One-pot efficient synthesis of novel fused pentacyclic indolopyridobenzimidazoles and pyridoimidazopyridoindoles from the reaction of pyranoindolones with 1,2-diaminobenzenes and 2,3-diaminopyridines

Article abstract of DOI:10.1016/j.tet.2012.03.101

The synthesis of a number of novel, fully conjugated, planar pentacyclic 5H-indolo[3′,2′:4,5]pyrido[1,2-a][1,3]benzimidazoles (8) and 11H-pyrido[3″,2″:4′,5′]imidazo[1′,2′:1,6] pyrido[3,4-b]indoles (12) by a one-pot reaction of pyranoindolones with substituted o-phenylenediamines or 2,3-diaminopyridines is described. In the case of 2,3-diaminopyridines the reaction proceeds regioselectively affording only regioisomers 12. Structural assignments of the new compounds as well as complete assignment of ¹H and ¹³C NMR signals were based on the analysis of their ¹H and ¹³C NMR (1D and 2D), IR, MS and elemental analysis data. Plausible mechanisms are proposed.

Full text of DOI:10.1016/j.tet.2012.03.101

Tetrahedron 68 (2012) 4202e4209
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot efficient synthesis of novel fused pentacyclic
indolopyridobenzimidazoles and pyridoimidazopyridoindoles from the reaction
of pyranoindolones with 1,2-diaminobenzenes and 2,3-diaminopyridines
*
*
Despina Livadiotou, Anna Maria Fadel, Constantinos A. Tsoleridis , Julia Stephanidou-Stephanatou
Department of Chemistry, Laboratory of Organic Chemistry, University of Thessaloniki, Thessaloniki 54124, Macedonia, Greece
a r t i c l e i n f o
a b s t r a c t
The synthesis of a number of novel, fully conjugated, planar pentacyclic 5H-indolo[30,20:4,5]pyrido[1,2-a]
[1,3]benzimidazoles (8) and 11H-pyrido[300,200:40,50]imidazo[10,20:1,6]pyrido[3,4-b]indoles (12) by a one-
pot reaction of pyranoindolones with substituted o-phenylenediamines or 2,3-diaminopyridines is de-
scribed. In the case of 2,3-diaminopyridines the reaction proceeds regioselectively affording only re-
gioisomers 12. Structural assignments of the new compounds as well as complete assignment of 1H
and 13C NMR signals were based on the analysis of their 1H and 13C NMR (1D and 2D), IR, MS and el-
emental analysis data. Plausible mechanisms are proposed.
Article history:
Received 8 December 2011
Received in revised form 7 March 2012
Accepted 26 March 2012
Available online 30 March 2012
Keywords:
Bisnucleophiles
o-Phenylenediamines
2,3-Diaminopyridines
Indolopyridobenzimidazoles
Pyranoindolones
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
some new polyheterocyclic systems by fusing pyranoindolones
with o-phenylenediamines.
p-systems, such as fluo-
Very recently interest in heterocyclic
rindine 1, has re-emerged1e9 owing to the presence of nitrogen
atoms, which offer a number of opportunities to manipulate and
control the electronic properties, the stability, and the supramo-
lecular arrangement in the solid state.10 In addition, poly-
heterocyclic systems are of potential pharmacological value since
nitrogen containing pentacyclic compounds constitute natural al-
kaloids (Fig. 1), such as rutaecarpine 2 and the luotonins 3, which
have shown antitumor activities,11,12 and yohimbenone 4, which is
a common structural motif found in a variety of physiologically
active compounds.13 Moreover, it has been reported14 that the
water soluble 14-azacamptothecin, a hybrid between luotonin A
and the naturally occurring antitumor agent camptothecin 5, is
nearly as potent as camptothecin in stabilizing the covalent binary
complex formed between human topoisimerase I and DNA. Since
activity of the pentacyclic compounds mentioned above encour-
ages the further identification of more potent analogs, as a contin-
uation of our research into the synthesis and reactivity of
new heterocyclic systems having an indole ring linked to various
heterocycles,15 we envisaged the possibility of synthesizing
2. Results and discussion
Initially, the pyranoindolone 6b was allowed to react with 1.2 M
equiv of 4,5-dimethyl-o-phenylenediamine 7b in refluxing xylene
H
N
N
N
O
N
N
H
N
H
N
1
2
O
N
N
H
N
N
H
H
4
N
3
O
O
N
N
O
O
5
H
O
* Corresponding authors. E-mail address: ioulia@chem.auth.gr (J. Stephanidou-
Fig. 1. Some representative fused pentacyclic heteroaromatic scaffolds of natural
Stephanatou).
products.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.101

D. Livadiotou et al. / Tetrahedron 68 (2012) 4202e4209
4203
in the presence of a catalytic amount of acetic acid, whereupon no
reaction was observed after 4.5 h at reflux. However, by changing
the solvent to bromobenzene and heating at reflux for 1 h, the
desired pentacyclic product 8e was isolated in 58% yield. Longer
reaction times or use of a DeaneStark apparatus did not improve
the reaction yield considerably. By changing the catalyst to p-tol-
uenesulfonic acid only unidentified decomposition products were
formed (Scheme 1, Table 1).
3 O
13
11
5
N
N
R3
R3
1
i
R3
R3
H2N
H2N
+
O
1R2
reflux
6R2
N
N
8
4
8
R1
R1
6
8
7
R3
R1
R2 R3
R1
R2 R3
R1
H
H
H
Me
Me
Me n-Pr
R2
Me
Et
n-Pr
Me
Et
a
H
g
h
i
Me Et
H
H
a
b
H
H
H
H
H
Et
H
H
b
Me
c
d
e
f
Me n-Pr
b
c
d
e
f
n-Pr
Me Me
Et Me
n-Pr Me
Me Me Me
Me Et Me
Me n-Pr Me
j
k
Scheme 1. Reaction of pyranoindolones 6 with o-phenylenediamines 7. (i) For reaction conditions see Table 1.
Table 1
Wishing to introduce an additional nitrogen atom into the
polycyclic system, the reaction was repeated with 2,3-
diaminopyridine 11, whereupon the corresponding products 12
were isolated in moderate yields (25e32%, Scheme 2) along with
polymeric material. Since the reactivity of the amino-groups is
reduced, due to the presence of the pyridine nitrogen, long reaction
times were required for the completion of the reaction (w18 h), and
even then in the case of 6e the reaction was not driven to com-
pletion, and the indole intermediate product 13e was also isolated
in 15% yield, whereas in some cases products 14 were formed
instead.
Various reaction conditions and products
Entry
Reagents
Solvent
Temp
(ꢀC)
Acid
catalyst
Time
(h)
Prod
Yield %
1
2
3
4
5
6
7
8
6a
6b
6b
6b
6b
6c
6c
6d
6d
6e
6e
6f
7b
PhBr
PhBr
PhBr
PhBr
xylene
xylene
xylene
PhBr
PhBr
PhBr
156
156
156
156
138
138
138
156
156
156
156
138
138
156
AcOH
AcOH
AcOH
p-TSA
AcOH
AcOH
AcOH
p-TSA
AcOH
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
1
1.5
1
8d
8b
78
86
58
d
7a
7b
7b
7b
7a
7b
7b
7b
7a
7b
7a
7b
7b
8e
a
1
b
4.5
3.5
3.5
1.5
1.5
2.5
2.5
4.5
4.5
1.5
d
8c
8f
9i
10
8g
8j
65
80
13
47
52
83
51
69
d
9
10
11
12
13
14
PhBr
p-TSA
4
5
7
O
6
N
N
xylene
xylene
PhBr
8h
4
H2N
H2N
PhBr
6f
6f
8k
+
O
b
N1
N
reflux
18 h
N
R1
N
R1
1 R2
6
12R2
8
10
a
Unidentified decomposition products.
Unreacted reagents.
b
11
12
R1
H
R2
Me
a
H2N
H2N
O
In order to investigate the possibility of a more general appli-
cation of the method, having established the optimum reaction
conditions concerning the acid catalyst, temperature and time, the
4
7
4
e
M
b
c
H
E
t
N
2'
N
N
H
N
n-Pr
Me
Et
n-Pr
H
O
R2
N1
R1
N1
R1
7
d
e
4' 5'
Me
Me
Me
reaction was repeated with
a
number of substituted pyr-
R2
anoindolones 6 and o-phenylenediamines 7, and the results are
summarized in Scheme 1 and Table 1. From a careful inspection of
the results given in Table 1 it can be proposed that the optimum
reaction conditions depend on the substituents of the pyr-
anoindolones 6. Thus, when the R1 substituent is hydrogen the
reaction proceeds successfully using acetic acid as the catalyst,
whereas when R1 is methyl better results are obtained by using p-
toluenesulfonic acid. Concerning the R2 substituents its size seems
to be of some importance to the reaction outcome. Thus, when R2 is
methyl or ethyl, bromobenzene is the required solvent, whereas
when it is propyl better results are obtained in xylene. Finally, in the
case of the dimethyl substituted pyranoindolone 6d, instead of the
expected pentacyclic product 8i, depending on the acid catalyst,
compounds 9i or 10, along with some polymeric material were
isolated by heating at reflux in bromobenzene, whereas no reaction
was observed in xylene.
f
13
14
Scheme 2. Reaction of pyranoindolones
bromobenzene.
6 with 2,3-diaminopyridine 11 in
A resonable mechanism for the reaction of pyranoindolones
with o-phenylenediamines is shown in Scheme 3. As it was pointed
out in our previous work,15cef the indolone ring can react with
nucleophiles either from position 1 or from position 3 depending
on the reactivity of the nucleophilic center. Thus, following path a,
the reaction begins by attack of an NH2 group of o-phenylenedi-
amine at position 1 of indolone 6, being the less reactive electro-
philic center, to form intermediate 15. This zwitterionic species by
subsequent cyclization-water abstraction leads to amide 9. Finally,
by a second internal nucleophilic attack of the former amine

4204
D. Livadiotou et al. / Tetrahedron 68 (2012) 4202e4209
Scheme 3. Plausible mechanism for the reaction of pyranoindolones 6 with o-phenylenediamines.
nitrogen to the amide carbonyl of 9 gives via a new ring closure
intermediate 16, from which by subsequent dehydration the pen-
tacyclic derivative 8 is obtained. Following the alternative pathway
b, the reaction can be initiated by attack to the carbonyl carbon of
indolone leading to 17. From 17 the same product 8 can be formed,
either through intermediate 9, or by following path c through in-
termediate 18. From 18, water abstraction leads to 19, from which
by subsequent attack of the free amino group to the carbonyl
carbon and cyclization, intermediate 16 is formed again. However,
the isolation of product 9i offers a realistic support to the in-
termediacy of 9.
Concerning the formation of compound 10, most probably the
reaction begins by attack of the amino nitrogen of 7d at position 1
of 6d (Scheme 4) resulting, in the high reaction temperature, after
decarboxylation of 20 to 21, from which by subsequent trans-
formations, finally, compound 10 is formed.
For the formation of compounds 12, from the reaction of pyr-
anoindolones with 2,3-diaminopyridine, a mechanism analogous
to path b (Scheme 3) can be considered, which is supported by
the isolation of intermediate product 13e. The alternative to 12,
regioisomeric structure 23 (Fig. 2), which could be formed by
attack of the 2-amino nitrogen at the indolone carbonyl carbon,
could be excluded (see also structure elucidation and theoretical
calculations).
However, in the case of a reaction beginning by attack of the 3-
amino nitrogen at position 1 of indolone, the next step, namely ring
formation, through reaction of the 2-amino nitrogen seems to be
disfavored, due to either electronic or stereochemical reasons,
resulting thus in the high reaction temperature, which lead to de-
carboxylation to compounds 14. The alternative to 14, regioiso-
meric structure 24, could also be excluded (see also structure
elucidation and theoretical calculations).
Scheme 4. Mechanistic rationale for the formation of compound 10.

D. Livadiotou et al. / Tetrahedron 68 (2012) 4202e4209
4205
carbon at 33.6 ppm. These 5-N-methyl group protons gave COLOC
correlations with the quaternary carbons at 129.54 ppm (C-5a) and
147.4 ppm (C-4a), whereas the ethyl methylene protons with the C-
6 carbon at 125.3 ppm. Finally, the two o-phenylenediamine methyl
group protons gave COLOC correlations with the quaternary car-
bons at 128.5 ppm (C-10) and 134.1 ppm (C-9) and also with the
protonated carbons at 115.2 ppm (C-8) and 118.9 ppm (C-11), thus
the whole molecule carbon sequence was identified. A NOESY ex-
periment was used to distinguish the proton in position 8 showing
correlations with 6-ethyl protons (Fig. 3). The structure of com-
pound 10, an almost symmetric quinoxalinic derivative, was fully
elucidated by the HMBC correlations (Fig. 3).
Analogous COLOC correlations were observed in products 12. In
NOESY experiments no NOE correlations were observed between
the 6-alkyl protons and the characteristic multiplets of the
pyridine-ring protons thus excluding structure 23. In Fig. 3 all the
COLOC (or HMBC) correlations between protons and carbons in
compounds 8j, 10, 12e, 13e and 14a are depicted.
H2N
N
12
11
4
N
N
e
M
4'
6'
N
2
3
N
6
P
N7
N 2
7
8
4
e
M
r
H
H
23
24
Fig. 2. Structures 23 and 24, alternatives of 12 and 14, which are excluded.
2.1. Structure elucidation
The assigned molecular structures of all new compounds 8, 10,
12, 13 and 14 are based on rigorous spectroscopic analysis including
IR, NMR [1H, 13C, DEPT, COSY, NOESY, HETCOR (or HMQC) and
COLOC (or HMBC)], MS and elemental analysis data.
Regarding the structure of the isolated indolopyr-
idobenzimidazoles 8 the assignment of 8j is described. The ele-
mental analysis and mass spectra established the reaction of one
molecule of pyranoindolone 6e with one molecule of 4,5-dimethyl-
o-phenylenediamine (7b) with the loss of two water molecules. In
the 1H NMR spectrum the presence and the position of the four
indole aromatic protons was unequivocally identified from their
splitting pattern and COLOC correlations (Fig. 3). Moreover, in the
aromatic region two one-proton singlets were observed at 7.73 and
7.81 ppm, corresponding to the former 3,6-o-phenylenediamine
protons, with their carbons at 118.9 and 115.2 ppm, and giving
COLOC correlations with the quaternary carbons at 127.4 (C-7a) and
134.1 (C-9) ppm, and at 128.5 (C-10) and 144.6 (C-11a) ppm, re-
spectively. One more singlet resonating at 8.08 ppm and corre-
sponding to the 13-position proton with its carbon resonating at
102.8 ppm was also observed. This proton gave COLOC correlations
with the quaternary carbon at 147.1 ppm (C-12a). Moreover, in
addition to the ethyl group and the two o-phenylenediamine
methyl groups, one N-methyl group appeared at 3.99 ppm with its
2.2. Theoretical calculations
To distinguish between structures 12 or 23 and define the po-
sition of the pyridine nitrogen theoretical calculations were carried
out at the B3LYP level of density functional theory (DFT) in con-
junction with DFT/GIAO calculated isotropic magnetic shield-
ings.16,17 Both, the geometries of the selected compounds 12c and
23 have been optimized and the isotropic nuclear magnetic
shielding constants (IMS) were calculated by using 6-311G(df,p)
basis set. The results are presented as DIMS differences relatively to
TMS shielding calculated at the same theoretical level.18 The cal-
culated values for the pyridine-ring carbons for structure 12c
compared with the ones for structure 23 have much less deviations
from the experimental data (23.4 vs 46.9 ppm) and analogously for
H
H
H
H
H
3C
H
N
H
C
NH
H
3
H
N
H
H
H
H
H
3
C
N
C
H
C
H
C
N
N
H
3
3
H
H
H
H
C
H
2
3
H
H
3C
H
C
3
H
H
3C
N
E Y
O S
8
j
10
H
H
H
H
N
H
N
N
N
C
H
H
C
2
H
3
N
E
O
Y
S
3C
e
12
O
H
H
H
H
H
N
H
H
H
H
O
H
H2N
H2N
H
N
N
H
C
3
H
N
C
N
H
H
H
C
2
H
3
N
H
H
H
H
H
C
3
H
3C
e
13
a
14
2
3
Fig. 3. COLOC (or HMBC) correlations between protons and carbons (via JCꢁH and JCꢁH) in compounds 8j, 10, 12e, 13e and 14a.

4206
D. Livadiotou et al. / Tetrahedron 68 (2012) 4202e4209
protons (0.69 vs 1.23 ppm), leading to the conclusion that the
structure of the isolated products corresponds to 12 (Table 2).
Moreover, as noted above, in a NOESY experiment no NOE corre-
lations were observed for compounds 12e and 12f between the
protons of 12-ethyl and 12-propyl groups with the protons at po-
sition 4 of the pyridine-ring.
them need heating up to 40e55 ꢀC. The chemical shifts are
expressed in
d values (ppm) relative to TMS as internal standard
for 1H and relative to TMS (0.00 ppm) or to CDCl3 (77.05 ppm) or
to DMSO-d6 (39.5 ppm) for 13C NMR spectra. Coupling constants
nJ are reported in Hertz; sex for sextet. IR spectra were recorded
on
a PerkineElmer 1600 series FTIR spectrometer and are
Table 2
Calculated isotropic magnetic shieldings relative to TMSa
compounds
(DIMS) in comparison with the observed chemical shifts for pyridine-ring carbon and proton nuclei of selected
Compd
Atom
12c
23
14a
24
D
IMSb
ppm
Devc
DIMS
ppm
Dev
Atom
DIMS
ppm
Dev
DIMS
ppm
Dev
2
3
4
4a
13a
143.9
125.0
131.8
144.8
150.2
139.6
122.1
125.3
137.6
147.7
SDevd
8.42
4.3
2.9
6.5
7.2
2.5
23.4
0.26
0.18
0.25
0.69
153.4
117.3
124.2
126.3
163.6
139.6
122.1
125.3
137.6
147.7
SDev
8.42
7.43
8.15
13.8
4.8
1.1
11.3
15.9
46.9
20
30
40
50
60
159.1
134.7
128.4
115.6
151.3
151.6
131.0
126.4
113.8
143.0
SDev
6.85
6.68
7.87
7.5
3.7
2.0
1.8
8.3
23.3
0.23
0.08
0.34
0.65
152.9
146.4
122.9
125.7
140.8
151.6
131.0
126.4
113.8
143.0
SDev
6.85
6.68
7.87
1.3
15.4
3.5
11.9
2.2
34.3
0.07
0.24
0.19
0.50
2-H
3-H
4-H
8.68
7.61
8.40
9.25
7.27
8.39
0.83
40-H
50-H
6΄-H
6.62
6.60
8.21
6.98
6.92
8.06
7.43
0.16
0.24
1.23
8.15
SDevd
SDev
SDev
SDev
a
Isotropic magnetic shieldings for TMS calculated by B3LYP/6-311G(df,p) method: For 1H IMSTMS¼31.99; for 13C IMSTMS¼184.67 ppm.
b
c
Relative
D
IMS¼IMSTMSꢁIMSx for magnetic nuclei X.
Absolute value of deviation of computed chemical shift from the experimental value.
Sum of absolute deviations. For atom numbering see Scheme 2 and Fig. 2.
d
Similarly, to define the position of the amine group of the
reported in wave numbers (cmꢁ1). LC-MS (ESI, 1.65 eV) spectra
were recorded on LCMS-2010 eV system (Shimadzu) and ele-
mental analyses performed with a PerkineElmer 2400-II CHN
analyzer.
pyridine-ring connected with the indole moiety in structures 14 or
24 theoretical calculations were carried out, as above, for their
isotropic nuclear magnetic shielding constants (Table 2). The cal-
culated values for structure 14a compared to those of structure 24
have much less deviations for the pyridine-ring carbons from the
experimental data (23.3 vs 34.3 ppm) and also comparable values
for the protons, leading to the conclusion that the isolated products
have the structure of 14.
The minimum energy conformations of compounds were
computed with the AM1 method as implemented in the MOPAC
2000 package21 and referred to vacuum. All geometry optimiza-
tions were carried out without symmetry constraints and sta-
tionary points were refined by minimization of the gradient
norm of the energy to at least 0.01 kcal/mol, using the LET and
PRECISE keywords. Moreover, the complete assignment of 1H and
13C NMR signals was possible using 1D and 2D experiments in
combination with DFT/GIAO calculated isotropic magnetic
shielding. For DFT optimizations the AM1 geometry was used as
input and total energy calculations have been performed with the
6-311G(df,p) basis set by using the restricted B3LYP functional as
implemented in the Gaussian 2004 package.22 The isotropic nu-
clear magnetic shielding constants (IMS) were calculated by us-
ing the same basis set and the results are presented as the
3. Conclusions
In conclusion, we have developed a direct method for the one-
pot synthesis of a series of the unknown fully conjugated and
planar fused pentacyclic 5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]
benzimidazoles and 11H-pyrido[300,200:40,50]imidazo[10,20:1,6]pyr-
ido[3,4-b]indoles. Moreover, the reaction of 2,3-diaminopyridines
proceeds regioselectively affording only regioisomers 12. Recent
studies revealed that analogous natural product scaffolds,19 but also
their synthetic analogs,20 show strong DNA binding properties and
dual topoisomerase I/II targeting or constitute DNA intercalating
agents.
differences
DIMS relatively to TMS shielding. Structural assign-
ments of the derived compounds were established by analysis of
their IR, MS and NMR spectra [1H, 13C, COSY, NOESY, HETCOR (or
HMQC), and COLOC (or HMBC)] using the standard commercial
pulse programs.
4. Experimental
4.1. General information
4.2. Experimental procedure for the reaction of
indolopyranones with o-phenylenediamines and
2,3-diaminopyridines
Melting points were measured on a Kofler hot-stage. Column
chromatography was carried out using Merck silica gel (70e230
mesh) and TLC was performed using precoated silica gel glass
plates 0.25 mm containing fluorescent indicator UV254 purchased
from MachereyeNagel using a 3:1 mixture of petroleum ether-
eethyl acetate. Petroleum ether refers to the fraction boiling
between 60 and 80 ꢀC. NMR spectra were measured at room
temperature, unless it is noted differently, on a Bruker AM 300 or
AVANCE300 spectrometer at 300 MHz for 1H and 75 MHz for 13C,
respectively, using CDCl3 or (CDCl3þDMSO-d6) as solvent. Gen-
erally, the products are insoluble in chloroform, especially those
without methyl group in position 1 of the indole ring, so some of
To
a stirred and refluxing solution of pyranoindolone 6
(1.5 mmol) in bromobenzene (or xylene, as indicated) (15 mL) with
a catalytic amount of acetic acid (two drops, 0.020 g, 0.33 mmol) or
p-toluenesulfonic acid (0.030 g, 0.16 mmol), o-phenylenediamine 7
(Fluka, purum) (3.0 mmol) was added and heating at reflux was
continued until indolone 6 was consumed completely (followed by
TLC). On completion of the reaction, the solvent was removed un-
der reduced pressure to yield the corresponding crude product,
which was subjected to chromatography on silica gel using petro-
leum ether/EtOAc (2:1) up to EtOAc as eluent to give the products:

D. Livadiotou et al. / Tetrahedron 68 (2012) 4202e4209
4207
4.2.1. 6-Ethyl-5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]benzimidazole
(C10), 128.7 (C3), 130.0 (C5a), 132.8 (C13a), ** 132.9 (C9), ** 144.8
(C11a), 146.7 (C12a),** 146.8 (C4a);** LC-MS (ESI, 1.65 eV) m/z 649
[25, (2ꢂMþNa)þ], 368 [10, (MþMeOHþNa)þ], 336 [5, (MþNa)þ],
314 [100, (MþH)þ]. Anal. Calcd for C21H19N3 (313.40): C, 80.48; H,
6.11; N, 13.41%. Found: C, 80.70; H, 6.18; N, 13.16%. (* Decomposed.
** The assignment may be interchanged).
(8b). Yellow crystals (0.368 g, 86%), mp 307e308 ꢀC (*) (ethanol); Rf
(EtOAc) 0.10; IR (KBr) nmax: 3446, 2962, 2930, 1619 cmꢁ1 1H NMR
;
(CDCl3þDMSO-d6): 1.57 (t, J¼7.3 Hz, 3H, 6-CH3), 3.73 (q, J¼7.3 Hz,
2H, 6-CH2), 7.14 (dd, J¼8.1, 7.0 Hz, 1H, 2-H), 7.28 (dd, J¼8.2, 7.0 Hz,
1H, 10-H), 7.39 (d, J¼8.1 Hz, 1H, 4-H), 7.49 (dd, J¼8.1, 7.0 Hz, 1H, 3-
H), 7.53 (dd, J¼8.5, 7.0 Hz, 1H, 9-H), 7.94 (d, J¼8.2 Hz, 1H, 11-H), 8.06
(d, J¼8.1 Hz, 1H, 1-H), 8.07 (s, 1H, 13-H), 8.18 (d, J¼8.5, 1H, 8-H),
10.60 (s br 1H, 5-H); 13C NMR (CDCl3þDMSO-d6 at 55 ꢀC): 10.9 (6-
CH3), 20.6 (6-CH2), 101.5 (C13), 110.4 (C4), 114.3 (C8), 117.8 (C10),
118.6 (C2),** 118.9 (C11),** 120.8 (C13b), 121.7 (C1), 123.7 (C9), 124.4
(C7a), 127.9 (C6), 128.2 (C5a), 129.0 (C3), 130.6 (C13a), 144.9
(C11a),** 145.0 (C12a),**147.1 (C4a); LC-MS (ESI, 1.65 eV) m/z 593
[20, (2ꢂMþNa)þ], 340 [10, (MþMeOHþNa)þ], 308 [5, (MþNa)þ],
286 [100, (MþH)þ]. Anal. Calcd for C19H15N3 (285.34): C, 79.98; H,
5.30; N, 14.73%. Found: C, 80.25; H, 5.55; N, 14.56%. (* Decomposed.
** The assignment may be interchanged).
4.2.5. 9,10-Dimethyl-6-propyl-5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]
benzimidazole (8f). Yellow crystals (0.393 g, 80%), mp 206e207 ꢀC
(ethanol); Rf (EtOAc) 0.13; IR (KBr) nmax: 3446, 2955, 1644 cmꢁ1; 1H
NMR 1.16 (t, J¼7.3 Hz, 3H, 6-CH2CH2CH3), 1.95 (sex, J¼7.3 Hz, 2H, 6-
CH2CH2CH3), 2.44 (s, 3H, 10-CH3), 2.49 (s, 3H, 9-CH3), 3.66 (t,
J¼7.3 Hz, 2H, 6-CH2CH2CH3), 7.10 (ddd, J¼8.0, 7.0, 1.3 Hz, 1H, 2-H),
7.38 (dd, J¼8.2, 1.3 Hz, 1H, 4-H), 7.45 (ddd, J¼8.2, 7.0, 1.1 Hz, 1H, 3-
H), 7.58 (s, 1H, 11-H), 7.91 (s, 1H, 8-H), 8.04 (s, 1H, 13-H), 8.12 (dd,
J¼8.0,1.1 Hz, 1H,1-H), 10.5 (s br,1H, 13-H); 13C NMR (CDCl3þDMSO-
d6 at 55 ꢀC): 12.7 (6-CH2CH2CH3), 19.4 (9-CH3, 10-CH3), 19.9 (6-
CH2CH2CH3), 29.0 (6-CH2CH2CH3), 101.4 (C13), 110.2 (C4), 114.0
(C8), 117.9 (C11),** 118.0 (C2),** 120.9 (C13b), 121.5 (C1), 122.5 (C6),
126.6 (C7a),** 126.9 (C10),** 128.5 (C5a), 128.7 (C3), 129.8 (C9),
132.6 (C13a), 144.0 (11a), 144.7 (C12a), 147.0 (C4a); LC-MS (ESI,
1.65 eV) m/z 677 [20, (2ꢂMþNa)þ], 382 [10, (MþMeOHþNa)þ], 350
[10, (MþNa)þ], 328 [100, (MþH)þ]. Anal. Calcd for C22H21N3
(327.42): C, 80.70; H, 6.46; N, 12.83%. Found: C, 80.76; H, 6.58; N,
12.55%. (** The assignment may be interchanged).
4.2.2. 6-Propyl-5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]benzimidazole
(8c). Yellow crystals (0.292 g, 65%), mp 251e253 ꢀC (*) (ethanol);
Rf (EtOAc) 0.10; IR (KBr) nmax: 3448, 2959, 2930, 1619 cmꢁ1 1H
;
NMR (CDCl3þDMSO-d6): 1.20 (t, J¼7.3 Hz, 3H, 6-CH2CH2CH3), 2.01
(sex, J¼7.3 Hz, 2H, 6-CH2CH2CH3), 3.60 (t, J¼7.3 Hz, 2H, 6-
CH2CH2CH3), 7.15 (dd, J¼8.1, 7.2 Hz, 1H, 2-H), 7.28 (dd, J¼8.2,
7.0 Hz, 1H, 10-H), 7.35 (d, J¼8.2 Hz, 1H, 4-H), 7.50 (dd, J¼8.2, 7.2 Hz,
1H, 3-H), 7.52 (dd, J¼8.3, 7.0 Hz, 1H, 9-H), 7.91 (d, J¼8.2 Hz, 1H, 11-
H), 8.01 (d, J¼8.1 Hz, 1H, 1-H), 8.05 (d, J¼8.3, 1H, 8-H), 8.06 (s, 1H,
13-H), 10.50 (s br 1H, 5-H); 13C NMR (CDCl3þDMSO-d6): 13.3 (6-
CH2CH2CH3), 19.9 (6-CH2CH2CH3), 29.8 (6-CH2CH2CH3), 101.4
(C13), 110.6 (C4), 114.3 (C8), 117.9 (C10), 118.6 (C2), 118.9 (C11),
121.0 (C13b), 121.8 (C1), 123.3 (C7a), 124.5 (C9), 127.9 (C6), 128.3
(C5a), 129.3 (C3), 129.5 (C13a), 145.0 (C11a),** 145.2 (C12a),** 145.5
(C4a);** LC-MS (ESI, 1.65 eV) m/z 621 [70, (2ꢂMþNa)þ], 354 [30,
(MþMeOHþNa)þ], 322 [7, (MþNa)þ], 300 [100, (MþH)þ]. Anal.
Calcd for C20H17N3 (299.37): C, 80.24; H, 5.72; N, 14.04%. Found: C,
80.05; H, 5.46; N, 14.36%. (* Decomposed. ** The assignment may
be interchanged).
4.2.6. 6-Ethyl-5-methyl-5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]benz-
imidazole (8g). Yellow crystals (0.233 g, 52%), mp 179e180 ꢀC (*)
(ethanol); Rf (EtOAc) 0.18; IR (KBr) nmax: 2966, 2930, 1650,
1616 cmꢁ1
;
1H NMR: 1.57 (t, J¼7.6 Hz, 3H, 6-CH2CH3), 3.64 (q,
J¼7.6 Hz, 2H, 6-CH2CH3), 3.83 (s, 3H, 5-CH3), 7.10 (d, J¼8.2 Hz, 1H, 4-
H), 7.12 (dd, J¼8.1, 7.0 Hz, 1H, 2-H), 7.20 (dd, J¼8.3, 7.2 Hz, 1H, 10-H),
7.45 (dd, J¼8.2, 7.0 Hz,1H, 3-H), 7.46 (dd, J¼8.1, 7.2 Hz,1H, 9-H), 7.92
(d, J¼8.3 Hz, 1H, 11-H), 7.98 (d, J¼8.1 Hz, 1H, 8-H), 7.99 (d, J¼8.1, 1H,
1-H), 8.00 (s, 1H, 13-H); 13C NMR: 7.7 (6-CH3), 29.7 (6-CH2), 31.9 (5-
CH3), 104.5 (C13), 109.8 (C4), 114.4 (C8), 120.1 (C13b), 121.4 (C11),
122.1 (C2), 123.2 (C1),** 123.3 (C6), 123.5 (C10),** 124.7 (C9), 125.2
(C3), 125.3 (C5a), 126.6 (C6a), 131.3 (C13a), 138.8 (C11a), 143.0
(C12a), 145.2 (C4a); LC-MS (ESI, 1.65 eV) m/z 621 [20, (2ꢂMþNa)þ],
354 [10, (MþMeOHþNa)þ], 322 [4, (MþNa)þ], 300 [100, (MþH)þ].
Anal. Calcd for C20H17N3 (299.37): C, 80.24; H, 5.72; N, 14.04%.
Found: C, 80.55; H, 5.51; N, 14.15%. (* Decomposed. ** The assign-
ment may be interchanged).
4.2.3. 6,9,10-Trimethyl-5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]benz-
imidazole (8d). Yellow crystals (0.350 g, 78%), mp 246e247 ꢀC
(ethanol); Rf (EtOAc) 0.10; IR (KBr) nmax: 3450, 2960, 1618 cmꢁ1; 1H
NMR (CDCl3þDMSO-d6): 2.44 (s, 3H, 10-CH3), 2.48 (s, 3H, 9-CH3),
3.30 (s, 3H, 5-CH3), 7.10 (dd, J¼8.0, 7.0 Hz,1H, 2-H), 7.37 (d, J¼7.9 Hz,
1H, 4-H), 7.45 (dd, J¼7.9, 7.0 Hz, 1H, 3-H), 7.58 (s, 1H, 11-H), 8.05 (s,
1H, 8-H), 8.07e8.12 (m, 2H, 1-H, 13-H), 10.5 (s br, 1H, 5-H); 13C NMR
(CDCl3þDMSO-d6 at 55 ꢀC): 15.4 (6-CH3), 19.6 (10-CH3), 19.7 (9-
CH3), 101.1 (C13), 110.2 (C4), 114.5 (C8), 118.1 (C11), 117.7 (C2),
121.1 (C13b), 121.6 (C1), 126.6 (C6), 127.7 (C7a), 128.4 (C10), 128.7
(C3),129.8 (C5a),132.66 (C13a), ** 132.75 (C9), ** 144.7 (C11a),146.6
(C12a),** 146.7 (C4a);** LC-MS (ESI, 1.65 eV) m/z 621 [10,
(2ꢂMþNa)þ], 355 [5, (MþMeOHþNaþH)þ], 300 [100, (MþH)þ].
Anal. Calcd for C20H17N3 (299.37): C, 80.24; H, 5.72; N, 14.04%.
Found: C, 80.47; H, 5.81; N, 14.19%. (* Decomposed. ** The assign-
ment may be interchanged).
4.2.7. 5-Methyl-6-propyl-5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]benz-
imidazole (8h). Yellow crystals (0.240 g, 51%), mp 155e156 ꢀC (*)
(ethanol); Rf (EtOAc) 0.18; IR (KBr) nmax: 3050, 2955, 2927, 1654,
1638 cmꢁ1; 1H NMR: 1.28 (t, J¼7.6 Hz, 3H, 6-CH2CH2CH3), 1.90e2.15
(m br, 2H, 6-CH2CH2CH3), 3.81 (t, J¼8.3 Hz, 2H, 6-CH2CH2CH3), 4.00
(s, 3H, 5-CH3), 7.20 (ddd, J¼8.0, 7.2, 0.9 Hz, 1H, 2-H), 7.27 (dd, J¼8.0,
0.9 Hz, 1H, 4-H), 7.31 (ddd, J¼8.3, 7.3, 1.2 Hz, 1H, 10-H), 7.51 (ddd,
J¼8.0, 7.2, 0.7 Hz,1H, 3-H), 7.57 (ddd, J¼8.1, 7.3, 1.4 Hz,1H, 9-H), 7.93
(dd, J¼8.3, 1.4 Hz, 1H, 11-H), 8.05 (dd, J¼8.1, 1.2 Hz, 1H, 8-H), 8.06
(dd, J¼8.0, 0.7 Hz, 1H, 1-H), 8.10 (s, 1H, 13-H); 13C NMR: 11.2 (6-
CH2CH2CH3), 20.4 (6-CH2CH2CH3), 29.3 (6-CH2CH2CH3), 31.5 (5-
CH3), 104.4 (C13), 109.3 (C4), 114.0 (C8), 120.3 (C13b), 121.2 (C11),
122.1 (C2), 123.1 (C1),** 123.3 (C6), 123.6 (C10),** 124.3 (C9), 125.2
(C3), 125.5 (C5a), 126.6 (C6a), 131.5 (C13a), 138.7 (C11a), 143.2
(C12a), 145.3 (C4a); LC-MS (ESI, 1.65 eV) m/z 649 [20, (2ꢂMþNa)þ],
368 [10, (MþMeOHþNa)þ], 336 [5, (MþNa)þ], 314 [100, (MþH)þ].
Anal. Calcd for C21H19N3 (313.40): C, 80.48; H, 6.11; N, 13.41%.
Found: C, 80.69; H, 6.05; N, 13.58%. (* Decomposed. ** The assign-
ment may be interchanged).
4.2.4. 9,10-Trimethyl-6-ethyl-5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]
benzimidazole (8e). Yellow crystals (0.273 g, 58%), mp 261e262 ꢀC
(*) (ethanol); Rf (EtOAc) 0.13; IR (KBr) nmax: 3437, 2963, 1617 cmꢁ1
;
1H NMR (CDCl3þDMSO-d6): 1.56 (t, J¼7.3 Hz, 3H, 6-CH3), 2.47 (s,
3H, 10-CH3), 2.51 (s, 3H, 9-CH3), 3.68 (q, J¼7.3 Hz, 2H, 6-CH2), 7.14
(dd, J¼8.0, 7.0 Hz, 1H, 2-H), 7.36 (d, J¼8.0 Hz, 1H, 4-H), 7.47 (dd,
J¼8.0, 7.0 Hz, 1H, 3-H), 7.70 (s, 1H, 11-H), 7.91 (s, 1H, 8-H), 8.04 (s,
1H, 13-H), 8.05 (d, J¼8.0 Hz, 1H, 1-H), 9.68 (s, 1H, 5-H); 13C NMR
(CDCl3þDMSO-d6 at 55 ꢀC): 10.9 (6-CH3), 19.3 (10-CH3), 19.6 (9-
CH3), 20.6 (6-CH2), 101.1 (C13), 110.1 (C4), 114.1 (C8), 118.1 (C11),
117.6 (C2), 121.0 (C13b), 121.5 (C1), 126.5 (C6), 127.1 (C7a), 128.0
4.2.8. 5,6,9,10-Tetramethyl-5H-indolo[30,20:4,5]pyrido[1,2-a][1,3]
benzimidazole (9i). Yellow crystals (0.065 g, 13%), mp 151e153 ꢀC

4208
D. Livadiotou et al. / Tetrahedron 68 (2012) 4202e4209
(ethanol); Rf (EtOAc) 0.20; IR (KBr) nmax: 2920, 1655 cmꢁ1; 1H NMR:
2.18 (s, 3H, 10-CH3), 2.23 (s, 3H, 9-CH3), 2.46 (s, 3H, 6-CH3), 3.79 (s,
3H, 5-CH3), 6.71 (s, 1H, 11-H), 6.78 (s, 1H, 8-H),* 7.07 (s, 1H, 14-H),
* 7.11 (dd, J¼8.0, 7.0 Hz,1H, 2-H), 7.17 (d, J¼8.0 Hz,1H, 4-H), 7.54 (dd,
J¼8.0, 7.0 Hz, 1H, 3-H), 7.89 (d, J¼8.0 Hz, 1H, 1-H)(**); 13C NMR: 16.9
(6-CH3), 18.8 (10-CH3), 19.6 (9-CH3), 33.6 (5-CH3), 103.8 (C14), 109.1
(C4), 118.9 (C8), 119.4 (C2), 120.8 (C14b), 122.9 (C1), 128.1 (C5a),
* 128.2 (C7a),* 128.8 (C10), 129.17 (C11), 129.18 (C6), 130.97 (C3),
131.02 (C14a), 138.5 (C9), 140.4 (C11a), 148.2 (C4a), 158.1 (C13); LC-
MS (ESI, 1.65 eV) m/z 386 [10, (MþMeOHþNa)þ], 354 [25,
(MþNa)þ], 332 [100, (MþH)þ]. Anal. Calcd for C21H21N3O (331.41):
C, 76.11; H, 6.39; N,12.68%. Found: C, 75.92; H, 6.55; N,12.47%. (*The
assignment may be interchanged.** The NH absorptions were not
identified).
6.79; N, 12.31%. Found: C, 80.70; H, 6.63; N, 12.50%. (* The assign-
ment may be interchanged).
4.3. Reaction of indolopyranones with 2,3-diaminopyridines
As described above using 1.5 mmol of pyranoindolone, 3.0 mmol
of 2,3-diaminopyridine in bromobenzene (15 mL) as solvent with
longer refluxing times (18 h) and p-toluenesulfonic acid (0.030 g,
0.16 mmol) as the catalyst. The target products 12 were isolated in
most cases. In the case of indolopyranones 5a and 5b degradation
products 14 were isolated instead, whereas in the case of indolo-
pyranone 5e both products 12e and 13e were formed.
4.3.1. 2-{1-[(2-Amino-3-pyridinyl)imino]ethyl}-3-methyl-1H-indole
(14a). Yellow crystals (0.100 g, 25%), mp 162e165 ꢀC (ethanol); Rf
(EtOAc) 0.73; IR (KBr) nmax: 3400, 3268, 3209, 3113, 2921,
1598 cmꢁ1; 1H NMR: 2.41 (s, 3H, 2-CeCH3), 2.63 (s, 3H, 3-CH3), 4.5
(s br, 2H, NH2), 6.71 (dd, J¼7.5, 5.1 Hz, 1H, 50-H), 6.88 (dd, J¼7.5,
1.5 Hz, 1H, 4΄-H), 7.13 (ddd, J¼8.0, 6.7, 0.9 Hz, 1H, 5-H), 7.29 (ddd,
J¼7.8, 6.7, 1.0 Hz, 1H, 6-H), 7.35 (dd, J¼7.8, 0.9 Hz, 1H, 7-H), 7.65 (dd,
J¼8.0, 1.0 Hz, 1H, 4-H), 7.86 (dd, J¼5.1, 1.5 Hz, 1H, 6΄-H), 9.3 (s, 1H, 1-
4.2.9. 3,6,7-Trimethyl-2-{1-[2-(methylamino)phenyl]ethyl}-quinoxa-
line (10). Yellow crystals (0.215 g, 47%), mp 108e109 ꢀC (ethanol);
Rf (EtOAc) 0.08; IR (KBr) nmax: 3438, 2967, 2921, 1603 cmꢁ1 1H
;
NMR: 1.78 (d, J¼7.1 Hz, 3H, 2-CH3), 2.47 (s, 3H, 6-CH3), 2.49 (s, 3H,
7-CH3), 2.54 (s, 3H, 3-CH3), 2.80 (s, 3H, NeCH3), 4.44 (q, J¼7.1 Hz,
1H, 2-CH), 5.04 (s, 1H, NH), 6.60 (dd, J¼8.2, 1.0 Hz, 1H, 60-H), 6.62
(ddd, J¼7.8, 7.3, 1.0 Hz, 1H, 40-H), 6.95 (dd, J¼7.8, 1.6 Hz, 1H, 30-H),
7.14 (ddd, J¼8.2, 7.3, 1.6 Hz, 1H, 50-H), 7.71 (s, 1H, 5-H), 7.82 (s, 1H, 8-
H); 13C NMR: 17.3 (2-CHCH3), 20.2 (7-CH3), 20.3 (6-CH3), 22.8 (3-
CH3), 30.7 (NH-CH3), 42.0 (2-CH), 110.6 (C60), 116.7 (C40), 126.2
(C20), 127.4 (C5), 127.8 (C8), 128.0 (C50), 129.2 (C30), 139.01 (C7),
* 139.14 (C8a),* 139.4 (C6),** 139.7 (C4a),** 147.4 (C10), 152.8 (C3),
156.3 (C2); LC-MS (ESI,1.65 eV) m/z 360 [(30, MþNaþMeOH)þ], 328
[(100, MþNa)þ], 306 [(60, MþH)þ]. Anal. Calcd for C20H23N3
(305.42): C, 78.65; H, 7.59; N, 13.76%. Found: C, 78.43; H, 7.74; N,
13.68%. (* & ** The assignment may be interchanged).
13
H); C NMR: 11.1 (3-CH3), 18.9 (2-CeCH3), 111.2 (C7), 113.8 (C50),
115.8 (C3), 119.6 (C5), 120.2 (C4), 125.2 (C6), 126.4 (C4΄), 129.8
(C3a), 131.0 (C30), 132.9 (C2), 135.8 (C7a), 143.0 (C6΄), 151.6 (C20),
162.1 (2-C]N); LC-MS (ESI, 1.65 eV) m/z 319 [5, (MþNaþMeOH)þ],
287 [8, (MþNa)þ], 265 [100, (MþH)þ]. Anal. Calcd for C16H16N4
(264.33): C, 72.70; H, 6.10; N, 21.20%. Found: C, 72.56; H, 6.35; N,
21.32%.
4.3.2. 2-{1-[(2-Amino-3-pyridinyl)imino]propyl}-3-methyl-1H-in-
dole (14b). Yellow crystals (0.113 g, 27%), mp 150e152 ꢀC (ethanol);
Rf (EtOAc) 0.75; IR (KBr) nmax: 3468, 3351, 3151, 2980,1588 cmꢁ1; 1H
NMR: 1.21 (t, J¼7.5 Hz, 3H, 2-CeCH2CH3), 2.62 (s, 3H, 3-CH3), 2.77
(q, J¼7.5 Hz, 2H, 2-CeCH2CH3), 4.83 (s br, 2H, NH2), 6.69 (dd, J¼7.5,
5.3 Hz, 1H, 50-H), 6.90 (dd, J¼7.5, 1.5 Hz, 1H, 4΄-H), 7.11 (ddd, J¼8.0,
6.7, 0.9 Hz, 1H, 5-H), 7.27 (ddd, J¼7.8, 6.7, 0.9 Hz, 1H, 6-H), 7.36 (dd,
J¼7.8, 0.9 Hz, 1H, 7-H), 7.65 (dd, J¼8.0, 0.9 Hz, 1H, 4-H), 7.84 (dd,
J¼5.3, 1.5 Hz, 1H, 6΄-H), 9.6 (s br, 1H, 1-H); 13C NMR: 10.6 (3-CH3),
12.9 (2-CeCH2CH3), 23.9 (2-CeCH2CH3), 111.3 (C7), 113.6 (C50),114.9
(C3), 119.5 (C5), 120.2 (C4), 125.0 (C6), 125.7 (C4΄), 129.8 (C3a), 131.4
(C30), 131.7 (C2), 136.0 (C7a), 142.1 (C6΄), 151.1 (C20), 168.2 (2-C]N);
LC-MS (ESI, 1.65 eV) m/z 301 [20, (MþNa)þ], 279 [100, (MþH)þ].
Anal. Calcd for C17H18N4 (278.35): C, 73.35; H, 6.52; N, 20.13%.
Found: C, 73.66; H, 6.73; N, 20.25%.
4.2.10. 6-Ethyl-5,9,10-trimethyl-5H-indolo[30,20:4,5]pyrido[1,2-a]
[1,3]benzimidazole (8j). Yellow crystals (0.408 g. 83%), mp
233e234 ꢀC (ethanol); Rf (EtOAc) 0.22; IR (KBr) nmax: 2935, 1653,
1636 cmꢁ1
;
1H NMR: 1.63 (t, J¼7.5 Hz, 3H, 6-CH3), 2.47 (s, 3H, 10-
CH3), 2.50 (s, 3H, 9-CH3), 3.85 (q, J¼7.5 Hz, 2H, 6-CH2), 3.99 (s,
3H, 5-CH3), 7.18 (dd, J¼8.0, 7.0 Hz, 1H, 2-H), 7.19 (d, J¼8.3 Hz, 1H, 4-
H), 7.51 (ddd, J¼8.3, 7.0, 1.0 Hz, 1H, 3-H), 7.73 (s, 1H, 11-H), 7.89 (s,
1H, 8-H), 8.05 (dd, J¼8.0, 1.0 Hz, 1H, 1-H), 8.08 (s, 1H, 13-H); 13C
NMR: 14.1 (6-CH3), 20.5 (10-CH3), 21.0 (9-CH3), 21.4 (6-CH2), 33.6
(5-CH3), 102.8 (C13), 108.6 (C4), 115.2 (C8), 118.9 (C11), 119.3 (C2),
121.4 (C13b), 121.6 (C1), 125.3 (C6), 127.4 (C7a), 128.5 (C10), 129.47
(C3), 129.54 (C5a), 131.3 (C13a), 134.1 (C9), 144.6 (C11a), 147.1
(C12a),* 147.4 (C4a);* LC-MS (ESI, 1.65 eV) m/z 677 [20,
(2ꢂMþNa)þ], 382 [10, (MþMeOHþNa)þ], 350 [10, (MþNa)þ], 328
[100, (MþH)þ]. Anal. Calcd for C22H21N3 (327.42): C, 80.70; H, 6.46;
N, 12.83%. Found: C, 80.97; H, 6.58; N, 12.55%. (* The assignment
may be interchanged).
4.3.3. 12-Propyl-11H-pyrido[300,200:40,50]imidazo[20,10:6,1]pyrido[3,4-
b]indole (12c). Yellow crystals (0.144 g, 32%), mp 245e247 ꢀC
(ethanol); Rf (EtOAc) 0.1; IR (KBr) nmax: 3448, 3053, 2956, 2927,
1618, 1593, 1555 cmꢁ1
;
1H NMR: (CDCl3þDMSO-d6): 1.14 (t,
J¼7.3 Hz, 3H, 12-CH2CH2CH3), 1.90e2.16 (m, 2H, 12-CH2CH2CH3),
4.05 (t, J¼7.5 Hz, 2H, 12-CH2CH2CH3), 7.15 (dd, J¼7.5, 7.0 Hz, 1H, 8-
H), 7.33e7.54 (m, 3H, 3-H,9-H,10-H), 8.08 (dd, J¼7.5, 1.1 Hz, 1H, 7-
H), 8.09 (s, 1H, 6-H), 8.17 (dd, J¼8.2, 1.5 Hz, 1H, 4-H), 8.43 (dd,
J¼4.3, 1.5 Hz, 1H, 2-H), 9.7 (s br, 1H, 11-H); 13C NMR (CDCl3þDMSO-
d6): 13.6 (12-CH2CH2CH3), 21.4 (12-CH2CH2CH3), 29.3 (12-
CH2CH2CH3), 101.9 (C6), 110.9 (C10), 119.0 (C8), 120.3 (C3), 121.5
(C6b), 122.2 (C7), 125.0 (C4), 125.2 (C12), 129.5 (C11a), 129.7 (C9),
132.6 (C6a), 137.8 (C4a), 139.3 (C2), 143.7 (C5a), 145.3 (C10a), 148.1
(C13a); LC-MS (ESI, 1.65 eV) m/z (%) 301 [100, (MþH)þ]. Anal. Calcd
for C19H16N4 (300.36): C, 75.98; H, 5.37; N, 18.65%. Found: C, 76.17;
H, 5.13; N, 18.33%.
4.2.11. 6-Propyl-5,9,10-trimethyl-6-propyl-5H-indolo[30,20:4,5]pyrido
[1,2-a][1,3]benzimidazole (8k). Yellow crystals (0.353 g, 69%), mp
107e108 ꢀC (ethanol); Rf (EtOAc) 0.23; IR (KBr) nmax: 2957, 1653,
1618, 1517 cmꢁ1
;
1H NMR: 1.25 (t, J¼7.5 Hz, 3H, 6-CH3), 1.85e2.05
(m br, 2H, 6-CH2CH2CH3), 2.38 (s, 3H, 10-CH3), 2.43 (s, 3H, 9-CH3),
3.60 (t, J¼7.5 Hz, 2H, 6-CH2CH2CH3), 3.90 (s, 3H, 5-CH3), 7.16 (dd,
J¼7.8, 7.5 Hz, 1H, 2-H), 7.19 (d, J¼7.8 Hz, 1H, 4-H), 7.51 (dd, J¼7.8,
7.5 Hz, 1H, 3-H), 7.57 (s, 1H, 11-H), 7.68 (s, 1H, 8-H), 7.92 (s, 1H, 13-
H), 7.96 (d, J¼7.8 Hz, 1H, 1-H); 13C NMR (CDCl3þDMSO-d6 at 40 ꢀC):
12.5 (6-CH3), 19.4 (9-CH3), 20.0 (9-CH3), 21.2 (6-CH2CH2CH3), 29.1
(6-CH2CH2CH3), 32.8 (5-CH3), 101.5 (C13), 108.1 (C4), 114.3 (C8),
117.9 (C11), 118.6 (C2), 120.5 (C13b), 120.6 (C1), 123.7 (C6), 127.0
(C7a), 128.5 (C10), 128.8 (C3), 129.5 (C5a), 131.3 (C13a), 134.1 (C9),
143.7 (C11a), 146.4 (C12a),* 146.5 (C4a);* LC-MS (ESI, 1.65 eV) m/z
705 [15, (2ꢂMþNa)þ], 396 [5, (MþMeOHþNa)þ], 364 [5, (MþNa)þ],
342 [100, (MþH)þ]. Anal. Calcd for C23H23N3 (341.45): C, 80.90; H,
4.3.4. 11,12-Dimethyl-11H-pyrido[300,200:40,50]imidazo[20,10:6,1]pyrido
[3,4-b]indole (12d). Brown crystals (0.129 g, 30%), mp 164e166 ꢀC
(ethanol); Rf (EtOAc) 0.17; IR (KBr) nmax
: 2933, 1651, 1633,
1516 cmꢁ1; 1H NMR: 3.82 (s, 3H, 12-CH3), 4.02 (s, 3H, 11-CH3), 7.22

D. Livadiotou et al. / Tetrahedron 68 (2012) 4202e4209
4209
(ddd, J¼8.0, 7.2, 0.8 Hz, 1H, 8-H), 7.29 (dd, J¼8.2, 0.8 Hz, 1H, 10-H),
7.47 (dd, J¼8.2, 4.6 Hz, 1H, 3-H), 7.59 (ddd, J¼8.2, 7.2, 1.1 Hz, 1H, 9-
H), 8.10 (dd, J¼8.0, 1.1 Hz, 1H, 7-H), 8.14 (s, 1H, 6-H), 8.20 (dd, J¼8.2,
1.5 Hz,1H, 4-H), 8.43 (dd, J¼4.6, 1.5 Hz, 1H, 2-H); 13C NMR: 20.5 (12-
CH3), 33.2 (11-CH3), 102.5 (C6), 108.3 (C10), 119.6 (C8), 120.5 (C3),
121.5 (C6b), 122.1 (C7), 125.7 (C4), 127.8 (C12), 130.1 (C9), 130.4
(C11a), 133.6 (C6a), 138.2 (C4a), 139.6 (C2), 144.3 (C5a), 147.4 (C10a),
147.8 (C13a); LC-MS (ESI, 1.65 eV) m/z (%) 287 [100, (MþH)þ]. Anal.
Calcd for C18H14N4 (286.33): C, 75.50; H, 4.93; N, 19.57%. Found: C,
75.75; H, 5.11; N, 19.38%.
(314.38): C, 76.41; H, 5.77; N, 17.82%. Found: C, 76.71; H, 5.53; N,
17.65%. (*The assignment may be interchanged).
References and notes
1. Lazarev, P. I. WO2007085810, 2007.
2. Lazarev, P. I.; Sidorenko, E. N.; Nokel, A. WO2007020442, 2007.
3. Lagrange, A. FR2864782, 2005.
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Met. 2001, 124, 79e81.
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11. (a) Dallavalle, S.; Merlini, L.; Beretta, G. L.; Tinelli, S.; Zunino, F. Bioorg. Med.
4.3.5. 12-Ethyl-11-methyl-11H-pyrido[300,200:40,50]imidazo[20,10:6,1]
pyrido[3,4-b]indole (12e). Brown crystals, (0.126 g, 28%) mp
171e173 ꢀC (ethanol); Rf (CH2Cl2:MeOH 20:1) 0.40; IR (KBr) nmax
:
2951, 2935, 2860, 1651, 1610 cmꢁ1
;
1H NMR: 1.60 (t, J¼7.4 Hz, 3H,
12-CH2CH3), 3.96 (s, 3H, 11-CH3), 4.30e4.35 (br m, 2H, 12-CH2CH3),
7.18 (ddd, J¼8.0, 7.2, 0.6 Hz, 1H, 8-H), 7.25 (dd, J¼8.2, 0.6 Hz, 1H, 10-
H), 7.44 (dd, J¼8.2, 4.5 Hz, 1H, 3-H), 7.56 (ddd, J¼8.2, 7.2, 1.0 Hz, 1H,
9-H), 8.065 (s, 1H, 6-H), 8.07 (dd, J¼8.0, 1.0 Hz, 1H, 7-H), 8.1 (dd,
J¼8.2, 1.4 Hz, 1H, 4-H), 8.42 (dd, J¼4.5, 1.4 Hz, 1H, 2-H); 13C NMR:
15.0 (12-CH2CH3), 20.8 (12-CH2CH3), 33.4 (11-CH3), 102.8 (C6),
108.8 (C10), 119.5 (C8), 120.5 (C3), 121.3 (C6b), 122.1 (C7), 125.6
(C4), 127.8 (C12), 130.2 (C9), 130.4 (C11a), 133.5 (C6a), 138.3 (C4a),
139.5 (C2), 144.3 (C5a), 147.5 (C10a), 147.8 (C13a); LC-MS (ESI,
1.65 eV) m/z (%) 301 [100, (MþH)þ]. Anal. Calcd for C19H16N4
(300.36): C, 75.98; H, 5.37; N, 18.65%. Found: C, 76.18; H, 5.64; N,
18.87%.
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phanatou, J. Arkivoc 2008, xiv, 132e157; (c) Hatzimimikou, D.; Livadiotou, D.;
Tsoleridis, C. A.; Stephanidou-Stephanatou, J. Synlett 2008, 1773e1776; (d) Li-
vadiotou, D.; Hatzimimikou, D.; Neochoritis, C.; Terzidis, M. A.; Tsoleridis, C. A.;
Stephanidou-Stephanatou, J. Synthesis 2008, 3273e3278; (e) Livadiotou, D.;
Tsoleridis, C. A.; Stephanidou-Stephanatou, J. Synthesis 2009, 2579e2583; (f)
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4.3.6. 3-{2-[(2-Amino-3-pyridinyl)amino]-2-oxoethyl}-1-methyl-2-
(1-oxopropyl)-1H-indole (13e). Yellow crystals (0.076 g, 15%), mp
203e205 ꢀC (ethanol); Rf (CH2Cl2:MeOH 20:1) 0.28; IR (KBr) nmax
:
3571, 3410, 3215, 3151, 3056, 2979, 2939, 1667, 1651, 1629,
1533 cmꢁ1
;
1H NMR: 1.28 (t, J¼7.3 Hz, 3H, 2-COCH2CH3), 2.99 (q,
J¼7.3 Hz, 2H, 2-COCH2CH3), 3.93 (s, 3H, 1-CH3), 3.98 (s, 2H, 3-CH2),
4.47 (s br, 2H, 20-NH2) 6.60 (dd, J¼7.7, 4.9 Hz, 1H, 50-H), 7.21 (ddd,
J¼8.0, 6.7,1.1 Hz,1H, 5-H), 7.35 (dd, J¼8.4,1.1 Hz,1H, 7-H), 7.41 (ddd,
J¼8.4, 6.7, 1.2 Hz, 1H, 6-H), 7.59 (dd, J¼7.7, 1.6 Hz 1H, 40-H), 7.81 (dd,
J¼8.0, 1.2 Hz, 1H, 4-H), 7.85 (dd, J¼4.9, 1.6 Hz, 1H, 60-H), 9.05 (s, 1H,
30-NH); 13C NMR (CDCl3þDMSO-d6 at 35 ꢀC): 8.6 (2-COCH2CH3),
33.1 (1-CH3), 34.9 (3-CH2), 36.4 (2-COCH2CH3), 110.5 (C7), 114.5
(C50), 116.4 (C3), 119.5 (C30), 121.0 (C5), 121.4 (C4), 126.6 (C6), 126.7
(C3a), 131.5 (C40), 136.4 (C2), 139.1 (C7a), 144.7 (C60), 152.1 (C20),
169.4 (CONH), 197.8 (2-CO); LC-MS (ESI, 1.65 eV) m/z (%) 375 [18,
(MþK)þ], 359 [20, (MþNa)þ], 337 [100, (MþH)þ]. Anal. Calcd for
C19H20N4O2 (336.39): C, 67.84; H, 5.99; N, 16.66%. Found: C, 67.59;
H, 6.23; N, 16.45%.
16. Tsoleridis, C. A.; Pozarentzi, M.; Mitkidou, S.; Stephanidou-Stephanatou, J. Ar-
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K. J. F.; Pulay, P. J. Am. Chem. Soc. 1990, 112, 8251e8260.
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(c) Catoen-Chackal, S.; Facompre, M.; Houssin, R.; Pommery, N.; Goossens, J. F.;
4.3.7. 11-Methyl-12-propyl-11H-pyrido[300,200:40,50]imidazo[20,10:6,1]
pyrido[3,4-b]indole (12f). Brown crystals (0.132 g, 28%), mp
145e147 ꢀC (ethanol); Rf (EtOAc) 0.22; IR (KBr) nmax: 3045, 2956,
ꢀ
Colson, P.; Bailly, C.; Henichart, J.-P. J. Med. Chem. 2004, 47, 3665e3673; (d)
ꢀ
Malecki, N.; Carato, P.; Rigo, B.; Goossens, J.-F.; Houssin, R.; Bailly, C.; Henichart,
J.-P. Bioorg. Med. Chem. 2004, 12, 641e647.
21. Mopac2000 Ver 1.11. Fujitsu in Chem3D Ultra 7.0.
2925, 2865, 1655, 1614, 1508 cmꢁ1
;
1H NMR: 1.21 (t, J¼7.4 Hz, 3H,
22. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Fores-
man, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov,
B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.
M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian03,
rev. E.01 11-Sep-2007; Gaussian: Wallingford CT, 2004.
12-CH2CH2CH3), 2.02 (sex, J¼7.4 Hz, 2H, 12-CH2CH2CH3), 4.01 (s,
3H, 11-CH3), 4.31e4.33 (m, 2H, 12-CH2CH2CH3), 7.18 (ddd, J¼7.7, 7.2,
0.9 Hz, 1H, 8-H), 7.25 (dd, J¼8.2, 0.9 Hz, 1H, 10-H), 7.44 (dd, J¼8.2,
4.5 Hz, 1H, 3-H), 7.56 (ddd, J¼8.2, 7.2, 1.1 Hz, 1H, 9-H), 8.06 (s, 1H, 6-
H), 8.07 (dd, J¼7.7, 1.1 Hz, 1H, 7-H), 8.15 (dd, J¼8.2, 1.5 Hz, 1H, 4-H),
8.42 (dd, J¼4.5, 1.5 Hz, 1H, 2-H); 13C NMR: 13.7 (12-CH2CH2CH3),
23.7 (12-CH2CH2CH3), 29.1 (12-CH2CH2CH3), 33.4 (11-CH3), 102.5
(C6), 108.8 (C10), 119.6 (C8), 120.6 (C3), 121.2 (C6b), 122.1 (C7), 125.4
(C4), 127.0 (C12), 130.2 (C9), 130.7 (C11a), 133.6 (C6a), 137.7 (C4a),
139.7 (C2), 144.3 (C5a), 147.4 (C10a), *147.8 (C13a); *LC-MS (ESI,
1.65 eV) m/z (%) 315 [100, (MþH)þ]. Anal. Calcd for C20H18N4