New synthesis of model dihydroazepine-fused indolo[2,3-c]quinolines

Article abstract of DOI:10.3987/com-02-9607

A synthetic route involving double Pictet-Spengler condensations at the indolic C-2 and C-4 positions of a 3-diaminophenylindole (8) is described leading to a novel dihydroazepine-fused indoloquinoline system. MS and NMR spectral data are in accordance with the assigned pentacyclic structures namely, 7,8-dihydro-1,12-iminobenzo[c]pyrido[4,3,2-ef][1]benzazepines (9a,b), as confirmed by X-Ray measurements.

Full text of DOI:10.3987/com-02-9607

HETEROCYCLES, Vol. 60, No. 1, 2003
73
HETEROCYCLES, Vol. 60, No. 1, 2003, pp. 73 - 87
Received, 23rd August, 2002, Accepted, 28th October, 2002, Published online, 28th October, 2002
NEW SYNTHESIS OF MODEL DIHYDROAZEPINE-FUSED
INDOLO[2,3-C]QUINOLINES
Adel M. Al-Khashashneh,a Mustafa M. El-Abadelah,*a and Roland Boese b
aChemistry Department, Faculty of Science, Jordan University, Amman, Jordan
bInstitut für Anorganische Chemie, Universität Essen, Universitätstrasse 3-5, D-
45117 Essen, Germany
Abstract– A synthetic route involving double Pictet-Spengler condensations at
the indolic C-2 and C- 4 positions of a 3-diaminophenylindole (8) is described
leading to a novel dihydroazepine-fused indoloquinoline system. MS and NMR
spectral data are in accordance with the assigned pentacyclic structures namely,
7,8-dihydro-1,12-iminobenzo[c]pyrido[4,3,2-ef][1]benzazepines (9a,b), as con-
firmed by X-Ray measurements.
INTRODUCTION
The Pictet-Spengler condensation reaction of indole bases, such as tryptamines (1a) and tryptophan
esters (1b), with various aldehydes constitutes a versatile synthetic route towards numerous 1,2,3,4-
tetrahydro-β-carbolines (e.g. 2a,b) (Scheme 1). This one-pot reaction, conducted under the classical
conditions of acid catalysis1 (1a→2a) or in nonacidic aprotic media 2,3 (1b→2b), is widely applicable in
the synthesis of indole alkaloids of more complex structure, and the subject has recently been reviewed.4
The electrophilic nature of the initially formed imine double bond provides the driving force for attack of
Scheme 1
X
X
NH2
X
RCHO
NH
N
..
N
H
N
H
R
N
H
R
2a (X = H)
2b (X = CO2Me)
1a (X = H)
1b (X = CO2Me)

74
HETEROCYCLES, Vol. 60, No. 1, 2003
the indolic C2 - C3 double bond and consequent cyclization which usually rests regioselectively at the
C-2 locus. 2,5
On the other hand, the acid-catalyzed condensation of dehydrotryptophan ester (3) with aldehydes was
reported to yield the respective 5,6-dihydroazepino[5,4,3-cd ]indoles (4) as the major products, implying
that cyclization occurred regioselectively at the indolic C- 4 position (Scheme 2). 6
Scheme 2
CO2Me
H
CO2Me
RCHO
CO2Me
R
N
H2N
R
N
..
N
N
N
H
H
H
4
3
Accordingly, we envisage that Lewis acid-catalyzed condensation of a 3-[2'-(1',3'-diaminophenyl)]-
indole (8) with aldehydes would bring about double cyclizations at the indolic C-2 and C-4 positions
with ultimate formation of the corresponding azepine-fused indoloquinolines (9a,b). This expectation is
realized in this study, which deals with the synthesis and characterization of 9a,b as outlined in Scheme
3. Our interest in this new pentacyclic ring system stems from the fact that it encompasses the following
biologically active entities: (i) a dihydroazepino[5,4,3-cd ]indole nucleus (rings C, D, E) present in the
ergot alkaloid, claviciptic acid; 7 (ii) an indolo[2,3-c]quinoline nucleus (rings A, B, C, D) of which some
8
synthetic derivatives exhibited antitumor potency; (iii) a β-carboline unit (rings B, C, D) of natural
9
occurrence in a wide variety of structures;
(iv) a dihydrobenzo[b]azepine (rings A, E), and (v) a
hitherto unprecedented azepino[4,3,2-de]quinoline system (rings A, B, E).
RESULTS AND DISCUSSION
CHEMISTRY
In this study, 3-(2,6-dinitro-4-trifluoromethylphenyl)indole (7) was prepared via interaction of
indolylzinc chloride (5)10 with 2-chloro-1,3-dinitro-5-trifluoromethylbenzene (6). Copper(II) acetate/
sodium borohydride system11 was employed for the reduction of 7 to afford the respective diamino
derivative (8) (Scheme 1). Condensation of 8 with the appropriate aldehyde under Pictet-Spengler
conditions, using boron triflouride etherate as a catalyst, delivered the respective target azepino-
indoloquinolines (9a,b) namely, (±)-2,8-diisopropyl-5-trifluoromethyl-7,8-dihydro-1,12-iminobenzo[c]-
pyrido[4,3,2-ef ]benzazepine (9a), and its 2,8-di-(4-chlorophenyl) analog (9b). 12

HETEROCYCLES, Vol. 60, No. 1, 2003
75
Scheme 3
(i)
(ii)
N
ZnCl
N
H
5
CF3
4'
5'
O2N
6'
3'
4
2'
1'
O2N
CF3
3
3a
5
(iii)
(iv)
NO2
2
(5)
+
6
Cl
7a
N
7
H
NO2
7
6
CF3
CF3
6
5
H
6a
N
R
H2N
8
7
4
A
*
E
12a
8a
12c
9
3a
RCHO
12b
3
N
B
D
NH2
10
(v)
C
12
1
2
11
13
N
N
H
8
R
H
9a,b
Compounds (9)
Entry
R
a
b
(i) MeMgI (3.0 M in Et2O)
(ii) ZnCl2 (1.0 M in Et2O)
(iii) Et2O /rt
(iv) NaBH4 , Cu(OAc)2 , MeOH
(v) BF3.OEt2 , CH2ClCH2Cl / reflux
1'
4'
Cl
Cl
(C2)
CHMe2
1'' (C8)
4''
Apparently, the formation of 9a,b proceeds via intermediate formation of the respective bis-imino
derivatives (10a,b) (Scheme 4), which undergoes two consecutive intramolecular cyclizations at the
indolic C-2 and C-4 positions. No attempt was, however, made to isolate the bis-imino substrates. We
anticipate that cyclization occurs first at the more reactive pyrrolic C-2 locus of 10a,b, leading to the
formation of the corresponding dihydroindolo[2,3-c]quinoline intermediates (11a,b) which undergo
aromatisation of the dihydropyridine nucleus through air oxidation under the reaction conditions, into the
indolo[2,3-c]quinolines (12a,b) (Scheme 4). The latter intermediates (12a,b) undergo second cyclization
involving the other exo - imine group and C-11 (recalled as the indolic C- 4 position) to deliver the final
pentacyclic products (9a,b).

76
HETEROCYCLES, Vol. 60, No. 1, 2003
Scheme 4
CF3
CF3
R
N
R
N
2 RCHO
N
- 2H
NH
(8)
..
N
H
BF3.OEt2 / reflux
N
H
R
R
10a,b
11a,b
CF3
1
R
N
4
11
BF3. OEt2
CH2ClCH2Cl / reflux
N
9a,b
6
..
N
R
8
H
12a,b
This assumption is substantiated by the actual isolation of the penultimate intermediate (12b) (Scheme 5),
under neutral aprotic conditions. The latter tetracyclic compound (12b) was converted in a separate step,
under acid- catalyzed Pictet-Spengler reaction conditions, into 9b (Scheme 5). These experimental
findings can be taken as supporting evidence for the timing of the two successive cyclizations of which
annulation at C-2 precedes that occurring at the C- 4 locus.
Scheme 5
4''
Cl
CF3
2
3
1''
N
1
CHO
4
11
10
11c
4a
11a
(i)
(ii)
11b
(8) +
9
9b
5
N
6a
7a
8
6
1'
7 N
H
Cl
4'
12b
Cl
(i) CH2ClCH2Cl / reflux ;
(ii) BF3. OEt2 , CH2ClCH2Cl / reflux
SPECTRAL DATA
The spectral (MS, NMR) and microanalytical data are compatible with the assigned structures (7, 8, 9a,b
and 12b), and are given in the experimental part. Thus, their MS spectra display the correct M+ for which
the measured HRMS data are in good agreement with the calculated values suggested by their molecular
formulas. Assignments of the 1H NMR signals to the different protons are straightforward, and 13C-signal

HETEROCYCLES, Vol. 60, No. 1, 2003
77
assignments are based on DEPT and 2D (COSY, HMBC, HMQC) experiments, which showed
correlations that helped in the full assignments of hydrogens and carbons. Thus, the HMBC spectra
showed long-range correlations of H-8 with C-9, C-12a (9a,b) and with C-2'/C-6' (9b); likewise, both of
H-4 and H-6 are correlated with C-12c. In the case of 9b, H-2''/H-6'' are correlated with C-2, while the
isopropyl methine protons in 9a are correlated with C-8a and C-1.
It is worth noting that the two doublets, belonging to H-2 and H-4 of the indole ring in the 1H NMR of 8,
are absent from the 1H NMR spectra of 9a,b. The formation of the dihydroazepine ring (E) is manifested
by the presence of the following diagnostic signals in the NMR spectra of 9a,b : (i) The benzylic methine
proton (H-8) in 9b is appreciably deshielded and resonates at δ 6.0 as a doublet (due to coupling with the
vicinal N7-H) which collapses to a singlet upon addition of D2O. In 9a, the H-8 proton signal is centered
at δ 4.23 as a doublet of doublet (a result of additional splitting by the vicinal methine proton of the
isopropyl moiety) that changes to one doublet upon D2O-addition; (ii) The exchangeable N7-H proton is
displayed as a doublet at δ 7.20 (9a) and δ 7.64 (9b) ppm; (iii) The benzylic tertiary sp3-carbon (C-8) is
deshielded (anchored to N7) and resonates at δ 66.3 (9a), and δ 62.5 (9b) ppm.
Due to dissymmetry of the molecular structure of 9b, the two p-chlorophenyls appended at C-2 and C-8
are chemically non-equivalent and give rise to signal doubling of their different 1H- and 13C- resonances.
This trend of signal doubling is also observed in 9a for the two non-equivalent isopropyl groups located
at the C-2 and C-8 positions. The C-4, C-5 and C-6 signals are distinguishable as quartets by virtue of
their characteristic couplings to fluorine nuclei of the nearby 5-CF3 group. All in all, the spectral data of
9a,b are in agreement with the dihydroazepine-fused indoloquinoline structure as determined by X-Ray
crystal structure measurements (vide infra).
Collection of X-Ray Diffraction Data and the Structure Analysis of 9a and 9b
Yellow plate crystals of 9a were grown by allowing a saturated solution of 9a in 70 % aq. ethanol to
evaporate slowly at room temperature over 3-4 days. Likewise, yellow rod crystals of 9b were grown by
allowing a clear solution of 9b in 95 % ethanol to evaporate slowly at room temperature for 5-6 days.
For both compounds, data were collected with a Siemens SMART CCD diffractometer [Mo-Kα radiation
(λ = 0.71073 Å), graphite monochromator] operating in the omega scan mode (0.3°). The data were
reduced with the Siemens-Bruker program suite XSCANS, 13 and the structure was solved by the direct
14
method using SHELXTL PLUS programs.
All non-hydrogen atoms were refined anisotropically by
full-matrix, least-squares procedure based on F2 using all unique data. The hydrogen atoms were located
from the difference Fourier electron density synthesis and were then refined isotropically using a ‘riding
model’.

78
HETEROCYCLES, Vol. 60, No. 1, 2003
The derivative (9a) with isopropyl appendages has three independent molecules together with two water
molecules in the asymmetric unit of an orthorhombic cell in the chiral space group P212121; the absolute
structure could not be determined reliably, and the crystallographic data are given in Table 1. The three
molecules have comparable geometries of which only one is displayed in Figure 1; the essential bond
distances and angles are given in Table 2. The predominant features are their almost planar shape with
exception of the puckering of the heterocyclic seven-membered ring for which the respective atoms C8,
C28 and C48, (one from each of the three molecules in the asymmetric unit) are the most deviating from
planarity. In each molecule, these atoms C8A, C28A and C48A deviate from the mean plane of the
molecule (apart from N7) by 0.23, 0.29 and 0.28 Å, respectively. The interplanar angles between these
mean planes of the three molecules and the planes, formed by C8, C28 and C48 together with their two
neighboring atoms, are 50.5, 51.8 and 47.7°; the torsion angles C6A-N7-C8-C8A, C26A-N27-C28-C28A
and C46A-N47-C48-C48A are 81.3, 83.0 and -79.6°, respectively, thus demonstrating the similarities of
the individual molecules. The three molecules form a trimeric motif linked via N−H···N hydrogen bonds
(Figure 2), which is possible because the NH groups in the seven-membered heterocyles are made
accessible by virtue of the influence of the neighboring axially positioned isopropyl groups (torsion
angles C6A-N7-C8-C18, C26A-N27-C28-C38 and C46A-C47-C48-C58 are -43.9, 44.5 and 47.5°,
respectively). The trimeric motifs are cross-linked by a complicated network of hydrogen bonds where
two water molecules are involved as displayed in Figure 3. The most important hydrogen bonds are
N7−H7···N47 (H···N 2.31 Å, N−H···N 179°, N···N 3.19 Å), N13−H13···N23 (H···N 2.34 Å, N−H···N
139°, N···N 3.06 Å), and N27···H47−N47 (H···N 2.43 Å, N−H···N 167°, N···N 3.30 Å). The hydrogen
bonds involving the two water molecules are N33−H33···O2 (H···O 2.30 Å, N−H···O 156°, N···O 3.12 Å)
and N53−H53···O1 (H···O 1.96 Å, N−H···N 164°, N···O 2.82 Å).
The molecular structure of 9b incorporating p-chlorophenyl substituents (Figure 4, Table 1) is rather
similar to that of 9a. The central framework does not show any significant differences, whereas the main
deviations exist at the external atoms (Table 3). Thus, the azepine ring of 9b is more puckered, with C8
deviating by 0.31Å from the mean plane of the molecule (except for N7), and the interplanar angle to the
plane formed by C8, N7 and C8A is 50.2°. The torsion angle C6A-N7-C8-C8a is 83.1°, similar to 9a. A
predominant difference is, however, the substitution at the seven-membered heterocycle. While the
isopropyl substituent in 9a is found in an axial position, the p-chlorophenyl substituent in 9b occupies an
equatorial position, the torsion angle C6A-N7-C8-C21 being 149.6°. This makes the hydrogen atom at
N7 in 9b less accessible for hydrogen bonding, as compared to 9a. Instead, this N7 nitrogen atom is
linked to the ethanol molecule, found in the asymmetric unit, forming a centrosymmetric dimer as shown
in Figure 5 (N'7H···O1 2.39Å, O1···H7N'−N7' 114°, O1···N7' 2.88Å; N13H ···O1 1.97Å, O1···H13N−N13

HETEROCYCLES, Vol. 60, No. 1, 2003
79
Table 1. Summary of crystal data and structure refinement parameters for (±)-9a and (±)-9b
Empirical formula
Formula weight
3 (C23 H22 N3 F3) · 2(H2O)
C29 H16 N3 Cl2 F3 · C2H5OH
409.45
1.325
580.42
1.441
-3
Density (calculated) (g cm )
F(000)
2576
1192
Temperature (K)
Crystal size (mm)
Wavelength (Å)
Crystal system
173(2)
203(2)
0.48 x 0.18 x 0.15
0.71073
0.21 x 0.11 x 0.05
0.71073
orthorhombic
P212121
monoclinic
P21/n
Space group
Unit cell dimensions
13.139(3)
16.481(3)
28.444(6)
9.6230(11)
11.6607(13)
23.891(3)
a (Å)
b (Å)
c (Å)
β ( ° )
Volume ( Å3 )
93.666(2)
2675.3(5)
6159(2)
Z
12
4
Theta range for data collection
Completeness to theta = 23.99°
Index ranges
1.89° to 23.99°
99.7 %
1.94° to 28.33°
99.6 %
-15 ≤ h ≤ 15, -18 ≤ k ≤ 18,
-32 ≤ l ≤ 32
-12 ≤ h ≤ 12, -15 ≤ k ≤ 15,
-31 ≤ l ≤ 31
0.295
-1
0.100
Absorption coefficient (mm )
Max. / min. transmission
R(merg) before/after correction
Reflections collected
1.00 / 0.72
1.00 / 0.83
0.1187 / 0.0690
56141
0.0842 / 0.0517
10870
Independent reflections
9634 [R int = 0.1718]
7386 / 0 / 820
1.086
5737 [R int = 0.0912]
2240 / 0 / 361
0.808
Data / restraints / parameters
2
Goodness-of-fit on F
2
2
2
2
2
Weighting details
w = 1/[σ (Fo )+ (0.0715
w = 1/[σ (Fo )+ (0.055 P) ] where P =
2
2
2
P) +7.7705·P] where P =
(Fo +2Fc )/3
2
2
(Fo +2Fc )/3
Final R indices [I > 2 sigma(I)]
R indices (all data)
R1 = 0.0771, wR 2 = 0.1778
R1 = 0.1049, wR 2 = 0.1999
-1.1(14)
R1 = 0.0555, wR2 = 0.1119
R1 = 0.1363, wR 2 = 0.1525
Absolute structure parameter
Largest difference peak (e·Å-3 )
Largest difference hole (e·Å-3 )
0.601
0.440
-0.330
-0.340

80
HETEROCYCLES, Vol. 60, No. 1, 2003
Table 2. Selected bond lengths (Å) and angles (°) for (±)-9a.
N(7)-C(8)
1.466(7)
1.380(7)
1.424(7)
1.400(7)
1.431(8)
1.369(9)
1.506(9)
1.422(9)
1.387(9)
1.366(7)
1.381(8)
1.388(9)
1.322(8)
1.392(6)
1.408(8)
C(12C)-C(12B)-C(12A) 131.8(5)
C(8A)-C(12A)-C(12B) 132.4(6)
C(6A)-N(7)
C(6A)-C(12C)
C(12B)-C(12C)
C(12A)-C(12B)
C(8A)-C(12A)
C(8)-C(8A)
C(12)-C(12A)
C(12)-N(13)
C(1)-N(13)
C(1)-C(12B)
C(1)-C(2)
C(12A)-C(8A)-C(8)
C(9)-C(8A)-C(8)
C(8A)-C(8)-C(18)
N(7)-C(6A)-C(6)
118.0(6)
123.9(6)
110.7(5)
121.2(5)
C(12)-C(12A)-C(12B) 107.5(6)
N(13)-C(12)-C(12A)
C(11)-C(12)-N(13)
C(1)-N(13)-C(12)
N(13)-C(1)-C(12B)
N(13)-C(1)-C(2)
C(1)-C(12B)-C(12A)
C(1)-C(12B)-C(12C)
C(12B)-C(1)-C(2)
N(3)-C(2)-C(1)
106.0(6)
133.0(7)
110.6(5)
108.8(6)
131.5(6)
107.1(5)
120.9(6)
119.8(5)
121.4(5)
119.0(5)
122.8(5)
118.2(5)
119.1(7)
119.5(6)
C(2)-N(3)
N(3)-C(3A)
C(3A)-C(12C)
C(2)-N(3)-C(3A)
N(3)-C(3A)-C(12C)
N(3)-C(3A)-C(4)
N(3)-C(2)-C(14)
C(1)-C(2)-C(14)
N(7)-C(8)-C(8A)
N(7)-C(8)-C(18)
C(6A)-N(7)-C(8)
N(7)-C(6A)-C(12C)
C(12B)-C(12C)-C(6A)
111.4(5)
112.7(5)
125.8(4)
120.6(4)
123.6(5)
156°, O1···N13 2.82Å). Comparison of the crystal structures (9a) and (9b) demonstrates the delicate
interplay of solvent mediated hydrogen bonds, direct hydrogen bonds of the individual molecules and the
importance of availability of hydrogen atoms for networking. Variation of solvents is expected to
produce more pseudo polymorphs, a field which recently gained importance in pharmaceutical
applications. However, this topic was not persecuted yet.
Supplementary Material
Crystallographic data for the structural analysis have been deposited with the Cambridge
Crystallographic Data Center, CCDC No. 185223 for compound (9a), and CCDC No. 185224 for
compound (9b). Copies of either information may be obtained free of charge from the Director, CCDC,
12 Union Road, Cambridge CB2 1 EZ, UK (Fax: +44-1223-336033; e-mail: (deposit@ccdc.cam.ac.uk or
http://www.ccdc.cam.ac.uk).

HETEROCYCLES, Vol. 60, No. 1, 2003
81
Figure 1. ORTEP plot (50%) of the molecular
Figure 2. Drawing of the three independent molecules in
the asymmetric unit of (±)-9a (non-relevant H-atoms and
pendent groups are omitted).
structure of (±)-9a.
Figure 3. Drawing of the cell of the crystal structure of (±)-9a with the networking water molecules
(non-relevant H-atoms and pendent groups are omitted).

82
HETEROCYCLES, Vol. 60, No. 1, 2003
Table 3. Selected bond lengths (Å) and angles (°) for (±)-9b.
N(7)-C(8)
1.497(4)
1.409(4)
1.416(4)
1.413(4)
1.433(4)
1.395(4)
1.530(4)
1.406(4)
1.379(4)
1.379(4)
1.400(4)
1.413(4)
1.339(4)
1.377(4)
1.420(4)
C(12C)-C(12B)-C(12A) 132.4(3)
C(8A)-C(12A)-C(12B) 132.0(3)
C(6A)-N(7)
C(6A)-C(12C)
C(12B)-C(12C)
C(12A)-C(12B)
C(8A)-C(12A)
C(8)-C(8A)
C(12)-C(12A)
C(12)-N(13)
C(1)-N(13)
C(1)-C(12B)
C(1)-C(2)
C(12A)-C(8A)-C(8)
C(9)-C(8A)-C(8)
C(8A)-C(8)-C(21)
N(7)-C(6A)-C(6)
117.9(3)
124.1(3)
115.9(3)
119.4(3)
C(12)-C(12A)-C(12B) 106.3(3)
N(13)-C(12)-C(12A)
C(11)-C(12)-N(13)
C(1)-N(13)-C(12)
N(13)-C(1)-C(12B)
N(13)-C(1)-C(2)
C(1)-C(12B)-C(12A)
C(1)-C(12B)-C(12C)
C(12B)-C(1)-C(2)
N(3)-C(2)-C(1)
108.9(3)
130.3(3)
108.9(2)
108.5(3)
131.2(3)
107.3(3)
120.2(3)
120.3(3)
120.2(3)
120.1(3)
123.1(3)
117.4(3)
114.8(3)
124.9(3)
C(2)-N(3)
N(3)-C(3A)
C(3A)-C(12C)
C(2)-N(3)-C(3A)
N(3)-C(3A)-C(12C)
N(3)-C(3A)-C(4)
N(3)-C(2)-C(14)
C(1)-C(2)-C(14)
N(7)-C(8)-C(8A)
N(7)-C(8)-C(21)
C(6A)-N(7)-C(8)
N(7)-C(6A)-C(12C)
112.3(3)
106.8(3)
122.9(3)
121.3(3)
C(12B)-C(12C)-C(6A) 124.1(3)
Figure 4. ORTEP plot (50%) of the molecular
structure of (±)-9b (disorder of CF3 group is
omitted).
Figure 5. Ethanol hydrogen bonded dimer of (±)-9b (C-
bonded H-atoms and pendent groups are omitted).

HETEROCYCLES, Vol. 60, No. 1, 2003
83
EXPERIMENTAL
2-Chloro-1,3-dinitro-5-trifluoromethylbenzene, indole and NaBH4 were purchased from Acros.
Methylmagnesium iodide (3.0 M in ether) and zinc chloride (1.0 M in ether) were purchased from Aldrich.
Melting points (uncorrected) were determined on Gallenkamp melting point apparatus. NMR spectra
were recorded on a Bruker DPX-300 spectrometer using TMS as internal reference. EIMS spectra and
high resolution data were obtained using a Finnigan MAT TSQ-70 spectrometer at 70 eV ; ion source
0
temperature = 200 C. Microanalyses were performed at the Microanalytical Laboratory, Inorganic
Chemistry Department, Tübingen University, Germany.
3-(2',6'-Dinitro-4'-trifluoromethylphenyl)indole (7)
To a solution of indole (2.3 g, 20 mmol) in dry ether (40 mL), an ethereal solution of methylmagnesium
iodide (3.0 M, 8 mL) was added and stirred at rt for 20 min. An ethereal solution of zinc chloride (1.0 M,
24 mL) was then added and stirred at rt for 30 min. 2-Chloro-1,3- dinitro-5-trifluoromethylbenzene 6 (2.7
g, 10 mmol) was added to the reaction mixture , and stirring was continued at rt for 4 h. Water (100 mL)
was then added, and stirred for 15 min. The ether layer was separated and the aqueous layer was extracted
with ether (3 × 50 mL). The combined organic portions were dried over anhydrous sodium sulfate, and
the solvent evaporated. The residual product was recrystallized from chloroform / petroleum ether (bp 40-
60 °C) to afford a yellow solid. Yield of 7 = 1.9 g (54%), mp 139-141 °C. Anal. Calcd for C15H8N3O4F3 :
C, 51.29; H, 2.30; N, 11.96; F, 16.23 . Found : C, 51.18; H, 2.21; N, 11.03; F, 15.88 . MS m/z (% rel.
int.) : 351(M+, 100), 322 (8), 305 (12), 276 (12), 248 (19), 222 (14), 182 (11), 179 (14), 149 (58), 120 (7),
119 (8); HRMS: Calcd for C15H8N3O4F3 : 351.04665. Found : 351.053506; 1H NMR (300 MHz, CDCl3) :
δ 7.17 (dd, 1H, J = 7.4, 7.6 Hz, H-5), 7.27 (d, 1H, J = 7.6 Hz, H-4), 7.30 (dd, 1H, J = 8.0, 7.4 Hz, H-6),
7.39 (d, 1H, J = 2.8 Hz, H-2), 7.45 (d, 1H, J = 8.0 Hz, H-7), 8.23 (br s, 2H, H-3´/H-5´), 8.56 (br s, 1H,
N1-H); 13C NMR (300 MHz, CDCl3) : δ 104.3 (C-3), 111.9 (C-7), 118.0 (C-4), 121.6 (C-5), 123.5 (q, 3JC-
1
= 3.8 Hz, C-3´/ C-5´), 123.7 (C-6), 124.9 (C-2), 125.7 (C-3a), 127.4 (C-1´), 129.1 (q, JC-F = 256 Hz,
F
CF3), 131.0 (q, 2JC-F = 36 Hz, C-4´), 135.7 (C-7a), 151.9 (C-2´/C-6´).
3-(2',6'-Diamino-4'-trifluoromethylphenyl)indole (8)
11
The following procedure is essentially similar to that reported
for nitro group reduction in related
systems: to a stirred solution of 3-(2,6-dinitro-4-trifluoromethylphenyl)indole (7) (1.7 g, 5 mmol) in 60
mL of methanol and 20 mL of saturated solution of copper acetate, was added sodium borohydride (1.9 g,
40 mmol) portion wise at rt until the reduction was completed. This is followed by immediate addition of
100 mL of ether, and the mixture was washed with 10% sodium carbonate. The aqueous layer was further
extracted with 40 mL of ether and the combined ether fractions were dried (anhydrous sodium sulfate),

84
HETEROCYCLES, Vol. 60, No. 1, 2003
filtered and the solvent was removed to yield 1.15 g of bright red solid which was recrystallized from
dichloromethane-hexane. Yield of 8a = 1.2 g (82 %), mp 162-164 °C. Anal. Calcd for C15H12N3F3 : C,
61.85 ; H, 4.15; N, 14.43; F, 19.57 . Found : C, 62.10 ; H, 4.13; N, 14.50; F, 19.51. MS m/z (% rel.
int.) : 291(M+, 100), 274 (19), 273 (8), 272 (7), 247 (7), 221 (9), 205 (5), 153 (10), 146 (3), 138 (6),
111 (10); HRMS: Calcd for C15H12N3F3 : 291.09833. Found : 291.09617; 1H NMR (300 MHz, CDCl3) : δ
3.67 (br s, 4H, C2´-NH2 / C6´-NH2), 6.46 (br s, 2H, H-3´/ H-5´), 7.15 (dd, 1H, J = 7.4, 8.0 Hz, H-5), 7.28
(dd, 1H, J = 7.4, 8.2 Hz, H-6), 7.30 (d, 1H, J = 2.0 Hz, H-2), 7.44 (d, 1H, J = 8.0 Hz, H-4), 7.48 (d, 1H, J
= 8.2 Hz, H-7), 8.47 (br s, 1H, N1-H); 13C NMR (75 MHz, CDCl3) : δ 101.7 (q, 3JC-F = 3.8 Hz, C-3´/ C-
5´), 108.1 (C-1´), 108.4 (C-3), 111.6 (C-7), 119.9 (C-4), 120.4 (C-5), 123.0 (C-6), 124.3 (C-2), 124.4
(q, 1JC-F = 271 Hz, CF3), 126.0 (C-3a), 131.1 (q, 2JC-F = 32 Hz, C-4´), 136.7 (C-7a), 146.9 (C-2´/ C-6´).
1-(4''-Chlorobenzylidinimino)-6-(4'-chlorophenyl)-7H-3-trifluoromethylindolo[2,3-c]quinoline (12b)
A solution of 8 (1.46 g, 5 mmol), and 4-chlorobenzaldehyde (1.45 g, 11 mmol) in 50 ml of 1,2-
dichloroethane was refluxed (oil bath, 90 °C) for 6 h. The solvent was evaporated, the residue was
soaked successively with 5% NaOH solution, and water (2 × 20 mL), collected, dried, and recrystallized
from CH2Cl2 / petroleum ether as bright yellow solid. Yield of 12b = 2.47 g (93 %), mp 257-259 °C.
Anal. Calcd for C29H16N3Cl2F3 : C, 65.18 ; H, 3.02; N, 7.86; Cl, 13.27 . Found : C, 65.04 ; H, 3.07; N,
7.95; Cl, 13.19. MS m/z (% rel. int.) : 533 (M+, 39), 422 (100), 360 (6), 268 (10), 267 (15), 249 (8), 211
1
(35), 188 (42), 146 (9); HRMS: Calcd for C29H16N3Cl2F3 : 533.067307. Found : 533.063713; H NMR
(300 MHz, DMSO-d6) : δ 7.05 (dd, 1H, J = 7.4, 8.5 Hz, H-10), 7.48 (dd, 1H, J = 7.4, 8.2 Hz, H-9), 7.58
(br s, 1H, H-4), 7.71 (d, 1H, J = 8.5 Hz, H-11), 7.76 (d, 4H, J = 8.3 Hz, H-3´/ H-5´ and H-3´´/ H-5´´),
8.09 (d, 2H, J = 8.3 Hz, H-2´´/ H-6´´), 8.18 (d, 2H, J = 8.3 Hz, H-2´/ H-6´), 8.38 (br s, 1H, H-2), 9.24
(d, 1H, J = 8.2 Hz, H-8), 12.20 (br s, 1H, N7-H); 13C NMR (75 MHz, DMSO-d6) : δ 111.8 (q, 3JC-F = 3.6
Hz, C-4), 113.2 (C-8), 120.2 (C-11), 121.1 (C-11b), 122.3 (C-6a), 122.5 (C-11c), 125.1 (q, 3JC-F = 3.6
Hz, C-2), 126.2 (q, 2JC-F = 38 Hz, C-3), 126.6 (q, 1JC-F = 270 Hz, CF3), 127.4 (C-10), 127.6 (C-9), 129.4
(C-3´´/ C-5´´), 129.7 (C-3´/ C-5´), 131.4 (C-2´´/ C-6´´), 131.7 (C-2´/ C-6´), 132.5 (C-7a), 134.8 (C-
4´´), 135.1 (C-4´), 136.5 (C-1´´), 137.4 (C-1´), 140.9 (C-11a), 143.0 (C-4a), 148.2 (C-6), 150.5 (C-1),
162.0 (exocyclic C=N-C1).
(±)-2,8-Diisopropyl-5-trifluoromethyl-7,8-dihydro-1,12-iminobenzo[c]pyrido[4,3,2-ef][1]benzazepines
(9a)
A mixture of 8 (1.46 g, 5 mmol) and isobutyraldehyde (0.8 g, 11 mmol) dissolved in 50 mL of 1,2-
dichloroethane and few drops of glacial acetic acid, was stirred at rt for 1 h. BF3.OEt2 (3 mL) was added,
and the mixture was refluxed (oil bath, 80 °C) for 2 h. The solvent was evaporated and the residue was

HETEROCYCLES, Vol. 60, No. 1, 2003
85
soaked successively with 5% NaOH solution and water (2 × 20 mL). The resulting solid product was
collected, dried, and purified using silica gel column chromatography, eluting with CH2Cl2. Yield of 9a =
1.43 g (76 %), mp 141-144 °C. Anal. Calcd for C23H22N3F3 : C, 69.51 ; H, 5.58 ; N, 10.57. Found :
C, 69.38 ; H, 5.64 ; N, 10.56. MS m/z (% rel. int.) : 397(M+, 7), 354 (100), 338 (16), 304 (23), 289 (3),
234 (2), 205 (3), 177 (3), 170 (8), 149 (38), 137 (4), 111 (6); HRMS: Calcd for C23H22N3F3 : 397.17658.
1
Found : 397.17806; H NMR (300 MHz, DMSO-d6) : δ 0.47, 1.03 (2d, 3H/3H, J = 6.3, 6.5 Hz, C8-
CH(CH3)2), 1.47 (d, 6H, J = 6.5 Hz, C2-CH(CH3)2), 1.56 (m, 1H, C8-CHMe2), 3.81 (m, 1H, C2-CHMe2),
4.23 (dd, 1H, J = 5.8, 7.8 Hz, H-8), 7.09 (d, 1H, J = 6.9 Hz, H-9), 7.20 (d, 1H, J = 5.8 Hz, N7-H), 7.26 (br
s, 1H, H-4), 7.49 (dd, 1H, J = 6.9, 8.0 Hz, H-10), 7.59 (d, 1H, J = 8.0 Hz, H-11), 7.75 (br s, 1H, H-6),
12.19 (br s, 1H, N13-H); 13C NMR (75 MHz, DMSO-d6) : δ 14.4, 20.6 (C8-CH(CH3)2), 21.1, 21.3 (C2-
CH(CH3)2), 31.7 (C8-CHMe2), 33.4 (C2-CHMe2), 66.3 (C-8), 106.9 (q, 3JC-F = 3.0 Hz, C-4), 110.5 (C-11),
115.5 (q, 3JC-F = 3.8 Hz, C-6), 117.8 (C-9), 118.3 (C-12b), 120.4 (C-1), 120.6 (C-12c), 124.9 (q, 1JC-F
=
271 Hz, CF3), 126.1 (q, 2JC-F = 32 Hz, C-5), 126.5 (C-10), 129.5 (C-12), 141.6 (C-3a), 146.0 (C-2), 155.2
(C-6a).
(±)-2,8-Di-(4-chlorophenyl)-5-trifluoromethyl-7,8-dihydro-1,12-iminobenzo[c]pyrido[4,3,2-ef][1]benz-
azepines (9b)
Method A. This compound was prepared from 8 (1.46 g, 5 mmol), and 4-chlorobenzaldehyde (1.54 g, 11
mmol) following the same procedure and experimental conditions noted above for 9a. Yield of 9b = 1.63
g (61 %), mp 251-253 °C.
Method B. This compound was also prepared from 12b (2.12 g, 4 mmol), dissolved in 40 mL of 1,2-
dichloroethane, and 3 mL of BF3.OEt2. The reaction mixture was refluxed (oil bath, 80 °C) for 2 h. The
solvent was evaporated and the residue was soaked successively with 5% NaOH solution (20 mL), and
water (2 × 20 mL). The resultant solid product was collected, dried, and purified using silica gel column
chromatography, eluting with CH2Cl2. Yield of 9b = 1.47 g (69 %), mp 251-253 °C, undepressed upon
admixture with an authentic sample of 9b, prepared by method A above. Anal. Calcd for C29H16N3Cl2F3
: C, 65.18; H, 3.02; N, 7.86; Cl , 13.27 . Found : C, 65.13; H, 3.08; N, 7.75; Cl , 13.21. MS m/z (%
rel. int.) : 533(M+ , 48), 514 (3), 496 (3), 424 (34), 422 (100), 386 (7), 352 (3), 310 (5), 267 (21), 258
(18), 240 (12), 210 (29), 194 (27), 158 (10), 144 (4), 111 (3); HRMS: Calcd for C29H16N3Cl2F3 :
533.06622. Found : 533.06734; 1H NMR (300 MHz, DMSO-d6) : δ 6.05 (d, 1H, J = 5.3 Hz, H-8), 6.90 (d,
2H, J = 8.4 Hz, H-3´´/ H-5´´), 7.16 (d, 2H, J = 8.4 Hz, H-2´´/ H-6´´), 7.18 (d, 1H, J = 7.3 Hz, H-9); 7.29
(br s, 1H, H-4), 7.58 (dd, 1H, J = 7.3, 8.2 Hz, H-10), 7.64 (d, 1H, J = 5.3 Hz, N7-H), 7.71 (d, 2H, J = 8.4
Hz, H-3´/ H-5´), 7.73 (d, 1H, J = 8.2 Hz, H-11), 7.85 (br s, 1H, H-6), 8.17 (d, 2H, J = 8.4 Hz, H-2´/ H-

86
HETEROCYCLES, Vol. 60, No. 1, 2003
6´), 12.23 (br s, 1H, N13-H); 13C NMR (75 MHz, DMSO-d6) : δ 62.5 (C-8), 108.6 (q, 3JC-F = 3.6 Hz, C-
3
4), 112.1 (C-11), 117.1 (q, JC-F = 3.6 Hz, C-6), 118.7 (C-9), 118.9 (C-12b), 121.5 (C-1), 122.8 (C-
1
2
12c), 125.2 (q, JC-F = 271 Hz, CF3), 127.4 (q, JC-F = 32 Hz, C-5), 128.3 (C-10), 128.8 (C-3´´/ C-5´´),
129.4 (C-3´/ C-5´), 129.5 (C-2´´/ C-6´´), 129.8 (C-12), 131.2 (C-2´/ C-6´), 132.0 (C-1´´), 135.0 (C-1´),
136.8 (C-4´´), 137.1 (C-4´), 140.3 (C-8a), 142.3 (C-12a), 142.9 (C-3a), 146.1 (C-2), 146.3 (C-6a).
ACKNOWLEDGEMENTS
We wish to thank the Advanced Pharmaceutical Industries Co. Ltd., Amman-Jordan for financial support.
We are grateful to Professor John Boulton (East Anglia University -UK) for his invaluable assistance in
naming the pentacyclic system.
REFERENCES AND NOTES
(*) Corresponding author, e-mail: mustelab@ju.edu.jo
1. (a) K. Staurt and R. Woo-Ming, Heterocycles, 1975, 3, 223. (b) M. Julia, J. Bagot, and O. Siffert,
Bull. Soc. Chim Fr., 1973, 1424. (c) J. Bergman, Acta Chem. Scand., 1971, 25, 3296. (d) J. Degraw,
J. G. Kennedy, and W. A. Skinner, J. Med. Chem., 1967, 10, 127.
2. (a) J. Sandrin, D. Soerens, P. Mokry, and J. M. Cook, Heterocycles, 1977, 6, 1133. (b) D. Soerens, J.
Sandrin, F. Ungemach, P. Mokry, G. S. Wu, E. Yamanaka, L. Hutchins, M. DiPierro, and J. M. Cook,
J. Org. Chem., 1979, 44, 535.
3. (a) L. Deng, K. M. Czerwinski, and J. M. Cook, Tetrahedron Lett., 1991, 32, 175. (b) K. M.
Czerwinski, L. Deng, and J. M. Cook, Tetrahedron Lett., 1992, 33, 4721.
4. E. D. Cox and J. M. Cook, Chem. Rev., 1995, 95, 1797.
5. (a) P. D. Bailey, S. P. Hollinshead, N. R. McLay, K. Morgan, S. J. Palmer, S. N. Prince, C. D.
Reynolds, and S. D. Wood, J. Chem. Soc., Perkin Trans. I, 1993, 431. (b) G. Casnati, A. Dossena, and
A. Pochini, Tetrahedron Lett., 1972, 5277. (c) A. H. Jackson, B. J. Naidoo, and P. Smith, Tetrahedron,
1968, 24, 6119.
6. S-I. Nakatsuka, H. Miyazaki, and T. Goto, Tetrahedron Lett., 1986, 27, 4757.
7. (a) G. S. King, P. G. Mantle, C. A. Szczyrbak, and E. S. Waight, Tetrahedron Lett., 1973, 215. (b) G.
S. King, E. S. Waight, P. G. Mantle, and C. A. Szczyrbak, J. Chem. Soc., Perkin Trans. I, 1977, 2099.
(c) D. A. Boyles and D. E. Nichols, J. Org. Chem., 1988, 53, 5128. (d) M. Iwao and F. Ishibashi,
Tetrahedron, 1997, 53, 51. (e) Y. Yokoyama, T. Matsumoto, and Y. Murakami, J. Org. Chem., 1995,
60, 1486. (f) M. Somei, S. Hamamoto, K. Nakagawa, F. Yamada, and T. Ohta, Heterocycles, 1994, 37,

HETEROCYCLES, Vol. 60, No. 1, 2003
87
719. (g) L. Novák, M. Hanania, P. Kovács, J. Rohály, P. Kolonits, and C. Szántay, Heterocycles, 1997,
45, 2331.
8. (a) R. I. Fryer, R. Y. F. Ning, L. H. Sternbach, and A. Walser (Hofmann-La Roche, Inc.), Swiss
Patent CH 602 728 (1978), 6 pp (Chem. Abstr., 1978, 89, 146890z). (b) R. I. Fryer, R. Y. F. Ning, L.
H. Sternbach, and A. Walser, US Patent 4, 014, 883 (1977), 26 pp (Chem. Abstr., 1977, 87, 39450t).
(c) N. Strojny , L. D'Arconte, and J. A. F. de Silva, J. Chromatogr., 1981, 223, 111. (d) E. Grunberg,
M. J. Kramer, M. Buch, and P. W. Trown, Chemotherapy, 1978, 24, 77. (e) A. Walser, G. Silverman,
T. Flynn, and R. I. Fryer, J. Heterocycl. Chem., 1975, 12, 351.
9. (a) R. A. Abramouvitch and I. D. Spenser, "Advanced Heterocyclic Chemistry : The β-Carbolines" ,
Vol. 3, ed. by A. R. Katritzky, A. J. Boulton, and J. M. Lagowski, Academic Press, New York, 1964,
pp. 79-207. (b) A. Brossi, " The alkaloids ", Vol. XXII, Academic Press, New York, 1983, Chapters 1
and 4. (c) B. J. Baker, "Alkaloids : Chemical and Biological Perspectives", Vol. 10, ed. by W.
Pelletier, Pergmon Press, Oxford, 1996, pp. 357-407.
10. For the preparation of N-indolylmetal salts and their utilization in the synthesis of 3-(heteroaryl)-
indoles, see : (a) R. A. Heacock and S. Kǎspárek, "Advances in Heterocyclic Chemistry : The Indole
Grignard Reagents", Vol. 10, ed. by A. R. Katritzky and A. J. Boulton , Academic Press, New York,
1969, pp. 43-112. (b) J. Bergman and L. Venemalm, Tetrahedron, 1990, 46, 6061. (c) W. A. Ayer,
P. A. Craw, Y-T. Ma, and S. Mialo, Tetrahedron, 1992, 48, 2919. (d) K. A. Abu Safieh, M. M. El-
Abadelah, S. S. Sabri, M. H. Abu Zarga, W. Voelter, and C. M.-Mössmer, J. Heterocycl. Chem.,
2001, 38, 623, and references cited therein.
11. J. A. Cowan, Tetrahedron Lett., 1986, 27, 1205. See also: H. V. Patel , K. A. Vyas, S. P. Pandey, and
P. S. Fernandes, Organic Preparations and Procedures Int., 1995, 27, 81.
R
11
H
N1
10 N
12. The pentacyclic skeleton of 9a,b is also named, by the
2
9
hetero-substitution (replacement) method, as follows:
3
8
CF3
4
7
6 N
5,6-dihydro-1H-1,6,10-triazabenzo[ij]naphtha[2,1,8-cde]azulene.
5
H
R
9a,b
13. R. H. Blessing, Acta Crystallogr., 1995, A51, 33.
14. G. M. Sheldrick, SHELXTL PLUS System of computer programs for the determination of crystal
structure from the X-Ray diffraction data, Vers.5.10.DOS/WIN 95/NT.