): 2806, 2639, 1475, 768, 649 cmꢂ1 1H
;
NMR (500 MHz, DMSO-d6): d 7.33–7.53 (m, 3H), 7.53–7.67
(m, 3H), 7.78 (br. s., 1H), 8.04 (s, 1H), 13.03 ppm (d, J ¼
13.73 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d 127.23,
127.48, 128.26, 129.55, 129.72, 130.00, 130.85, 131.02,
133.23, 133.31, 133.79, 133.97, 135.90, 137.76, 138.30 ppm;
HRMS: m/z calcd. for C15H10ClN2S: 285.0253 [MþH]þ, found
285.0245.
General procedures for N-alkylation of the compounds 3
(preparation of compounds 4). N-Methylation. To a solu-
tion of 3 (0.5 g, 2.13 mmol) in dry tetrahydrofuran (23 mL)
the 60% suspension of NaH in mineral oil (0.26 g, 6.4 mmol)
was added under stirring at 0ꢁC. The reaction mixture was
stirred for 30 min at 0ꢁC, then MeI (0.13 mL, 2.13 mmol) was
added and reaction mixture was stirred at room temperature
for 2 h. Then it was concentrated, diluted with water (100
mL), and extracted with dichloromethane (3 ꢄ 50 mL). The
organic extract was washed with brine (100 mL), dried over
anhydrous sodium sulfate, and evaporated. After purification
on silica gel SPE cartridge using step gradient system for elu-
tion dichloromethane/(dichloromethane/methanol/ammonium
hydroxide 90:5:0.5) N-methylated compounds 4a and 4b were
isolated.
2-Chlorodibenzo[b,f]oxepin-10,11-dione (2c). Obtained
from 1c as a yellow solid: Yield 74%; mp 103.23ꢁC; IR
(KBr): 1691, 1673, 1599, 1467, 1449, 1402, 1290, 1266, 1224,
1118, 842, 765 cmꢂ1 1H NMR (500 MHz, CDCl3): d 7.35–
;
7.44 (m, 3H), 7.60 (dd, J ¼ 8.70, 2.59 Hz, 1H), 7.65–7.70 (m,
1H), 7.95–8.01 ppm (m, 2H); 13C NMR (126 MHz, CDCl3): d
156.42, 136.01, 135.74, 131.87, 131.10, 130.89, 125.87,
123.36, 121.52 ppm; MS: m/z 259.1 [MþH]þ.
2-Chlorodibenzo[b,f]thiepin-10,11-dione (2d). Obtained
from 1d as a yellow solid: Yield 79%; mp 167.94ꢁC; IR
(KBr): 1689, 1583, 1274, 1213, 1094, 829, 761 cmꢂ1 1H
;
NMR (500 MHz, CDCl3): d 7.40–7.52 (m, 3H), 7.56–7.65 (m,
2H), 7.77 (d, J ¼ 2.14 Hz, 1H), 7.80 ppm (dd, J ¼ 7.02, 1.83
Hz, 1H); 13C NMR (126 MHz, CDCl3): d 129.78, 131.25,
131.65, 132.44, 133.08, 133.21, 133.41, 133.73, 134.21,
135.92, 139.49, 140.76, 189.21, 189.83 ppm; MS: m/z 275.0
[MþH]þ.
General procedure for reaction of diketones 2 with para-
formaldehyde (preparation of compounds 3). A suspension
of compound 2 (5.35 mmol), ammonium acetate (4.13 g, 53.5
mmol), and paraformaldehyde (0.19 g, 5.0 mmol) in glacial
acetic acid (32 mL) was heated to reflux. After 2 h, reaction
mixture was cooled, diluted with water (100 mL), and
extracted with ethyl acetate (2 ꢄ 50 mL). Organic extracts
were washed with water (3 ꢄ 100 mL), saturated sodium
hydrogencarbonate (3 ꢄ 100 mL), and brine (100 mL), dried
over anhydrous sodium sulfate, concentrated, and then purified
on silica gel SPE cartridge using step gradient system for elu-
tion dichloromethane/(dichloromethane/methanol/ammonium
hydroxide 90:9:1.5) to give compound 3.
1-Methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazole
(4a). Obtained from 3a as a yellowish solid: Yield 73%; mp
138.05ꢁC; IR (KBr): 1514, 1444, 1248, 1201, 810, 765, 733
;
cmꢂ1 1H NMR (500 MHz, DMSO-d6): d 3.91 (s, 3H), 7.26
(ddd, J ¼ 7.55, 6.49, 2.14 Hz, 1H), 7.29–7.38 (m, 3H), 7.39–
7.44 (m, 1H), 7.45–7.48 (m, 1H), 7.66 (dd, J ¼ 7.63, 1.53 Hz,
1H), 7.71–7.74 (m, 1H), 7.94 ppm (s, 1H); 13C NMR (126
MHz, DMSO-d6): d 33.62, 121.47, 122.63, 123.27, 125.78,
125.85, 126.65, 126.72, 126.83, 128.20, 129.20, 129.65,
137.54, 141.60, 155.79, 155.89 ppm; HRMS: m/z calcd. for
C16H13N2O: 249.1028 [MþH]þ, found 249.1019.
1H-Dibenzo[2,3:6,7]oxepino[4,5-d]imidazole (3a). Obtained
from 2a as a white solid: Yield 81%; mp 234.05ꢁC; IR (KBr):
1-Methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazole
(4b). Obtained from 3b as a yellowish solid: Yield 94%; mp
137.12ꢁC; IR (KBr): 3051, 2922, 1510, 1467, 773, 758, 741,
1
3286, 2941, 2871, 1730, 1165, 1096, 856 cmꢂ1; H NMR (500
MHz, DMSO-d6): d 7.27 (d, J ¼ 4.88 Hz, 2H), 7.32 (br. s.,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ
R. Rupcic, M. Modric, A. Hutinec, A. Cikos, B. Stanic, M. Mesic, D. Pesic, and M. Mercep
ˇ ´
´
ˇ
´
´
ˇ ´
´
648
Vol 47
643 cmꢂ1
;
1H NMR (500 MHz, DMSO-d6): d 3.83 (s, 3H),
diluted with water (100 mL), and extracted with dichlorome-
7.33–7.37 (m, 1H), 7.40–7.50 (m, 3H), 7.57 (dd, J ¼ 7.63,
1.22 Hz, 1H), 7.64 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.70 (dd, J ¼
7.48, 1.37 Hz, 1H), 7.78 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.97
ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d 33.49,
128.23, 128.37, 128.78, 129.15, 129.26, 130.57, 132.50,
133.16, 133.84, 134.16, 138.41, 140.73, 141.29 ppm; HRMS:
m/z calcd. for C16H13N2S: 265.0799 [MþH]þ, found 265.0791.
N-Phenylethylation. To a solution of 3 (0.2 g, 0.85 mmol)
in dry tetrahydrofuran (7 mL) the 60% suspension of sodium
hydride in mineral oil (0.10 g, 2.56 mmol) was added under
stirring at 0ꢁC. The reaction mixture was stirred for 30 min at
0ꢁC, then 2-phenylethyl bromide (0.17 mL, 1.28 mmol) was
added and reaction mixture was heated under stirring and
reflux. After 2 h, another portion of the 60% suspension of so-
dium hydride in mineral oil (0.03 g, 0.85 mmol) and 2-phenyl-
ethyl bromide (0.12 mL, 0.85 mmol) were added and stirring
under reflux was continued. After 1 day, another portion of the
60% suspension of sodium hydride in mineral oil (0.03 g, 0.85
mmol) and 2-phenylethyl bromide (0.12 mL, 0.85 mmol) were
added and stirring under reflux was continued for 1 day. Then
it was cooled to room temperature, concentrated, and diluted
with water (50 mL) and extracted with dichloromethane (3 ꢄ
30 mL). The organic extract was washed with brine (50 mL),
dried over anhydrous sodium sulfate, and evaporated. After pu-
rification on silica gel SPE cartridge using step gradient system
for elution n-hexane/ethyl acetate N-phenylethylated com-
pounds 4c and 4d were isolated.
thane (3 ꢄ 50 mL). The organic extract was washed with brine
(100 mL), dried over anhydrous sodium sulfate, and evapo-
rated. After purification on silica gel SPE cartridge using step
gradient system for elution ethyl acetate/n-hexane N-trimethyl-
sylil-ethoxymethylated compounds 4e and 4f were isolated.
1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]oxe-
pino[4,5-d]imidazole (4e). Obtained from 3a as a yellowish
solid: Yield 60%; mp 98.50ꢁC; IR (KBr): 1513, 1250, 1244,
1
1080, 838, 766 cmꢂ1; H NMR (500 MHz, DMSO-d6): d 0.00
(s, 9H), 0.93–0.98 (m, 2H), 3.68–3.73 (m, 2H), 5.57 (s, 2H),
7.29–7.36 (m, 2H), 7.39–7.42 (m, 2H), 7.44–7.52 (m, 2H),
7.78 (ddd, J ¼ 7.48, 1.22, 1.07 Hz, 1H), 7.91 (dd, J ¼ 7.93,
1.53 Hz, 1H), 8.22 ppm (s, 1H); 13C NMR (126 MHz, DMSO-
d6): d ꢂ1.03, 17.58, 65.96, 74.46, 121.50, 122.66, 123.16,
125.83, 125.98, 126.76, 126.94, 127.14, 127.92, 129.52,
130.04, 137.99, 141.99, 156.01, 156.09 ppm; HRMS: m/z
calcd. for C21H25N2O2Si: 365.1685 [MþH]þ, found 365.1660.
1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]-
thiepino[4,5-d]imidazole (4f).ꢁObtained from 3b as a yellowish
solid: Yield 79%; mp 104.47 C; IR (KBr): 2955, 1504, 1248,
1
1083, 863, 835, 776, 763 cmꢂ1; H NMR (500 MHz, DMSO-
d6): d 0.00 (s, 9H), 0.85–0.97 (m, 2H), 3.55 (td, J ¼ 9.54,
6.56 Hz, 1H), 3.69 (td, J ¼ 9.46, 6.71 Hz, 1H), 5.46 (d, J ¼
11.29 Hz, 1H), 5.66 (d, 1H), 7.41–7.46 (m, 1H), 7.47–7.55 (m,
3H), 7.64 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.75–7.79 (m, 1H),
7.85 (dd, J ¼ 7.93, 1.22 Hz, 2H), 8.27 ppm (s, 1H); 13C NMR
(126 MHz, DMSO-d6): d ꢂ1.07, 17.61, 66.02, 74.52, 128.46,
128.70, 129.06, 129.20, 129.27, 129.61, 130.49, 132.51,
132.61, 133.45, 133.90, 134.50, 138.08, 141.16, 141.69 ppm;
HRMS: m/z calcd. for C21H25N2OSSi: 381.1451 [MþH]þ,
found 381.1436.
1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imid-
azole (4c). Obtained from 3a as a yellowish amorphous solid:
Yield 64%; IR (KBr): 1509, 1443, 1201, 1079, 809, 762, 741,
696 cmꢂ1
;
1H NMR (500 MHz, DMSO-d6): d 3.02 (t, J ¼
7.48 Hz, 2H), 4.55 (t, J ¼ 7.48 Hz, 2H), 7.13–7.17 (m, 2H),
7.17–7.22 (m, 1H), 7.23–7.28 (m, 3H), 7.30–7.39 (m, 3H),
7.40–7.45 (m, 1H), 7.46–7.49 (m, 1H), 7.64–7.72 (m, 2H),
7.89 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d 36.10,
47.44, 121.43, 122.69, 123.49, 125.75, 126.02, 126.07, 126.31,
126.82, 126.95, 128.13, 128.80, 128.99, 129.26, 129.72,
137.93, 138.02, 141.15, 155.81, 156.10 ppm; HRMS: m/z
calcd. for C23H19N2O: 339.1497 [MþH]þ, found 339.1496.
1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imid-
azole (4d). Obtained from 3b as a white solid: Yield 79%; mp
156.93ꢁC; IR (KBr): 3049, 3022, 2939, 1505, 756, 740, 658
General procedure for N-trimethylsylil-ethoxymethyla-
tion of the compounds 3 (preparation of structural isomers
5 and 6). To a solution of 3 (1.0 g, 3.72 mmol) in dry tetrahy-
drofuran (30 mL) the 60% suspension of sodium hydride in
mineral oil (0.45 g, 11.20 mmol) was added under stirring at
0ꢁC. The reaction mixture was stirred for 30 min at 0ꢁC, then
2-(trimethylsilyl)ethoxymethyl chloride (0.66 mL, 3.72 mmol)
was added and reaction mixture was stirred at room tempera-
ture for 2 h. Then it was concentrated, diluted with water (30
mL), and extracted with dichloromethane (3 ꢄ 25 mL). The
organic extract was washed with brine (50 mL), dried over an-
hydrous sodium sulfate, and evaporated. After purification on
silica gel SPE cartridge using step gradient system for elution
1
cmꢂ1; H NMR (500 MHz, DMSO-d6): d 2.79–2.95 (m, 2H),
4.36–4.45 (m, 1H), 4.58 (ddd, J ¼ 13.73, 7.78, 5.34 Hz, 1H),
7.05–7.09 (m, 2H), 7.14–7.24 (m, 3H), 7.32–7.37 (m, 1H),
7.39–7.45 (m, 2H), 7.48 (td, J ¼ 7.55, 1.37 Hz, 1H), 7.58 (dd,
J ¼ 7.63, 1.22 Hz, 1H), 7.64 (dd, J ¼ 7.63, 1.53 Hz, 1H),
7.71 (dd, J ¼ 7.63, 1.53 Hz, 1H), 7.75 (dd, J ¼ 7.93, 1.53 Hz,
1H), 7.85 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d
36.15, 47.36, 126.86, 127.97, 128.30, 128.73, 128.78, 128.99,
129.13, 129.31, 129.84, 132.50, 132.84, 133.59, 133.87,
134.39, 137.96, 138.32, 140.28, 141.84 ppm; HRMS: m/z
calcd. for C23H19N2S: 355.1269 [MþH]þ, found 355.1273.
N-Trimethylsylil-ethoxymethylation. To a solution of 3 (0.5
g, 2.13 mmol) in dry tetrahydrofuran (23 mL) the 60% suspen-
sion of sodium hydride in mineral oil (0.26 g, 6.40 mmol) was
added under stirring at 0ꢁC. The reaction mixture was stirred
for 30 min at 0ꢁC, then 2-(trimethylsilyl)ethoxymethyl chloride
(0.38 mL, 2.13 mmol) was added and reaction mixture was
stirred at room temperature for 2 h. Then it was concentrated,
ethyl acetate/n-hexane structural isomers
isolated.
5 and 6 were
11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazole (5a). Obtained from 3c as a
yellowish solid: Yield 31%; mp 84.67ꢁC; IR (KBr): 3093, 2957,
1
1515, 1245, 1200, 1077, 833, 768 cmꢂ1; H NMR (500 MHz,
DMSO-d6): d 0.00 (s, 9H), 0.96 (t, J ¼ 7.9 Hz, 2H), 3.72 (t, J ¼
8.0 Hz, 2H), 5.56 (s, 2H), 7.32 (m, 1H), 7.41 (m, 2H), 7.51 (m,
2H), 7.77 (d, J ¼ 7.0 Hz, 1H), 7.96 (d, J ¼ 1.8 Hz, 1H), 8.25
ppm (s, 1H) 13C NMR (126 MHz, DMSO-d6): dꢂ1.04, 17.58,
66.04, 74.55, 122.69, 122.80, 123.46, 126.04, 126.28, 127.27,
127.47, 129.07, 129.74, 129.94, 130.37, 136.67, 142.32, 154.50,
155.78 ppm ; HRMS: m/z calcd. for C21H24N2O2SiCl: 399.1296
[MþH]þ, found 399.1281.
11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]thiepino[4,5-d]imidazole (5b). Obtained from 3d as
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,
and Anti-Inflammatory Evaluation
649
a yellowish solid: Yield 33%; mp 117.74ꢁC; IR (KBr): 2976,
2940, 1738, 1621, 1456, 1381, 1169, 1074, 1014, 732 cmꢂ1
121.44, 121.73, 122.96, 126.13, 126.21, 126.75, 127.16,
128.33, 130.46, 131.64, 133.19, 139.34, 144.74, 156.88,
157.26, 182.69 ppm; HRMS: m/z calcd. for C17H13N2O2:
277.0977 [MþH]þ, found 277.0963.
;
1H NMR (600 MHz, DMSO-d6): d 0.00 (m, 9H), 0.932 (m,
2H), 3.60 (td, J ¼ 9.7, 6.4 Hz, 1H), 3.71 (td, J ¼ 9.7, 6.5 Hz,
1H), 5.41 (d, J ¼ 11.3 Hz, 1H), 5.63 (d, J ¼ 11.3 Hz, 1H),
7.43 (ddd, J ¼ 7.6, 7.5, 1.5 Hz, 1H), 7.50 (td, J ¼ 7.5, 1.3 Hz,
1H), 7.53 (dd, J ¼ 8.3, 2.4 Hz, 1H), 7.62 (dd, J ¼ 7.8, 1.0 Hz,
1H), 7.74 (d, J ¼ 8.4 Hz, 1H), 7.83 (dd, J ¼ 7.7, 1.2 Hz, 1H),
7.95 (d, J ¼ 2.3 Hz, 1H), 8.28 ppm (s, 1H); 13C NMR (151
MHz, DMSO-d6): d ꢂ0.01, 18.67, 67.04, 75.52, 129.00,
129.61, 130.20, 130.28, 130.38, 130.43, 133.55, 134.00,
134.08, 135.18, 135.36, 136.37, 138.88, 142.55, 143.45 ppm ;
HRMS: m/z calcd. for C21H24N2OSClSi: 415.1067 [MþH]þ,
found 415.1067.
1-Methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazole-2-car-
baldehyde (7b). Obtained from 4b as a yellow solid: Yield
52%; mp 215.10ꢁC; IR (ATR): 2918, 2835, 1682, 1443, 825,
760 cmꢂ1 1H NMR (500 MHz, DMSO-d6): d 4.08 (s, 3H),
;
7.41–7.52 (m, 2H), 7.52–7.57 (m, 2H), 7.65 (dd, J ¼ 7.78,
1.37 Hz, 1H), 7.71–7.80 (m, 2H), 7.87 (dd, J ¼ 7.78, 1.68 Hz,
1H), 9.92 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d
34.46, 128.63, 129.39, 129.58, 129.72, 129.85, 130.80, 130.89,
132.78, 134.26, 134.30, 135.74, 136.40, 137.03, 142.85,
143.76, 182.99 ppm; HRMS: m/z calcd. for C17H13N2OS:
293.0749 [MþH]þ, found 293.0740.
5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazole (6a). Obtained from 3c as
a yellowish solid: Yield 47%; mp 93.25ꢁC; IR (KBr): 2950,
1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidaz-
ole-2-carbaldehyde (7c). Obtained from 4c as a yellowish solid:
Yield 70%; mp 157.69ꢁC; IR (ATR): 3062, 3025, 2821, 1674,
1
1514, 1246, 1094, 1074, 834, 811 cmꢂ1; H NMR (500 MHz,
1508, 1449, 1421, 1202, 770, 743 cmꢂ1 1H NMR (500 MHz,
;
DMSO-d6): d 0.00 (m, 9H), 0.96 (t, J ¼ 7.9 Hz, 2H), 3.72 (t,
J ¼ 8.0 Hz, 2H), 5.56 (s, 2H), 7.32 (m, 1H), 7.41 (m, 2H),
7.51 (m, 2H), 7.77 (d, J ¼ 7.0 Hz, 1H), 7.96 (d, J ¼ 1.8 Hz,
1H), 8.25 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d
ꢂ0.98, 17.57, 66.03, 74.42, 121.50, 124.37, 124.95, 125.53,
126.11, 126.45, 127.06, 127.56, 129.53, 129.86, 130.17,
138.80, 142.44, 154.55, 155.76 ppm ; HRMS: m/z calcd. for
C21H24N2O2SiCl: 399.1296 [MþH]þ, found 399.1289.
DMSO-d6): d 3.03 (t, J ¼ 7.32 Hz, 2H), 4.90 (t, J ¼ 7.48 Hz, 2H),
7.07–7.11 (m, 2H), 7.15–7.24 (m, 3H), 7.33 (ddd, J ¼ 7.55, 6.03,
2.59 Hz, 1H), 7.38–7.49 (m, 3H), 7.49–7.57 (m, 2H), 7.75–7.82 (m,
2H), 9.82 ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d 36.41,
47.23, 121.64, 123.02, 126.17, 126.31, 126.72, 127.06, 127.29,
127.72, 128.79, 128.88, 130.51, 131.65, 132.70, 137.41, 139.83,
144.54, 157.18, 157.57 ppm, 182.55; HRMS: m/z calcd. for
C24H19N2O2: 367.1447 [MþH]þ, found 367.1454.
5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]thiepino[4,5-d]imidazole (6b). Obtained from 3d as
a yellowish solid: Yield 49%; mp 113.80ꢁC; IR (KBr): 3098,
2950, 1583, 1505, 1407, 1330, 1263, 1249, 1091, 1083, 1071,
1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imid-
azole-2-carbaldehyde (7d). Obtained from 4d as a yellowish
solid: Yield 52%; mp 193.04ꢁC; IR (ATR): 1684, 1421, 827,
1019, 859, 838, 810, 767, 638 cmꢂ1 1H NMR (600 MHz,
;
1
748, 696 cmꢂ1; H NMR (500 MHz, DMSO-d6): d 2.80–2.95
DMSO-d6): d 0.00 (s, 9H), 0.91 (m, 2H), 3.55 (td, J ¼ 9.6, 6.7
Hz, 1H), 3.69 (td, J ¼ 9.5, 6.8 Hz, 1H), 5.48 (d, J ¼ 11.3 Hz,
1H), 5.67 (d, J ¼ 11.3 Hz, 1H), 7.50 (dd, J ¼ 8.4, 2.4 Hz,
1H), 7.53 (m, 1H), 7.55 (m, 1H), 7.66 (d, J ¼ 8.4 Hz, 1H),
7.77 (m, 1H), 7.81 (d, J ¼ 2.4 Hz, 1H), 7.87 (m, 1H), 8.31
ppm (s, 1H); 13C NMR (151 MHz, DMSO-d6): d 0.00, 18.67,
67.16, 75.69, 128.73, 129.81, 129.88, 130.62, 130.99, 132.24,
133.21, 133.45, 134.96, 135.04, 135.08, 135.22, 140.88,
141.49, 142.55 ppm; HRMS: m/z calcd. for C21H24N2OSClSi:
415.1067 [MþH]þ, found 415.1053.
(m, 2H), 4.74 (dt, J ¼ 14.04, 7.02 Hz, 1H), 5.04 (dt, J ¼
14.11, 7.13 Hz, 1H), 6.95–6.99 (m, 2H), 7.12–7.17 (m, 3H),
7.42 (td, J ¼ 7.55, 1.68 Hz, 1H), 7.46–7.57 (m, 3H), 7.62 (dd,
J ¼ 7.63, 1.22 Hz, 1H), 7.72–7.77 (m, 2H), 7.83 (dd, J ¼
7.48, 1.68 Hz, 1H), 9.81 ppm (s, 1H); 13C NMR (126 MHz,
DMSO-d6): d 36.48, 46.88, 126.91, 128.68, 128.72, 128.89,
129.29, 129.51, 129.71, 130.69, 131.12, 132.71, 132.77,
134.26, 134.90, 136.03, 136.38, 136.97, 137.30, 143.46,
182.82 ppm; HRMS: m/z calcd. for C24H19N2OS: 383.1218
[MþH]þ, found 383.1229.
General procedure for C(2) formylation of the com-
pounds 4, 5, and 6 (preparation of compounds 7). To a so-
lution of 4 (0.44 g, 1.77 mmol) in dry tetrahydrofuran (8 mL)
1.6M solution of n-butyllithium in n-hexane (1.22 mL, 1.95
mmol) was added under stirring at ꢂ78ꢁC. The reaction mix-
ture was stirred for 15 min at ꢂ78ꢁC, then dry DMF (0.17
mL, 2.13 mmol) was added and reaction mixture was stirred at
room temperature for 1 h. Then it was diluted with water (50
mL) and extracted with dichloromethane (3 ꢄ 30 mL). The or-
ganic extract was washed with brine (50 mL), dried over anhy-
drous sodium sulfate, evaporated, and then purified on silica
gel SPE cartridge using step gradient system for elution n-hex-
ane/dichloromethane to give compound 7.
1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]oxe-
pino[4,5-d]imidazole-2-carbaldehyde (7e). Obtained from 4e as a
white solid: Yield 78%; mp 83.24ꢁC; IR (ATR): 952, 1686,
1507, 1450, 1430, 1240, 1211, 1082, 856, 832, 801, 762, 691
1
cmꢂ1; H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.93–
0.98 (m, 2H), 3.73–3.79 (m, 2H), 5.93 (s, 2H), 7.36–7.46 (m,
2H), 7.49–7.57 (m, 2H), 7.57–7.65 (m, 2H), 7.87–7.96 (m,
1H), 7.96–8.04 (m, 1H), 9.97 ppm (s, 1H); 13C NMR (126
MHz, DMSO-d6): d ꢂ1.07, 17.71, 66.45, 73.60, 121.51,
121.71, 123.04, 126.26, 126.35, 126.51, 127.35, 128.47,
130.72, 132.01, 133.32, 139.67, 144.69, 157.02, 157.56,
182.76 ppm; HRMS: m/z calcd. for C22H25N2O3Si: 393.1634
[MþH]þ, found 393.1631.
1-Methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazole-2-car-
baldehyde (7a). Obtained from 4a as a yellow solid: Yield
74%; mp 161.69ꢁC; IR (ATR): 2921, 2849, 1681, 1511, 1445,
1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]-
thiepino[4,5-d]imidazole-2-carbaldehyde (7f). Obtained from
4f as a yellowish solid: Yield 74%; mp 82.94ꢁC; IR (ATR):
1
1209, 800, 768, 745 cmꢂ1; H NMR (500 MHz, DMSO-d6): d
1
2951, 1687, 1445, 1420, 1083, 831, 760 cmꢂ1; H NMR (500
4.17 (s, 3H), 7.31–7.41 (m, 2H), 7.44–7.46 (m, 2H), 7.55–7.57
(m, 2H), 7.74–7.80 (m, 1H), 7.83 (d, J ¼ 7.63 Hz, 1H), 9.88
ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d 34.48,
MHz, DMSO-d6): d 0.00 (s, 9H), 0.88 (t, J ¼ 8.24 Hz, 2H),
3.51 (td, J ¼ 9.08, 7.78 Hz, 1H), 3.66 (td, J ¼ 9.08, 8.09 Hz,
1H), 5.87–5.93 (m, 1H), 5.93–6.00 (m, 1H), 7.53–7.63 (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ
R. Rupcic, M. Modric, A. Hutinec, A. Cikos, B. Stanic, M. Mesic, D. Pesic, and M. Mercep
ˇ ´
´
ˇ
´
´
ˇ ´
´
650
Vol 47
2H), 7.63–7.66 (m, 2H), 7.75 (dd, J ¼ 7.78, 1.37 Hz, 1H),
7.86–7.95 (m, 2H), 7.97 (dd, J ¼ 7.63, 1.53 Hz, 1H), 10.04
ppm (s, 1H); 13C NMR (126 MHz, DMSO-d6): d ꢂ1.14,
17.58, 66.23, 73.80, 128.82, 129.61, 129.64, 129.97, 131.09,
131.11, 132.78, 134.31, 134.58, 136.05, 136.52, 136.70,
143.11, 143.79, 182.87 ppm; HRMS: m/z calcd. for
C22H25N2O2SiS: 409.1406 [MþH]þ, found 409.1398.
General procedure for reduction of aldehydes 7 (prepa-
ration of compounds 8). To a solution of 7 (0.34 g, 1.23
mmol) in mixture of methanol (15 mL) and dichloromethane
(45 mL) sodium borohydride (0.074 g, 1.97 mmol) was added
portionwise. The reaction mixture was stirred for 2 h at room
temperature, pH adjusted to 5–6, concentrated, diluted with
water (50 mL), and extracted with dichloromethane (3 ꢄ 30
mL). The organic extract was washed with saturated sodium
hydrogencarbonate (50 mL), dried over anhydrous sodium sul-
fate and evaporated to give compound 8.
(1-Methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl)me-
thanol (8a). Obtained from 7a as a white solid: Yield 97%;
mp 237.31ꢁC; IR (ATR): 3184, 2923, 1515, 1196, 1024, 742
cmꢂ1 1H NMR (500 MHz, DMSO-d6): d 3.88 (s, 3H), 4.67
;
(d, J ¼ 5.80 Hz, 2H), 5.52 (t, J ¼ 5.65 Hz, 1H), 7.22–7.27
(m, 1H), 7.29–7.38 (m, 3H), 7.42 (td, J ¼ 7.63, 1.53 Hz,
1H), 7.45–7.49 (m, 1H), 7.62 (dd, J ¼ 7.78, 1.68 Hz, 1H),
7.72 ppm (dd, J ¼ 8.09, 1.68 Hz, 1H); 13C NMR (126
MHz, DMSO-d6): d 32.81, 56.46, 121.46, 122.65, 123.41,
125.76, 125.88, 126.59, 126.72, 127.95, 128.09, 129.10,
129.61, 135.65, 150.62, 155.84, 156.01 ppm; HRMS: m/z
calcd. for C17H14N2O2Na: 301.0953 [MþNa]þ, found
301.0957.
11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazole-2-carbaldehyde (7g). Obtained
from 5a as a yellowish solid: Yield 78%; mp 94.58ꢁC; IR
(ATR): 2952, 1684, 1449, 1215, 1073, 824, 772 cmꢂ1 1H
;
NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.94–0.99 (m,
2H), 3.74–3.80 (m, 2H), 5.90 (s, 2H), 7.37–7.42 (m, 1H),
7.49–7.54 (m, 2H), 7.61–7.68 (m, 2H), 7.87 (ddd, J ¼ 7.48,
1.22, 1.07 Hz, 1H), 8.08 (d, J ¼ 2.44 Hz, 1H), 9.96 ppm (s,
1H); 13C NMR (126 MHz, DMSO-d6): d ꢂ1.03, 17.76, 66.45,
73.50, 121.70, 123.34, 124.78, 126.22, 126.50, 127.44, 127.77,
130.49, 130.97, 131.49, 131.90, 140.12, 144.81, 156.01,
156.74, 182.96 ppm; HRMS: m/z calcd. for C22H24N2O3SiCl:
427.1245 [MþH]þ, found 427.1228.
11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]thiepino[4,5-d]imidazole-2-carbaldehyde (7h). Obtained
from 5b as an amorphous yellowish solid: Yield 78%; IR
(ATR): 2951, 1690, 1248, 1081, 832, 762 cmꢂ1 1H NMR
;
(1-Methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl)me-
thanol (8b). Obtained from 7b as a white solid: Yield 77%;
mp 182.69ꢁC; IR (ATR): 3179, 2957, 2919, 1451, 1375, 1031,
(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.89–0.93 (m, 2H),
3.55–3.64 (m, 1H), 3.64–3.72 (m, 1H), 5.75 (d, J ¼ 10.68 Hz,
1H), 5.99 (d, J ¼ 10.68 Hz, 1H), 7.52–7.61 (m, 2H), 7.66–
7.73 (m, 2H), 7.85 (d, J ¼ 8.54 Hz, 1H), 7.94 (dd, J ¼ 7.78,
1.37 Hz, 1H), 8.04 (d, J ¼ 2.44 Hz, 1H), 10.02 ppm (s, 1H);
13C NMR (126 MHz, DMSO-d6): d ꢂ1.09, 17.71, 66.21,
73.79, 128.93, 129.26, 129.84, 130.20, 130.74, 132.83, 132.88,
134.10, 134.45, 134.63, 135.05, 135.77, 136.53, 143.53,
143.88, 183.02 ppm; HRMS: m/z calcd. for C22H24N2O2SiSCl:
443.1016 [MþH]þ, found 443.1005.
1
1018, 759, 741, 719 cmꢂ1; H NMR (500 MHz, DMSO-d6): d
3.81 (s, 3H), 4.66–4.74 (m, 2H), 5.55 (t, J ¼ 5.65 Hz, 1H),
7.31–7.38 (m, 1H), 7.38–7.51 (m, 3H), 7.54–7.60 (m, 2H),
7.70 (dd, J ¼ 7.78, 1.07 Hz, 1H), 7.78 ppm (dd, J ¼ 7.63,
1.53 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d 32.73,
56.57, 128.10, 128.45, 128.70, 129.12, 129.17, 129.26, 131.67,
132.51, 132.71, 133.22, 133.90, 134.08, 138.25, 139.56,
149.69 ppm; HRMS: m/z calcd. for C17H14N2OSNa: 317.0725
[MþNa]þ, found 317.0716.
5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazole-2-carbaldehyde (7i). Obtained
from 6a as a yellowish solid: Yield 83%; mp 113.81ꢁC; IR
[1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imi-
dazol-2-yl]methanol (8c). Obtained from 7c as a white solid:
Yield 98%; mp 169.09ꢁC; IR (ATR): 3119, 3059, 3030, 1513,
(ATR): 2946, 1688, 1238, 1211, 1083, 825, 773 cmꢂ1 1H
;
1451, 1207, 1029, 763, 738, 696 cmꢂ1 1H NMR (500 MHz,
;
NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.92–0.99 (m,
2H), 3.72–3.79 (m, 2H), 5.92 (s, 2H), 7.43–7.49 (m, 1H),
7.54–7.59 (m, 2H), 7.59–7.67 (m, 2H), 7.83 (dd, J ¼ 2.29,
0.76 Hz, 1H), 8.01–8.05 (m, 1H), 9.96 ppm (s, 1H); 13C NMR
(126 MHz, DMSO-d6): d –1.08, 17.71, 66.51, 73.70, 121.23,
123.07, 123.70, 126.51, 126.63, 128.32, 128.55, 130.29,
130.33, 132.26, 133.73, 138.24, 144.82, 155.53, 157.19,
182.77 ppm; HRMS: m/z calcd. for C22H24N2O3ClSi:
427.1245 [MþH]þ, found 427.1229.
DMSO-d6): d 2.94 (t, J ¼ 7.48 Hz, 2H), 4.49 (d, J ¼ 5.49 Hz,
2H), 4.60 (t, J ¼ 7.63 Hz, 2H), 5.57–5.60 (m, 1H), 7.08–7.11
(m, 2H), 7.17–7.27 (m, 4H), 7.32–7.39 (m, 3H), 7.41–7.50 (m,
2H), 7.68–7.76 ppm (m, 2H); 13C NMR (126 MHz, DMSO-
d6): d 36.26, 46.43, 56.56, 121.39, 122.72, 123.69, 125.75,
126.01, 126.07, 126.78, 126.98, 128.07, 128.81, 128.95,
129.23, 129.72, 136.50, 138.12, 150.84, 156.00, 156.35 ppm;
HRMS: m/z calcd. for C24H20N2O2Na: 391.1422 [MþNa]þ,
found 391.1423.
5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]thiepino[4,5-d]imidazole-2-carbaldehyde (7j). Obtained
from 6b as an amorphous yellowish solid: Yield 62%; IR
[1-(2-Phenylethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imi-
dazol-2-yl]methanol (8d). Obtained from 7d as a white solid:
Yield 97%; mp 188.04ꢁC; IR (ATR): 3162, 1454, 1418, 1036,
(ATR): 2950, 1688, 1434, 1247, 1084, 833, 767 cmꢂ1 1H
;
1
754, 715, 692 cmꢂ1; H NMR (500 MHz, DMSO-d6): d 2.68–
NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.85–0.91 (m,
2H), 3.52 (td, J ¼ 9.00, 7.63 Hz, 1H), 3.66 (td, J ¼ 9.16, 7.93
Hz, 1H), 5.88–5.93 (m, 1H), 5.93–5.99 (m, 1H), 7.61 (dd, J ¼
8.24, 2.44 Hz, 1H), 7.64–7.69 (m, 2H), 7.76 (d, J ¼ 8.54 Hz,
1H), 7.87–7.97 (m, 3H), 10.05 ppm (s, 1H); 13C NMR (126
MHz, DMSO-d6): d ꢂ1.14, 17.58, 66.29, 73.91, 128.09,
129.65, 129.87, 130.07, 130.94, 131.34, 133.31, 134.36,
134.40, 134.44, 135.38, 136.93, 138.44, 141.74, 143.94,
182.88 ppm; HRMS: m/z calcd. for C22H24N2O2SiSCl:
443.1016 [MþH]þ, found 443.1002.
2.83 (m, 2H), 4.29 (d, J ¼ 13.12 Hz, 1H), 4.42–4.54 (m, 2H),
4.62–4.71 (m, 1H), 5.59 (br. s., 1H), 6.97–7.03 (m, 2H), 7.13–
7.23 (m, 3H), 7.32–7.53 (m, 4H), 7.58 (dd, J ¼ 7.78, 1.37 Hz,
1H), 7.66–7.78 ppm (m, J ¼ 16.25, 16.25, 7.63, 1.37 Hz, 3H);
13C NMR (126 MHz, DMSO-d6): d 36.24, 46.31, 56.46,
126.89, 127.80, 128.21, 128.75, 128.97, 129.12, 129.30,
129.37, 130.79, 132.50, 133.03, 133.91, 134.62, 138.08,
138.21, 140.51, 149.91 ppm; HRMS: m/z calcd. for
C24H21N2OS: 385.1375 [MþH]þ, found 385.1375.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,
and Anti-Inflammatory Evaluation
651
3203, 3066, 2953, 2895, 1496, 1446, 1249, 1216, 10991, 1081,
1
[1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]ox-
epino[4,5-d]imidazol-2-yl]methanol (8e). Obtained from 7e as a
white solid: Yield 99%; mp 147.68ꢁC; IR (ATR): 3189, 2951,
856, 835, 771, 742 cmꢂ1; H NMR (500 MHz, DMSO-d6): d
0.00 (s, 9H), 0.91–0.98 (m, 2H), 3.67–3.73 (m, 2H), 4.76 (d, J
¼ 5.80 Hz, 2H), 5.64 (s, 2H), 5.72 (t, J ¼ 5.80 Hz, 1H), 7.35–
7.41 (m, 1H), 7.44–7.56 (m, 4H), 7.71 (dd, J ¼ 1.98, 0.76 Hz,
1H), 7.86 ppm (dd, J ¼ 7.78, 1.37 Hz, 1H); 13C NMR (126
MHz, DMSO-d6): d ꢂ1.07, 17.67, 56.45, 66.03, 73.24, 122.69,
122.94, 123.42, 125.93, 126.30, 127.23, 128.76, 129.00,
129.59, 129.91, 130.34, 134.79, 151.49, 154.69, 155.87 ppm;
HRMS: m/z calcd. for C22H26ClN2O3Si: 429.1401 [MþH]þ,
found 429.1395.
2893, 1450, 1210, 1080, 835, 765, 743 cmꢂ1 1H NMR (500
;
MHz, DMSO-d6): d 0.00 (s, 9H), 0.92–0.98 (m, 2H), 3.67–
3.73 (m, 2H), 4.76 (d, J ¼ 5.80 Hz, 2H), 5.63 (s, 2H), 5.69 (t,
J ¼ 5.80 Hz, 1H), 7.28–7.37 (m, 2H), 7.38–7.44 (m, 2H),
7.45–7.54 (m, 2H), 7.75–7.81 (m, 1H), 7.84 ppm (dd, J ¼
7.93, 1.53 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d
ꢂ1.06, 17.68, 56.48, 65.96, 73.15, 121.47, 122.65, 123.30,
125.80, 125.98, 126.82, 127.10, 127.78, 128.06, 129.45,
130.00, 136.08, 151.14, 156.21 ppm; HRMS: m/z calcd. for
C22H26N2O3SiNa: 417.1610 [MþNa]þ, found 417.1591.
[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methanol (8j). Obtained
from 7j as a white amorphous solid: Yield 99%; IR (ATR):
3184, 3059, 2951, 1582, 1483, 1247, 1080, 1036, 834, 766,
[1-({[2-(Trimethylsilyl)ethyl]oxy}methyl)-1H-dibenzo[2,3:6,7]-
thiepino[4,5-d]imidazol-2-yl]methanol (8f). Obtained from 7f
as a white amorphous solid: Yield 98%; IR (ATR): 3195,
749 cmꢂ1 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H),
;
3051, 2952, 1487, 1249, 1082, 1033, 858, 835, 760, 740 cmꢂ1
;
0.82–0.93 (m, 2H), 3.43–3.54 (m, 1H), 3.54–3.66 (m, 1H),
4.82 (dd, J ¼ 5.65, 2.29 Hz, 2H), 5.59–5.66 (m, 1H), 5.66–
5.74 (m, 1H), 5.77 (t, J ¼ 5.65 Hz, 1H), 7.52 (dd, J ¼ 8.24,
2.44 Hz, 1H), 7.54–7.62 (m, 2H), 7.69 (d, J ¼ 8.24 Hz, 1H),
7.75–7.82 (m, 2H), 7.83 ppm (d, J ¼ 2.44 Hz, 1H); 13C NMR
(126 MHz, DMSO-d6): d ꢂ1.13, 17.57, 56.53, 65.82, 73.23,
127.52, 128.68, 128.87, 129.61, 129.94, 132.26, 132.46,
132.58, 133.90, 133.95, 134.03, 134.17, 138.65, 139.60,
150.75 ppm; HRMS: m/z calcd. for C22H26ClN2O2SSi:
445.1173 [MþH]þ, found 445.1164.
1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.84–0.91 (m,
2H), 3.40–3.47 (m, 1H), 3.59–3.66 (m, 1H), 4.78–4.86 (m,
2H), 5.58–5.65 (m, 1H), 5.65–5.72 (m, 1H), 5.75 (t, J ¼ 5.65
Hz, 1H), 7.43–7.48 (m, 1H), 7.50–7.60 (m, 3H), 7.67 (dd, J ¼
7.63, 1.22 Hz, 1H), 7.74 (dd, J ¼ 7.48, 1.68 Hz, 1H), 7.80
(dd, J ¼ 7.63, 1.53 Hz, 1H), 7.88 ppm (dd, J ¼ 7.63, 1.53 Hz,
1H); 13C NMR (126 MHz, DMSO-d6): d ꢂ1.12, 17.58, 56.58,
65.75, 73.13, 128.32, 128.75, 129.01, 129.20, 129.32, 129.60,
131.90, 132.54, 132.69, 133.58, 133.90, 134.58, 137.86,
139.89, 150.40 ppm; HRMS: m/z calcd. for C22H27N2O2SSi:
411.1563 [MþH]þ, found 411.1548.
General procedure for preparation of compounds 9. To a
40% aq sodium hydroxide (1.66 mL) solution of 8 (60 mg,
0.216 mmol) in toluene (2.8 mL), appropriate x-chloroalkyl-
dimethylamine (0.862 mmol), and a catalytic amount of ben-
zyltriethylammonium chloride were added. Reaction mixture
was heated at reflux until TLC indicated the reaction was com-
plete, and then cooled to room temperature, diluted with water
(30 mL), and extracted with ethyl acetate (3 ꢄ 15 mL). The
organic extract was washed with brine (30 mL), dried over an-
hydrous sodium sulfate, and evaporated. After purification on
silica gel SPE cartridge using step gradient system for elution
n-hexane/(ethyl acetate/n-hexane/diethylamine 10:10:1.5) com-
pound 9 was isolated.
[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methanol (8g). Obtained
from 7g as a white amorphous solid: Yield 100%; IR (ATR):
3179, 2951, 1491, 1446, 1248, 1211, 1076, 1031, 828, 773,
741 cmꢂ1 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H),
;
0.93–1.02 (m, 2H), 3.69–3.77 (m, 2H), 4.73 (d, J ¼ 5.80 Hz,
2H), 5.58 (s, 2H), 5.69 (t, J ¼ 5.65 Hz, 1H), 7.26–7.34 (m,
1H), 7.37–7.44 (m, 2H), 7.47–7.55 (m, 2H), 7.72–7.78 (m,
1H), 7.91 ppm (d, J ¼ 2.44 Hz, 1H); 13C NMR (126 MHz,
DMSO-d6): d ꢂ1.02, 17.80, 56.36, 65.93, 73.08, 121.47,
124.35, 125.08, 126.08, 126.42, 126.81, 126.94, 127.43,
129.51, 129.79, 130.19, 136.90, 151.50, 154.65, 155.95 ppm;
HRMS: m/z calcd. for C22H26ClN2O3Si: 429.1401 [MþH]þ,
found 429.1398.
Dimethyl(2-{[(1-methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imi-
dazol-2-yl)methyl]oxy}ethyl)amine (9a). Obtained from 8a as a
yellowish amorphous solid: Yield 59%; IR (ATR): 3059, 2939,
2859, 2820, 2770, 1516, 1496, 1456, 1444, 1207, 1106, 1090,
[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methanol (8h). Obtained
from 7h as a white amorphous solid: Yield 99%; IR (ATR):
3191, 3070, 2952, 2923, 2889, 1581, 1480, 1366, 1249, 1078,
1
1029, 762, 742 cmꢂ1; H NMR (500 MHz, DMSO-d6): d 2.15
(s, 6H), 2.45 (t, J ¼ 5.95 Hz, 2H), 3.61 (t, J ¼ 5.95 Hz, 2H),
3.87 (s, 3H), 4.69 (s, 2H), 7.22–7.28 (m, 1H), 7.30–7.39 (m,
3H), 7.41–7.50 (m, 2H), 7.63 (dd, J ¼ 7.78, 1.68 Hz, 1H),
7.70–7.75 ppm (m, 1H); 13C NMR (126 MHz, DMSO-d6): d
32.77, 45.86, 58.61, 64.80, 68.31, 121.48, 122.67, 123.22,
125.81, 125.91, 126.67, 126.86, 127.89, 128.30, 129.26,
129.80, 135.88, 147.59, 155.92, 156.06 ppm; HRMS: m/z
calcd. for C21H24N3O2: 350.1869 [MþH]þ, found 350.1854.
Dimethyl(3-{[(1-methyl-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imi-
dazol-2-yl)methyl]oxy}propyl)amine (9b). Obtained from 8a as a
yellowish amorphous solid: Yield 80%; IR (ATR): 3062, 2944,
2859, 2817, 2768, 1517, 1497, 1458, 1444, 1207, 1089, 798,
763, 743 cmꢂ1; 1H NMR (500 MHz, DMSO-d6): d 1.68 (quin, J
¼ 6.79 Hz, 2H), 2.10 (s, 6H), 2.26 (t, J ¼ 7.17 Hz, 2H), 3.55 (t,
J ¼ 6.41 Hz, 2H), 3.87 (s, 3H), 4.66 (s, 2H), 7.22–7.28 (m, 1H),
7.30–7.50 (m, 5H), 7.64 (dd, J ¼ 7.93, 1.53 Hz, 1H), 7.68–7.75
ppm (m, 1H); 13C NMR (126 MHz, DMSO-d6): d 27.65, 32.75,
1
1030, 858, 835, 769, 736 cmꢂ1; H NMR (500 MHz, DMSO-
d6): d 0.00 (s, 9H), 0.90–0.97 (m, 2H), 3.53 (td, J ¼ 9.00,
7.93 Hz, 1H), 3.60–3.72 (m, 1H), 4.77 (d, J ¼ 5.80 Hz, 2H),
5.44 (d, J ¼ 10.99 Hz, 1H), 5.66 (d, J ¼ 10.99 Hz, 1H), 5.72
(t, J ¼ 5.65 Hz, 1H), 7.41–7.52 (m, 2H), 7.55 (dd, J ¼ 8.39,
2.29 Hz, 1H), 7.63 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.75 (d, J ¼
8.24 Hz, 1H), 7.81–7.87 ppm (m, 2H); 13C NMR (126 MHz,
DMSO-d6): d ꢂ1.07, 17.79, 56.42, 65.72, 73.11, 127.97,
128.46, 129.28, 129.32, 129.42, 130.50, 132.58, 133.09,
134.19, 134.43, 135.37, 137.65, 140.63, 150.67 ppm; HRMS:
m/z calcd. for C22H26ClN2O2SSi: 445.1173 [MþH]þ, found
445.1157.
[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methanol (8i). Obtained
from 7i as a white amorphous solid: Yield 93%; IR (ATR):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ
R. Rupcic, M. Modric, A. Hutinec, A. Cikos, B. Stanic, M. Mesic, D. Pesic, and M. Mercep
ˇ ´
´
ˇ
´
´
ˇ ´
´
652
Vol 47
45.54, 56.30, 64.85, 68.58, 121.48, 122.66, 123.22, 125.80,
125.91, 126.67, 126.88, 127.88, 128.30, 129.26, 129.80, 135.87,
147.64, 155.93, 156.06 ppm; HRMS: m/z calcd. for
C22H26N3O2: 364.2025 [MþH]þ, found 364.2014.
2939, 2859, 2818, 2768, 1485, 1454, 1422, 1109, 1057, 1032,
758, 741, 698 cmꢂ1; 1H NMR (500 MHz, DMSO-d6): d 2.15 (s,
6H), 2.45 (t, J ¼ 5.80 Hz, 2H), 2.68–2.83 (m, 2H), 3.53–3.64
(m, 2H), 4.34 (d, J ¼ 12.51 Hz, 1H), 4.37–4.46 (m, 1H), 4.54 (d,
J ¼ 12.21 Hz, 1H), 4.66 (ddd, J ¼ 14.19, 8.24, 5.34 Hz, 1H),
6.98–7.03 (m, 2H), 7.14–7.23 (m, 3H), 7.33–7.53 (m, 4H), 7.59
(dd, J ¼ 7.78, 1.37 Hz, 1H), 7.67–7.78 ppm (m, 3H); 13C NMR
(126 MHz, DMSO-d6): d 36.17, 45.88, 46.33, 58.68, 64.84,
68.30, 126.92, 127.93, 128.30, 128.77, 128.84, 128.96, 129.15,
129.39, 129.42, 131.10, 132.51, 132.86, 133.93, 134.03, 134.80,
138.00, 138.05, 140.73, 146.74 ppm; HRMS: m/z calcd. for
C28H30N3OS: 456.2110 [MþH]þ, found 456.2095.
Dimethyl(2-{[(1-methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imi-
dazol-2-yl)methyl]oxy}ethyl)amine (9c). Obtained from 8b as a
yellowish amorphous solid: Yield 62%; IR (ATR): 3051, 2940,
1
2859, 2819, 2770, 1487, 1452, 1103, 1031, 759, 741 cmꢂ1; H
NMR (500 MHz, DMSO-d6): d 2.16 (s, 6H), 2.46 (t, J ¼ 5.80
Hz, 2H), 3.58–3.69 (m, 2H), 3.79 (d, J ¼ 0.92 Hz, 3H), 4.68–
4.75 (m, 2H), 7.32–7.52 (m, 4H), 7.55–7.61 (m, 2H), 7.69–7.74
(m, 1H), 7.74–7.81 ppm (m, 1H); 13C NMR (126 MHz, DMSO-
d6): d 32.69, 45.88, 58.65, 64.96, 68.40, 128.19, 128.57, 128.79,
129.15, 129.20, 129.39, 131.96, 132.52, 132.55, 133.34, 133.93,
134.22, 138.10, 139.79, 146.71 ppm; HRMS: m/z calcd. for
C21H24N3OS: 366.1640 [MþH]þ, found 366.1628.
Dimethyl[3-({[1-(2-phenylethyl)-1H-dibenzo[2,3:6,7]thie-
pino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]amine (9h). Obtained
from 8d as a yellowish amorphous solid: Yield 65%; IR (ATR):
3055, 3025, 2941, 2857, 2815, 2765, 1485, 1455, 1432, 1089,
1078, 758, 741, 698 cmꢂ1; 1H NMR (500 MHz, DMSO-d6): d 1.68
(quin, J ¼ 6.79 Hz, 2H), 2.09 (s, 6H), 2.21–2.32 (m, 2H), 2.68–
2.84 (m, 2H), 3.46–3.59 (m, 2H), 4.29 (d, J ¼ 12.51 Hz, 1H), 4.39
(ddd, J ¼ 14.88, 7.78, 7.55 Hz, 1H), 4.53 (d, J ¼ 12.21 Hz, 1H),
4.62–4.71 (m, 1H), 6.98–7.02 (m, 2H), 7.14–7.22 (m, 3H), 7.33–
7.38 (m, 1H), 7.40–7.47 (m, 2H), 7.50 (td, J ¼ 7.55, 1.37 Hz, 1H),
7.59 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.67–7.77 ppm (m, 3H); 13C
NMR (126 MHz, DMSO-d6): d 27.67, 36.21, 45.52, 46.33, 56.34,
64.92, 68.74, 126.94, 127.94, 128.30, 128.79, 128.85, 128.93,
129.14, 129.37, 129.42, 131.12, 132.51, 132.84, 133.93, 134.03,
134.79, 137.96, 138.02, 140.69, 146.78 ppm; HRMS: m/z calcd. for
C29H32N3OS: 470.2266 [MþH]þ, found 470.2253.
Dimethyl(3-{[(1-methyl-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imi-
dazol-2-yl)methyl]oxy}propyl)amine (9d). Obtained from 8b as a
yellowish amorphous solid: Yield 80%; IR (ATR): 3051, 2943,
1
2857, 2816, 2766, 1487, 1453, 1092, 1030, 759, 741 cmꢂ1; H
NMR (500 MHz, DMSO-d6): d 1.70 (quin, J ¼ 6.82 Hz, 2H),
2.11 (s, 6 H), 2.27 (t, J ¼ 7.32 Hz, 2H), 3.53–3.62 (m, 2H), 3.79
(s, 3H), 4.65–4.72 (m, 2H), 7.32–7.52 (m, 4H), 7.59 (ddd, J ¼
10.83, 7.63, 1.37 Hz, 2H), 7.71 (dd, J ¼ 7.63, 1.53 Hz, 1H), 7.78
ppm (dd, J ¼ 7.63, 1.53 Hz, 1H); 13C NMR (126 MHz, DMSO-
d6): d 27.68, 32.69, 45.57, 56.32, 65.01, 68.70, 128.18, 128.59,
128.80, 129.14, 129.19, 129.39, 131.96, 132.52, 132.55, 133.33,
133.92, 134.20, 138.09, 139.76, 146.76 ppm; HRMS: m/z calcd.
for C22H25N3OSNa: 402.1616 [MþNa]þ, found 402.1610.
Dimethyl[2-({[1-(2-phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-
d]imidazol-2-yl]methyl}oxy)ethyl]amine (9e). Obtained from 8c
as a yellowish amorphous solid: Yield 72%; IR (ATR): 3062,
3025, 2939, 2860, 2819, 2769, 1513, 1495, 1450, 1207, 1095,
Dimethyl[2-({[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]amine
(9i). Obtained from 8e as a yellowish amorphous solid: Yield
74%; IR (ATR): 2949, 2893, 2851, 2819, 2769, 1450, 1248,
1210, 1077, 856, 834, 763, 743 cmꢂ1 1H NMR (500 MHz,
;
1
1037, 760, 743, 699 cmꢂ1; H NMR (500 MHz, DMSO-d6): d
DMSO-d6): d ꢂ0.01 (br. s., 9H), 0.94 (t, J ¼ 7.93 Hz, 2H),
2.20 (s, 6H), 2.49 (t, J ¼ 5.95 Hz, 2H), 3.63–3.73 (m, 4H),
4.77 (s, 2H), 5.59 (s, 2H), 7.27–7.38 (m, 2H), 7.38–7.45 (m,
2H), 7.45–7.55 (m, 2H), 7.73–7.80 (m, 1H), 7.81–7.88 ppm
(m, 1H); 13C NMR (126 MHz, DMSO-d6): d ꢂ1.04, 17.74,
45.90, 58.62, 64.74, 65.99, 68.42, 73.32, 121.48, 122.68,
122.71, 123.15, 125.85, 126.02, 126.90, 127.20, 127.62,
128.37, 129.59, 130.17, 136.32, 147.98, 156.27 ppm; HRMS:
m/z calcd. for C26H36N3O3Si: 466.2526 [MþH]þ, found
466.2529.
2.15 (s, 6H), 2.45 (t, J ¼ 5.80 Hz, 2H), 2.94 (t, J ¼ 7.63 Hz,
2H), 3.59 (t, J ¼ 5.80 Hz, 2H), 4.53 (s, 2H), 4.57 (t, J ¼ 7.48
Hz, 2H), 7.08–7.13 (m, 2H), 7.17–7.28 (m, 4H), 7.32–7.40 (m,
3H), 7.42–7.50 (m, 2H), 7.69–7.77 ppm (m, 2H); 13C NMR
(126 MHz, DMSO-d6): d 36.20, 45.87, 46.44, 58.67, 64.82,
68.27, 121.40, 122.75, 123.49, 125.79, 126.09, 126.16, 126.86,
127.01, 127.34, 127.87, 128.84, 128.94, 129.38, 129.91,
136.73, 138.02, 147.68, 156.11, 156.41 ppm; HRMS: m/z
calcd. for C28H30N3O2: 440.2338 [MþH]þ, found 440.2325.
Dimethyl[3-({[1-(2-phenylethyl)-1H-dibenzo[2,3:6,7]oxepino[4,5-
d]imidazol-2-yl]methyl}oxy)propyl]amine (9f). Obtained from 8c
as a yellowish amorphous solid: Yield 52%; IR (ATR): 3059,
3025, 2942, 2859, 2816, 2766, 1513, 1495, 1450, 1207, 1092,
Dimethyl[3-({[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]amine
(9j). Obtained from 8e as a yellowish amorphous solid: Yield
83%; IR (ATR): 2949, 2855, 2815, 2765, 1450, 1210, 1075,
761, 743, 699 cmꢂ1
;
1H NMR (500 MHz, DMSO-d6): d 1.68
857, 833, 764, 743 cmꢂ1; H NMR (500 MHz, DMSO-d6): d
1
(quin, J ¼ 6.72 Hz, 2H), 2.07 (s, 6H), 2.25 (t, J ¼ 7.17 Hz,
2H), 2.94 (t, J ¼ 7.63 Hz, 2H), 3.53 (t, J ¼ 6.41 Hz, 2H),
4.50 (s, 2H), 4.57 (t, J ¼ 7.48 Hz, 2H), 7.08–7.12 (m, 2H),
7.18–7.28 (m, 4H), 7.32–7.40 (m, 3H), 7.42–7.50 (m, 2H),
7.69–7.76 ppm (m, 2H); 13C NMR (126 MHz, DMSO-d6): d
27.69, 36.23, 45.51, 46.43, 56.34, 64.90, 68.69, 121.40,
122.75, 123.48, 125.78, 126.08, 126.17, 126.86, 127.04,
127.36, 127.86, 128.85, 128.91, 129.38, 129.91, 136.70,
137.98, 147.70, 156.12, 156.41 ppm; HRMS: m/z calcd. for
C29H32N3O2: 454.2495 [MþH]þ, found 454.2498.
0.00 (s, 9H), 0.91–0.99 (m, 2H), 1.72 (quin, J ¼ 6.82 Hz, 2H),
2.14 (s, 6H), 2.29 (t, J ¼ 7.17 Hz, 2H), 3.60 (t, J ¼ 6.41 Hz,
2H), 3.66–3.73 (m, 2H), 4.73 (s, 2H), 5.58 (s, 2H), 7.27–7.38
(m, 2H), 7.38–7.44 (m, 2H), 7.45–7.54 (m, 2H), 7.74–7.79 (m,
1H), 7.84 ppm (dd, J ¼ 7.93, 1.22 Hz, 1H); 13C NMR (126
MHz, DMSO-d6): d ꢂ1.07, 17.74, 27.66, 45.55, 56.31, 64.84,
66.02, 68.80, 73.30, 121.48, 122.68, 123.15, 125.83, 126.01,
126.90, 127.19, 127.62, 128.39, 129.58, 130.17, 136.29,
148.01, 156.27 ppm; HRMS: m/z calcd. for C27H38N3O3Si:
480.2682 [MþH]þ, found 480.2692.
Dimethyl[2-({[1-(2-phenylethyl)-1H-dibenzo[2,3:6,7]thiepino[4,5-
d]imidazol-2-yl]methyl}oxy)ethyl]amine (9g). Obtained from 8d
as a yellowish amorphous solid: Yield 44%; IR (ATR): 3055,
Dimethyl[2-({[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]amine
(9k). Obtained from 8f as a yellowish amorphous solid: Yield
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,
and Anti-Inflammatory Evaluation
653
61%; IR (ATR): 2949, 2897, 2863, 2818, 2768, 1485, 1461,
1
[2-({[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-
dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]di-
methylamine (9o). Obtained from 8h as a yellowish amorphous
solid: Yield 62%; IR (ATR): 2949, 2893, 2863, 2863, 2768,
1580, 1479, 1460, 1364, 1248, 1101, 1076, 1030, 833, 769,
1365, 1248, 1077, 1037, 833, 759 cmꢂ1; H NMR (500 MHz,
DMSO-d6): d 0.00 (s, 9H), 0.84–0.91 (m, 2H), 2.25 (s, 6H),
2.55 (t, J ¼ 5.95 Hz, 2H), 3.38–3.48 (m, 1H), 3.58–3.66 (m,
1H), 3.69–3.78 (m, 2H), 4.78–4.87 (m, 2H), 5.55 (d, J ¼
10.99 Hz, 1H), 5.67 (d, J ¼ 10.99 Hz, 1H), 7.42–7.48 (m,
1H), 7.49–7.59 (m, 3H), 7.67 (d, J ¼ 7.63 Hz, 1H), 7.73–7.82
(m, 2H), 7.87 ppm (dd, J ¼ 7.78, 1.37 Hz, 1H); 13C NMR
(126 MHz, DMSO-d6): d ꢂ1.12, 17.63, 45.91, 58.64, 64.88,
65.77, 68.55, 73.31, 128.39, 128.83, 129.09, 129.22, 129.34,
129.71, 132.14, 132.54, 132.56, 133.71, 133.93, 134.67,
137.72, 140.13, 147.25 ppm; HRMS: m/z calcd. for
C26H36N3O2SSi: 482.2298 [MþH]þ, found 482.2314.
744 cmꢂ1 1H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H),
;
0.88–0.96 (m, 2H), 2.21 (s, 6H), 2.50 (t, J ¼ 5.80 Hz, 2H),
3.52 (td, J ¼ 9.16, 7.93 Hz, 1H), 3.62–3.74 (m, 3H), 4.78 (s,
2H), 5.41 (d, J ¼ 10.99 Hz, 1H), 5.63 (d, J ¼ 10.68 Hz, 1H),
7.41–7.53 (m, 2H), 7.56 (dd, J ¼ 8.39, 2.29 Hz, 1H), 7.63 (dd,
J ¼ 7.63, 1.22 Hz, 1H), 7.76 (d, J ¼ 8.54 Hz, 1H), 7.83 (dd, J
¼ 7.63, 1.53 Hz, 1H), 7.87 ppm (d, J ¼ 2.14 Hz, 1H); 13C
NMR (126 MHz, DMSO-d6): d ꢂ1.07, 17.82, 45.90, 58.62,
64.68, 65.71, 68.55, 73.28, 128.07, 128.53, 129.41, 129.46,
130.77, 132.59, 133.19, 133.23, 134.21, 134.30, 135.39,
137.49, 140.83, 147.58 ppm; HRMS: m/z calcd. for
C26H35ClN3O2SSi: 516.1908 [MþH]þ, found 516.1909.
Dimethyl[3-({[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]amine
(9l). Obtained from 8f as a yellowish amorphous solid: Yield
82%; IR (ATR): 2949, 2859, 2815, 2764, 1485, 1461, 1248,
1
1076, 833, 759, 694 cmꢂ1; H NMR (500 MHz, DMSO-d6): d
[3-({[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-
dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)pro-
pyl]dimethylamine (9p). Obtained from 8h as a yellowish
amorphous solid: Yield 77%; IR (ATR): 2949, 2859, 2815,
2765, 1581, 1461, 1365, 1248, 1075, 1029, 857, 833, 769, 744
0.00 (s, 9H), 1.78 (quin, J ¼ 6.79 Hz, 2H), 2.19 (s, 6H), 2.31–
2.40 (m, 2H), 3.37–3.49 (m, 1H), 3.58–3.71 (m, 3H), 4.74–
4.84 (m, 2H), 5.53 (d, J ¼ 11.29 Hz, 1H), 5.66 (d, J ¼ 11.29
Hz, 1H), 7.42–7.49 (m, 1H), 7.49–7.60 (m, 3H), 7.67 (dd, J ¼
7.63, 1.22 Hz, 1H), 7.78 (ddd, J ¼ 18.16, 7.48, 1.53 Hz, 2H),
7.87 ppm (dd, J ¼ 7.78, 1.37 Hz, 1H); 13C NMR (126 MHz,
DMSO-d6): d ꢂ1.14, 17.64, 27.68, 45.57, 56.32, 64.96, 65.80,
68.92, 73.31, 128.40, 128.84, 129.09, 129.22, 129.33, 129.72,
132.15, 132.54, 132.56, 133.70, 133.93, 134.66, 137.70,
140.09, 147.30 ppm; HRMS: m/z calcd. for C27H38N3O2SSi:
482.2298 [MþH]þ, found 482.2314.
1
cmꢂ1; H NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.89–
0.98 (m, 2H), 1.74 (quin, J ¼ 6.79 Hz, 2H), 2.15 (s, 6H),
2.26–2.37 (m, 2H), 3.47–3.56 (m, 1H), 3.58–3.72 (m, 3H),
4.71–4.80 (m, 2H), 5.41 (d, J ¼ 10.99 Hz, 1H), 5.62 (d, J ¼
10.99 Hz, 1H), 7.41–7.53 (m, 2H), 7.56 (dd, J ¼ 8.24, 2.14
Hz, 1H), 7.63 (dd, J ¼ 7.63, 1.22 Hz, 1H), 7.76 (d, J ¼ 8.24
Hz, 1H), 7.83 (dd, J ¼ 7.63, 1.53 Hz, 1H), 7.87 ppm (d, J ¼
2.44 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d ꢂ1.09,
17.82, 27.66, 45.56, 56.30, 64.78, 65.74, 68.91, 73.29, 128.07,
128.53, 129.41, 129.46, 130.79, 132.60, 133.19, 133.22,
134.21, 134.30, 135.39, 137.48, 137.50, 140.80, 147.64 ppm;
HRMS: m/z calcd. for C27H37ClN3O2SSi: 530.2064 [MþH]þ,
found 530.2061.
[2-({[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]dime-
thylamine (9m). Obtained from 8g as a yellowish amorphous
solid: Yield 72%; IR (ATR): 2949, 2893, 2859, 2819, 2769,
1
1491, 1446, 1248, 1211, 1075, 830, 773, 742 cmꢂ1; H NMR
(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.94–1.00 (m, 2H),
2.19 (s, 6H), 2.48 (t, J ¼ 5.80 Hz, 2H), 3.65 (t, J ¼ 5.80 Hz,
2H), 3.68–3.76 (m, 2H), 4.75 (s, 2H), 5.55 (s, 2H), 7.27–7.34
(m, 1H), 7.41 (d, J ¼ 3.66 Hz, 2H), 7.49–7.55 (m, 2H), 7.75
(dd, J ¼ 7.02, 0.61 Hz, 1H), 7.92 ppm (d, J ¼ 2.14 Hz, 1H);
13C NMR (126 MHz, DMSO-d6): d ꢂ1.02, 17.87, 45.83,
58.55, 64.58, 65.93, 68.35, 73.24, 121.48, 124.38, 124.93,
126.11, 126.52, 127.01, 127.14, 127.27, 129.68, 129.91,
130.20, 137.12, 148.37, 154.71, 156.01 ppm; HRMS: m/z
calcd. for C26H35ClN3O3Si: 500.2136 [MþH]þ, found
500.2136.
[2-({[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]dime-
thylamine (9r). Obtained from 8i as a yellowish amorphous
solid: Yield 74%; IR (ATR): 2949, 2893, 2859, 2814, 2765,
1495, 1445, 1213, 1098, 1075, 853, 828, 769, 745 cmꢂ1 1H
;
NMR (500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.91–0.98 (m, 2H),
2.20 (s, 6H), 2.50 (t, J ¼ 5.80 Hz, 2H), 3.63–3.74 (m, 4H), 4.77
(s, 2H), 5.61 (s, 2H), 7.34–7.41 (m, 1H), 7.44–7.57 (m, 4H),
7.70–7.73 (m, 1H), 7.87 ppm (dd, J ¼ 7.78, 1.37 Hz, 1H); 13C
NMR (126 MHz, DMSO-d6): d ꢂ1.07, 17.72, 45.89, 58.61,
64.67, 66.06, 68.45, 73.42, 122.72, 122.80, 123.43, 126.01,
126.32, 127.32, 129.07, 129.12, 129.43, 129.95, 130.49, 135.03,
148.33, 154.76, 155.94 ppm; HRMS: m/z calcd. for
C26H35ClN3O3Si: 500.2136 [MþH]þ, found 500.2135.
[3-({[11-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-
dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]di-
methylamine (9n). Obtained from 8g as a yellowish amorphous
solid: Yield 85%; IR (ATR): 2950, 2860, 2816, 2765, 1492,
1446, 1249, 1212, 1074, 857, 831, 772, 742 cmꢂ1 1H NMR
;
[3-({[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-diben-
zo[2,3:6,7]oxepino[4,5-d]imidazol-2-yl]methyl}oxy)propyl]dime-
thylamine (9s). Obtained from 8i as a yellowish amorphous
solid: Yield 81%; IR (ATR): 2949, 2855, 2816, 2765, 1495,
(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.94–1.00 (m, 2H),
1.70 (quin, J ¼ 6.79 Hz, 2H), 2.12 (s, 6H), 2.27 (t, J ¼ 7.17
Hz, 2H), 3.57 (t, J ¼ 6.41 Hz, 2H), 3.68–3.75 (m, 2H), 4.71
(s, 2H), 5.53 (s, 2H), 7.28–7.33 (m, 1H), 7.41 (d, J ¼ 3.66 Hz,
2H), 7.49–7.55 (m, 2H), 7.74–7.77 (m, 1H), 7.92 ppm (d, J ¼
2.14 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d ꢂ1.04,
17.86, 27.62, 45.52, 56.28, 64.69, 65.96, 68.81, 73.23, 121.49,
124.38, 124.92, 126.11, 126.50, 127.02, 127.15, 127.25,
129.68, 129.91, 130.20, 137.08, 148.43, 154.71, 156.01 ppm;
HRMS: m/z calcd. for C27H37ClN3O3Si: 514.2293 [MþH]þ,
found 514.2288.
1
1478, 1445, 1247, 1213, 1074, 854, 828, 769 cmꢂ1; H NMR
(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.91–0.98 (m, 2H),
1.73 (quin, J ¼ 6.82 Hz, 2H), 2.14 (s, 6 H), 2.30 (t, J ¼ 7.17
Hz, 2H), 3.60 (t, J ¼ 6.41 Hz, 2H), 3.67–3.73 (m, 2H), 4.74
(s, 2H), 5.59 (s, 2H), 7.38 (ddd, J ¼ 7.78, 7.02, 1.37 Hz, 1H),
7.44–7.57 (m, 4H), 7.71 (t, J ¼ 0.92 Hz, 1H), 7.86 ppm (dd, J
¼ 7.78, 1.37 Hz, 1H); 13C NMR (126 MHz, DMSO-d6): d
ꢂ1.08, 17.72, 27.65, 45.54, 56.30, 64.74, 66.09, 68.83, 73.40,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ
R. Rupcic, M. Modric, A. Hutinec, A. Cikos, B. Stanic, M. Mesic, D. Pesic, and M. Mercep
ˇ ´
´
ˇ
´
´
ˇ ´
´
654
Vol 47
122.72, 122.79, 123.43, 126.01, 126.32, 127.32, 129.08,
129.13, 129.42, 129.95, 130.51, 135.00, 148.38, 154.75,
155.94 ppm; HRMS: m/z calcd. for C27H37ClN3O3Si:
514.2293 [MþH]þ, found 514.2296.
2860, 2824, 2776, 1501, 1453, 1216, 1096, 1031, 760, 742 cmꢂ1
;
1H NMR (500 MHz, DMSO-d6): d 1.69 (quin, J ¼ 6.82 Hz, 2H),
2.11 (s, 6H), 2.27 (t, J ¼ 7.17 Hz, 2H), 3.55 (t, J ¼ 6.56 Hz, 2H),
4.56 (s, 2H), 7.21–7.29 (m, 2H), 7.30–7.39 (m, 4H), 7.65 (d, J ¼
6.10 Hz, 2H), 12.91 ppm (br. s., 1H); 13C NMR (126 MHz,
DMSO-d6): d 27.66, 45.51, 56.34, 65.61, 68.70, 122.00, 125.75,
126.11, 129.31, 147.34, 154.62 ppm; HRMS: m/z calcd. for
C21H24N3O2: 350.1869 [MþH]þ, found 350.1854.
[2-({[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-
dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)ethyl]di-
methylamine (9t). Obtained from 8j as a yellowish amorphous
solid: Yield 82%; IR (ATR): 2949, 2889, 2859, 2765, 1582,
1482, 1456, 1248, 1078, 1038, 834, 765, 748 cmꢂ1
;
1H NMR
{2-[(1H-Dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-ylmethy-
l)oxy]ethyl}dimethylamine (10c). Obtained from 9k as a yel-
lowish amorphous solid: Yield 90%; IR (ATR): 3044, 2944,
(500 MHz, DMSO-d6): d 0.00 (s, 9H), 0.84–0.92 (m, 2H), 2.26
(s, 6H), 2.56 (t, J ¼ 5.80 Hz, 2H), 3.40–3.48 (m, 1H), 3.58–3.66
(m, 1H), 3.69–3.78 (m, 2H), 4.78–4.88 (m, 2H), 5.57 (d, J ¼
11.29 Hz, 1H), 5.68 (d, J ¼ 10.99 Hz, 1H), 7.50–7.62 (m, 3H),
7.69 (d, J ¼ 8.24 Hz, 1H), 7.76–7.85 ppm (m, 3H); 13C NMR
(126 MHz, DMSO-d6): d ꢂ1.14, 17.60, 45.89, 58.62, 64.80,
65.84, 68.58, 73.42, 127.59, 128.78, 128.96, 129.63, 130.05,
132.33, 132.39, 132.81, 134.00, 134.02, 134.06, 134.19, 138.87,
139.44, 147.62 ppm; HRMS: m/z calcd. for C26H35ClN3O2SSi:
516.1908 [MþH]þ, found 516.1909.
2855, 2824, 2772, 1489, 1459, 1340, 1115, 1032, 757 cmꢂ1
;
1H NMR (500 MHz, DMSO-d6): d 2.18 (s, 6H), 2.49 (t, J ¼
6.10 Hz, 2H), 3.66 (t, J ¼ 5.80 Hz, 2H), 4.62 (s, 2H), 7.32–
7.47 (m, 4H), 7.58 (d, J ¼ 7.63 Hz, 2H), 7.67 (d, J ¼ 2.75
Hz, 2H), 13.02 ppm (br. s., 1H); 13C NMR (126 MHz,
DMSO-d6): d 45.81, 58.60, 65.64, 68.60, 127.69, 129.09,
129.20, 131.71, 132.87, 146.82 ppm; HRMS: m/z calcd. for
C20H22N3OS: 352.1484 [MþH]þ, found 352.1477.
[3-({[5-Chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-
dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-yl]methyl}oxy)pro-
pyl]dimethylamine (9v). Obtained from 8j as a yellowish oil:
Yield 87%; IR (ATR): 2949, 2859, 2815, 2765, 1582, 1460,
{3-[(1H-Dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-2-ylmethy-
l)oxy]propyl}dimethylamine (10d). Obtained from 9l as a yel-
lowish amorphous solid: Yield 86%; IR (ATR): 3051, 2944,
2860, 2820, 2772, 1489, 1461, 1355, 1093, 1032, 757 cmꢂ1
;
1
1248, 1077, 834, 766, 748 cmꢂ1; H NMR (500 MHz, DMSO-
1H NMR (500 MHz, DMSO-d6): d 1.70 (quin, J ¼ 6.82 Hz,
2H), 2.11 (s, 6H), 2.29 (t, J ¼ 7.32 Hz, 2H), 3.57 (t, J ¼ 6.41
Hz, 2H), 4.59 (s, 2H), 7.33–7.47 (m, 4H), 7.58 (d, J ¼ 7.63
Hz, 2H), 7.67 (br. s., 2H), 12.90 ppm (br. s., 1H); 13C NMR
(126 MHz, DMSO-d6): d 45.81, 58.60, 65.64, 68.60, 127.69,
129.09, 129.20, 131.71, 132.87, 146.82 ppm; HRMS: m/z
calcd. for C21H24N3OS: 366.1640 [MþH]þ, found 366.1646.
(2-{[(11-Chloro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-
2-yl)methyl]oxy}ethyl)dimethylamine (10e).. Obtained either
from 9m (yield 90%) or 9r (yield 83%) as a yellowish amor-
phous solid: IR (ATR): 3059, 2946, 2858, 2825, 2772, 1601,
d6): d 0.00 (s, 9H), 0.85–0.92 (m, 2H), 1.79 (quin, J ¼ 6.82
Hz, 2H), 2.20 (s, 6H), 2.37 (t, J ¼ 6.87 Hz, 2H), 3.57–3.73
(m, 4H), 4.74–4.85 (m, 2H), 5.55 (d, J ¼ 11.29 Hz, 1H), 5.67
(d, J ¼ 11.29 Hz, 1H), 7.50–7.62 (m, 3H), 7.69 (d, J ¼ 8.24
Hz, 1H), 7.76–7.85 ppm (m, 3H); 13C NMR (126 MHz,
DMSO-d6): d ꢂ1.14, 17.61, 27.63, 40.37, 45.54, 56.30, 64.85,
65.87, 68.93, 73.41, 127.59, 128.79, 128.97, 129.63, 130.07,
132.32, 132.38, 132.81, 134.00, 134.06, 134.19, 138.84,
139.43, 147.68 ppm; HRMS: m/z calcd. for C27H37ClN3O2SSi:
530.2064 [MþH]þ, found 530.2048.
General procedure for preparation of compounds 10. To
a solution of 9 (61.6 mg, 0.132 mmol) in methanol (3.4 mL),
0.5M hydrochloric acid in methanol (1.15 mL) was slowly
added. The reaction mixture was heated for 2 h at 60ꢁC, then
cooled to room temperature, and concentrated. Ethyl acetate (4
mL) and water were added (6 mL) and pH adjusted to 1.0 using
a 3M hydrochloric acid. The layers were separated and the aque-
ous layer washed with diethyl ether (2 ꢄ 10 mL). The pH of the
aqueous layer was adjusted to pH 9.5 with 5M sodium hydroxide
and extracted with ethyl acetate (3 ꢄ 10 mL). The combined or-
ganic extracts were washed with brine (15 mL) and dried over
anhydrous sodium sulfate. The drying agent was filtered off, and
solvent was removed in vacuo to give the crude product 10.
{2-[(1H-Dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-ylmethy-
l)oxy]ethyl}dimethylamine (10a). Obtained from 9i as a yel-
lowish amorphous solid: Yield 89%; IR (ATR): 3055, 2947,
2858, 2826, 2772, 1501, 1454, 1341, 1216, 1098, 1035, 743
1497, 1444, 1220, 1101, 836, 768, 742 cmꢂ1 1H NMR (500
;
MHz, DMSO-d6): d 2.18 (s, 6H), 2.48 (t, J ¼ 5.95 Hz, 2H),
3.63 (t, J ¼ 5.80 Hz, 2H), 4.60 (s, 2H), 7.25–7.32 (m, 1H),
7.34–7.41 (m, 4H), 7.61–7.68 (m, 2H), 13.00 ppm (br. s., 1H);
13C NMR (126 MHz, DMSO-d6): d 45.82, 58.58, 65.64, 68.54,
122.09, 123.83, 125.28, 126.07, 126.14, 128.68, 129.71,
129.84, 147.94, 153.09, 154.29 ppm; HRMS: m/z calcd. for
C20H21N3O2Cl: 370.1322 [MþH]þ, found 370.1335.
(3-{[(11-Chloro-1H-dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-
2-yl)methyl]oxy}propyl)dimethylamine (10f). Obtained either
from 9n (yield 89.0%) or 9s (yield 88.0%) as a yellowish
amorphous solid: IR (ATR): 3055, 2946, 2861, 2823, 2776,
1496, 1446, 1220, 1092, 835, 814, 767, 741 cmꢂ1 1H NMR
;
(500 MHz, DMSO-d6): d 1.69 (quin, J ¼ 6.82 Hz, 2H), 2.11
(s, 6H), 2.28 (t, J ¼ 7.32 Hz, 2H), 3.55 (t, J ¼ 6.56 Hz, 2H),
4.56 (s, 2H), 7.24–7.31 (m, 1H), 7.34–7.40 (m, 4H), 7.62–7.70
(m, 2H), 12.96 ppm (br. s., 1H); 13C NMR (126 MHz, DMSO-
d6): d 27.63, 45.50, 56.32, 65.57, 68.76, 122.08, 123.82,
125.33, 126.04, 126.21, 128.69, 129.71, 129.83, 147.87,
153.09, 154.29 ppm; HRMS: m/z calcd. for C21H23N3O2Cl:
384.1479 [MþH]þ, found 384.1471.
1
cmꢂ1; H NMR (500 MHz, DMSO-d6): d 2.17 (s, 6H), 2.48 (t,
J ¼ 5.95 Hz, 2H), 3.63 (t, J ¼ 5.80 Hz, 2H), 4.60 (s, 2H),
7.21–7.30 (m, 2H), 7.30–7.37 (m, 4H), 7.64 (d, J ¼ 7.32 Hz,
2H), 12.98 ppm (br. s., 1H); 13C NMR (126 MHz, DMSO-d6):
d 45.83, 58.59, 65.67, 68.49, 122.01, 125.78, 126.05, 129.30,
147.43, 154.61 ppm; HRMS: m/z calcd. for C20H22N3O2:
336.1712 [MþH]þ, found 336.1726.
(2-{[(11-Chloro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-
2-yl)methyl]oxy}ethyl)dimethylamine (10g). Obtained either
from 9o (yield 90%) or 9t (yield 91%) as a white amorphous
solid: IR (ATR): 3202, 2937, 2865, 2824, 2773, 1580, 1485,
{3-[(1H-Dibenzo[2,3:6,7]oxepino[4,5-d]imidazol-2-ylme-
thyl)oxy]propyl}dimethylamine (10b). Obtained from 9j as a
yellowish amorphous solid: Yield 76%; IR (ATR): 3055, 2946,
1
1456, 1353, 1093, 1030, 811, 766 cmꢂ1; H NMR (500 MHz,
DMSO-d6): d 2.18 (s, 6H), 2.50 (t, J ¼ 6.10 Hz, 2H), 3.66 (t,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
Novel Tetracyclic Imidazole Derivatives: Synthesis, Dynamic NMR Study,
and Anti-Inflammatory Evaluation
655
ˇ
J ¼ 5.80 Hz, 2H), 4.63 (s, 2H), 7.36–7.50 (m, 3H), 7.56–7.62
(m, 2H), 7.63–7.72 (m, 2H), 13.07 ppm (br. s., 1H); 13C NMR
(126 MHz, DMSO-d6): d 45.79, 58.57, 65.60, 68.64, 126.99,
127.78, 128.61, 129.48, 130.29, 131.20, 133.03, 133.95,
134.41, 147.33 ppm; HRMS: m/z calcd. for C20H21N3OSCl:
386.1094 [MþH]þ, found 386.1110.
Acknowledgment. The authors express gratitude to Josip Kles-
ˇ
cic for his assistance with the synthesis, Zeljko Osman and
ˇ ´
Dubravka Gembarovski for the mass spectroscopy support, Stef-
ica Flegar and Goran Landek for IR spectra, Biserka Metelko for
ˇ
ˇ
the NMR spectroscopy, and Vitomir Sunjic for helpful
´
discussions.
(3-{[(11-Chloro-1H-dibenzo[2,3:6,7]thiepino[4,5-d]imidazol-
2-yl)methyl]oxy}propyl)dimethylamine (10h). Obtained either
from 9p (yield 95%) or 9v (yield 91%) as a yellowish amor-
phous solid: IR (ATR): 2943, 2860, 2819, 2772, 1579, 1484,
REFERENCES AND NOTES
[1] Current address: Department of Translational Medicine,
Children’s Hospital ‘‘Srebrnjak,’’ Srebrnjak 100, Zagreb HR-10000,
Croatia.
1459, 1094, 1030, 810, 765 cmꢂ1 1H NMR (500 MHz,
;
DMSO-d6): d 1.70 (quin, J ¼ 6.82 Hz, 2H), 2.11 (s, 6H), 2.29
(t, J ¼ 7.32 Hz, 2H), 3.58 (t, J ¼ 6.56 Hz, 2H), 4.59 (s, 2H),
7.34–7.49 (m, 3H), 7.54–7.62 (m, 2H), 7.62–7.75 (m, 2H),
13.01 ppm (br. s., 1H); 13C NMR (126 MHz, DMSO-d6): d
27.65, 45.52, 56.34, 65.51, 68.85, 127.05, 127.86, 128.62,
129.46, 129.50, 130.30, 131.22, 133.02, 133.94, 134.40,
147.21 ppm; HRMS: m/z calcd. for C21H23N3OSCl: 400.1250
[MþH]þ, found 400.1254.
ˇ ´ ´ ´
[2] Pesic, D.; Ozimec Landek, I.; Mercep, M.; Mesic, M. J Het-
erocycl Chem 2006, 43, 749.
ˇ
[3] Pesic, D.; Ozimec Landek, I.; Cikos, A.; Metelko, B.;
ˇ ´
ˇ
´ ´ ´
Gabelica, V.; Stanic, B.; Mercep, M.; Mesic, M. J Heterocycl Chem
2007, 44, 1129.
ˇ ´ ´ ´
[4] Ozimec Landek, I.; Pesic, D.; Novak, P.; Stanic, B.; Nujic,
´
´
K.; Mercep, M.; Mesic, M. Heterocycles 2009, 78, 2489.
[5] Corall, L. G.; Haslett, A. J.; Muller, G. W.; Chen, R.;
Wong, L. M.; Ocampo, C. J.; Paterson, R. T.; Stirling, D. I.; Kaplan,
G. J Immunol 1999, 163, 380.
Biology
Cell isolation. Peripheral blood mononuclear cells (PBMC)
were obtained from buffy coat of healthy volunteer donors by
a density gradient centrifugation. Buffy coat was mixed with
one volume of sterile saline, sample layered over FicollPa-
queTM Plus (Amersham Biosciences), and centrifuged at 400
ꢄ g for 30 min. PBMCs were collected, washed in RPMI
1640 medium, and centrifuged. Finally, cells were resuspended
in RPMI 1640 containing 10% heat inactivated fetal bovine se-
rum (Biowest) and counted.
Cell culture. PBMCs were cultured at a concentration of
3.5 ꢄ 104 in 200 lL volumes in 96-well cell culture plates
(Falcon, St. Albans, UK) at 37ꢁC in humidified atmosphere
containing 5% CO2. The cells were either stimulated with
LPS (serotype 0111:B4, Sigma) at 1 ng/mL final concentra-
tion or left unstimulated (cultured in medium alone). Com-
pound stock solutions were prepared as 10 mM in DMSO.
Final 10 lM and 3 lM (10–0.03 lM) concentration made in
cell culture medium were tested when they had been added
together with LPS. The final DMSO volume ratio in all
assays did not exceed 0.1%. Negative and LPS control sam-
ples were prepared in sextaplicates and tested compound sam-
ples in triplicates.
Cytokine measurement. Cell free supernatants were taken
after overnight period and quantified for TNF-a content by
enzyme linked immunosorbent assay (ELISA). To ensure the
detection specificity and sensitivity, assay was performed
according to manufacturer instructions (R&D Systems) using
suggested pair of antibodies specific for human TNF-a. Test
sensitivity for measuring human TNF-a was under 5 pg/mL.
To calculate results, standard curve was made out of measured
OD values for recombinant TNF-a of known concentrations.
TNF-a content in unknown samples was calculated out of OD
values extrapolated from the standard curve. Inhibition values
were calculated according to formula:
[6] Muller, G. W.; Chen, R.; Huang, S. Y.; Corall, G. L.;
Wong, L. M.; Paterson, R. T.; Chen, Y.; Kaplan, G.; Stirling, D. I.
Bioorg Med Chem Lett 1999, 9, 1625.
[7] Hanson, G. J. Expert Opin Ther Pat 1997, 7, 729.
[8] Boehm, J. C.; Adams, J. L. Expert Opin Ther Pat 2000, 10,
25.
[9] Beers, S. A.; Malloy, E.; Wachter, M. P.; Wu, W. WO
Pat.9,847,892 A1, 1998; Chem Abstr 1998, 129, 330728.
[10] Harris, N. V.; Smith, C. EP Pat.0,424,195 A1, 1991; Chem
Abstr 1991, 115, 92279.
[11] Harris, N. V.; Smith, C.; Stuttle, K. A. J.; Walsh, R. J. A.;
Wyman, B. M. EP Pat.0,506,437 A1, 1992; Chem Abstr 1993, 118,
80943.
[12] Bamborough, P. L.; Collis, A. J.; Halley, F.; Lewis, R. A.;
Lythgoe, D. J.; McKenna, J. M.; Mclay, I. Mc.; Porter, B.; Ratcliffe,
A. J.; Wallace, P. A. WO Pat.9856788 A1, 1998; Chem Abstr 1993,
130, 66503.
[13] Adams, J. L.; Gallagher, T. F.; Sisko, J.; Peng, Z.-Q.; Osifo,
I. K.; Boehm, J. C. WO Pat.9,640,143 A1, 1996; Chem Abstr 1997,
126, 144274.
[14] Gallagher, T. F.; Fier-Thompson, S. M.; Garigipati, R. S.;
Sorenson, M. E.; Smietana, J. M.; Lee, D.; Bender, P. E.; Lee, J. C.;
Laydon, J. T.; Chabot-Fletcher, M. C.; Breton, J. J.; Adams, J. L. Bio-
org Med Chem Lett 1995, 5, 1171.
[15] Cherkofsky, S. C.; Sharpe, T. R. US Pat.4,215,135, 1980;
Chem Abstr 1981, 94, 47331.
[16] Lombardino, J. G. FR Pat.2,211,218, 1974; Chem Abstr
1975, 82, 98006.
[17] Lombardino, J. G. J Heterocycl Chem 1974, 11, 17.
[18] Lombardino, J. G. US Pat.3,711,489, 1973; Chem Abstr
1973, 78, 84410.
[19] Lombardino, J. G. US Pat.3,781,294, 1973; Chem Abstr
1974, 80, 70805.
[20] Lombardino, J. G. CA Pat.967573, 1975; Chem Abstr 1975,
83, 147479.
[21] Cherkofsky, S. C.; Sharpe, T. R. US4,198,421, 1980; Chem
Abstr 1980, 93, 71783.
ConcðcompoundÞ ꢂ Concðmedium controlÞ
X ¼
ꢄ 100ð%Þ
ConcðLPS controlÞ ꢂ Conc ðmedium controlÞ
[22] Schouteeten, A.; Christidis, Y. FR Pat.2,717,474 A1, 1995;
Chem Abstr 1995, 124, 146153.
IC50 values are calculated using GraphPad Prism
software.
[23] Davidson, D.; Weiss, M.; Jelling, J. J Org Chem 1937, 2,
319.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

ˇ
R. Rupcic, M. Modric, A. Hutinec, A. Cikos, B. Stanic, M. Mesic, D. Pesic, and M. Mercep
ˇ ´
´
ˇ
´
´
ˇ ´
´
656
Vol 47
[24] Coleman, C. M.; MacElroy, J. M. D.; Gallagher, J. F.;
[32] Durr, H. Zeitschr fur Naturforsch 1967, 22, 786.
O’Shea, D. F. J Comb Chem 2002, 4, 87.
[33] Werner, H.; Ricca, S.; Rossi, A.; DeStevens, G. J Med
Chem 1967, 10, 575.
[25] Wolkenberg, S. E.; Wisnoski, D. D.; Leister, W. H.; Wang,
Y.; Zhao, Z.; Lindsley, C. W. Org Lett 2004, 6, 1453.
[26] Lopez-Rodrigez, M. L.; Benhamu, B.; Ayala, D.; Romin-
guera, J. L.; Murcia, M.; Ramos, J. A.; Viso, A. Tetrahedron 2000, 56,
3245.
[34] Hassner, A.; Amit, B. Tetrahedron Lett 1977, 18, 3023.
[35] Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.; White,
J. P.; Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J Org Chem 2005,
70, 1545.
[27] Whitten, J. P.; Matthews, D. P.; McCarthy, J. R. J Org
Chem 1986, 51, 1891.
[36] Qadir, M.; Cobb, J.; Sheldrake, P. W.; Whittall, N.; White,
J. P.; Hii, K. K.; Horton, P. N.; Hursthouse, M. B. J Org Chem 2005,
70, 1552.
[28] Katritzky, A. R.; Rewcastle, G. W.; Fan, W.-Q. J Org
Chem 1983, 53, 5685.
[37] Abraham, J.; Kricka, L. J.; Ledwith, A. J. C. S. Perkin II
1974, 1648.
[29] Menozzi, G.; Mosti, L.; Fossa, P.; Mattioli, F.; Ghia, M.
J Heterocycl Chem 1997, 34, 963.
[38] Nogradi, M.; Ollis, W. D.; Sutherland, I. O. Chem Commun
1970, 158.
[30] Liljefors, T.; Bogeso, K. P. J Med Chem 1988, 31, 306.
[31] Bogeso, K. P.; Liljefors, T.; Arnt, J.; Hyttel, J.; Pedersen,
H. J Med Chem 1991, 34, 2023.
[39] Pearce, G. J.; Chikanza, I. C. BioDrugs 2001, 15, 139.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet