Microwave-assisted three-component reaction for the synthesis of pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones

Article abstract of DOI:10.1055/s-0028-1083602

Pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones can be obtained by a microwave-assisted three-component reaction between 2-aminopyridines, isocyanides, and 2-carboxybenzaldehydes under acidic conditions. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0028-1083602

PAPER
3649
Microwave-Assisted Three-Component Reaction for the Synthesis of
Pyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones
S
a
ynthesisof
P
a
yrido[2
¢
,1
¢
:
d
i
4,5-
c
]is
m
oquinolin-5(6
H
)
-on
e
es Mert-Balci,a Jürgen Conrad,a Kathrin Meindl,b Thomas Schulz,b Dietmar Stalke,b Uwe Beifuss*a
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstr. 30, 70599 Stuttgart, Germany
Fax +49(711)45922951; E-mail: ubeifuss@uni-hohenheim.de
b
Institut für Anorganische Chemie, Universität Göttingen, Tammannstr. 4, 37077 Göttingen, Germany
Received 30 April 2008; revised 12 August 2008
siderably when the nucleophilicity of the amino group in
the 3-position of the imidazole moiety is employed for
further transformations. Here we report on experiments to
try out this approach. The reaction between 2-carboxy-
substituted benzaldehydes, 2-aminopyridines, and isocya-
nides was chosen as an example. The spatial proximity of
the amino nitrogen of the imidazole moiety and the car-
boxy group of the aryl moiety should allow the formation
of a lactam and, hence, provide a new access to pyri-
do[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones in a
single synthetic operation.7
Abstract: Pyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones
can be obtained by a microwave-assisted three-component reaction
between 2-aminopyridines, isocyanides, and 2-carboxybenzalde-
hydes under acidic conditions.
Key words: heterocycles, lactams, multicomponent reaction, Ugi
reaction, isocyanides
There is no doubt that multicomponent reactions (MCRs)
are of central importance to the rapid assembly of large ar-
rays of compounds with diverse substitution patterns.1 A
particularly efficient variant of the Ugi reaction,2 the so-
called Groebke reaction, makes use of the conversion of
2-aminoazines, aldehydes, and isocyanides in the pres-
ence of a Brønsted acid for the synthesis of fused 3-
aminoimidazoles, such as imidazo[1,2-a]pyridines, imi-
dazo[1,2-a]pyrimidines, and imidazo[1,2-a]pyrazines.3
As these types of heterocycles have proven to be success-
ful in the field of medicinal chemistry,4 different reaction
conditions have been developed that allow this three-com-
ponent reaction (3CR) to be carried out efficiently.3,5
NH2
montmorillonite
toluene
N
OHC
MW (300 W)
7 min, 160 °C
1a
(1 equiv)
5a
CO2H
N
+
(1.09 equiv)
46%
N
NC
O
N
6a
Bn
3a
(1.25 equiv)
Scheme 2 Microwave-assisted synthesis of pyrido[2¢,1¢:2,3]imida-
zo[4,5-c]isoquinolin-5(6H)-one 6a
R2
NH2
R2
montmorillonite
N
toluene
The model reaction between 2-aminopyridine (1a), ben-
zyl isocyanide (3a), and 2-carboxybenzaldehyde (5a) was
performed under the conditions that had proven success-
ful for the synthesis of 4; compound 6a, with a pyri-
do[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one skele-
ton, was isolated in 46% yield (Scheme 2). Obviously,
this three-component reaction allows the formation of two
heterocyclic rings and four new bonds in a single opera-
tion. The positive outcome of the model reaction prompt-
ed detailed studies on the scope of the new reaction.
OHC
N
R1
MW
2
1
+
N
R3 NC
NH
R3
R1
4
3
Scheme 1 Microwave-assisted synthesis of imidazo[1,2-a]pyri-
dines 4
When we performed experiments towards the microwave-
assisted synthesis of imidazo[1,2-a]pyridines 4 by reac-
tion of different substituted 2-aminopyridines 1, benzal-
dehydes 2, and isocyanides 3, it was found that these
transformations can be effectively conducted with mont-
morillonite as the reagent and toluene as the solvent. Un-
der these conditions the corresponding imidazo[1,2-
NH2
toluene
MW (300 W)
7 min, 160 °C
N
Br
OHC
N
1b
+
5a
CO2H
29–66%
a]pyridines
4
could be synthesized successfully
(Scheme 1).6 Analysis of the studies published so far re-
vealed that the scope of this reaction can be expanded con-
N
O
NC
Br
N
6b
Bn
3a
SYNTHESIS 2008, No. 22, pp 3649–3656
Advanced online publication: 29.10.2008
DOI: 10.1055/s-0028-1083602; Art ID: T07208SS
x
x.
x
x
.
2
0
0
8
Scheme 3 Optimization of the reaction conditions using the synthe-
sis of 6b as an example
© Georg Thieme Verlag Stuttgart · New York

3650
F. Mert-Balci et al.
PAPER
To start with, the reaction conditions were optimized us-
ing the example of the transformation of the aminopyri-
dine 1b with 3a and 5a. It was found that not only
montmorillonite, but also several Brønsted acids, like 4-
toluenesulfonic acid, methanesulfonic acid, and trifluo-
romethanesulfonic acid (Scheme 3, Table 1), can be used
as a reagent. By varying the amount of methanesulfonic
acid, it could be established that the highest yield of 6b
was obtained with 0.2 equivalents of this acid (Table 1,
entry 5). A further increase in the yield of 6b from 54% to
66% was achieved by using the isocyanide 3a in excess
(2.25 equiv) (Table 1, entry 7). It was also possible to run
the reaction of 1b, 3a, and 5a in different imidazolium and
guanidinium salts as ionic liquids in the presence or in the
absence of montmorillonite and methanesulfonic acid, re-
spectively. It should be noted that the synthesis of 6b from
1b, 3a and 5a can also be achieved in the absence of any
reagent and solvent. However, in no case did the yield of
6b exceed that obtained under the conditions given in
Table 1, entry 7.
N
N
N
N
N
N
N
O
O
O
O
Br
N
N
Bn
6a
6b
Bn
N
N
O
N
N
6d
6c
Cy
i-Pr
N
N
N
N
O
N
N
n-Bu
6f
6e
CO2Me
N
N
N
O
O
Cl
N
N
Table 1 Optimizing the Reaction Conditions for the Reaction of 1b
with 3a and 5a
Bn
Bn
6g
6h
Entry Equiv Equiv
Equiv Reagent
of 5a
Equiv
Yielda
(%) of 6b
N
N
of 1b of 3a
N
N
N
N
1
2
3
4
5
6
7
1
1
1
1
1
1
1
1.25
1.25
1.25
1.25
1.25
1.25
2.25
1.09
1.09
1.09
1.09
1.09
1.09
1.09
clayb
76 mg
0.1
29
46
42
52
54
52
66
O
O
O
N
N
Bn
6j
6i
Bn
TsOH
OMe
OMe
OMe
TfOH
0.1
N
N
OMe
MeSO3H
MeSO3H
MeSO3H
MeSO3H
0.1
O
O
O
N
Br
N
0.2
Bn
Bn
6k
6l
0.7
OMe
OMe
OMe
OMe
0.2
N
N
a Isolated yield of product.
b Montmorillonite was used as clay.
N
N
N
O
O
Cl
N
N
6n
6m
Bn
Bn
OMe
OMe
OMe
OMe
After optimizing the reaction conditions we focused on
the question of whether this domino process could be used
for the generation of libraries of pyrido[2¢,1¢:2,3]imida-
zo[4,5-c]isoquinolin-5(6H)-ones. For this purpose reac-
tions with different substituted 2-aminopyridines 1,
isocyanides 3, and 2-carboxybenzaldehydes 5 were per-
formed under our optimized reaction conditions
(Scheme 4).
OBn
N
N
N
N
N
6o
Bn
Bn
6p
Figure 1 Structures of pyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-
5(6H)-ones 6a–p
To start with, reactions of 1a and 5a with different isocy-
anides 3a–e were conducted. We found that apart from
benzyl isocyanide (3a), cyclohexyl isocyanide (3b), iso-
propyl isocyanide (3c), butyl isocyanide (3d), and methyl
isocyanoacetate (3e) could be successfully employed. The
yields of the tetracycles 6a,c–f isolated ranged between
46% and 56% (Figure 1, Table 2, entries 1, 3–6). The
variation of the aminopyridines also met with success. In
the reactions of 3a and 5a with the differently substituted
aminopyridines 1b–f, the heterocycles 6b,g–j were isolat-
R4
R3
R4
R3
NH2
MsOH (0.2 equiv)
toluene
MW (300 W)
7 min, 160 °C
N
OHC
5a, b
N
R1
1a–g
CO2H
+
N
35–68 %
O
N
R1
6a–p
R2 NC
R2
3a–e
Scheme 4 Microwave-assisted synthesis of pyrido[2¢,1¢:2,3]imida-
zo[4,5-c]isoquinolin-5(6H)-ones 6 under optimized reaction condi-
tions
Synthesis 2008, No. 22, 3649–3656 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones
3651
ed as single products in analytically pure form with yields
ranging from 50% to 66% (Figure 1, Table 2, entries 2, 7–
10). In addition to the parent 2-aminopyridine (1a) the
halogen-substituted compounds 1b,c, the alkyl-substitut-
ed derivatives 1d–f, and the benzyl ether 1g could also be
reacted. Finally, the reactions of differently substituted
aminopyridines 1 with benzyl isocyanide (3a), and 2-car-
boxy-3,4-dimethoxybenzaldehyde (5b) were performed.
Here, the products 6k–p were obtained in analytically
pure form as single products in 35–68% yields (Figure 1,
Table 2, entries 11–16).
NH2
+
+ H+
H
+N
N
– H2O
OHC
N
CO2H
3a
CO2H
1a
5a
C –
A
+
N
Bn
H
N
N
+ H+
6a
N
N
– H2O
CO2H
CO2H
N
NHBn
B
C
Bn
It is assumed that the reaction proceeds according to the
mechanism depicted in Scheme 5. The key step of the se-
quence is the nonconcerted [4+1] cycloaddition between
the protonated Schiff base A and the isocyanide 3a with
formation of B, which then undergoes a proton shift to
yield C; after elimination of water, the lactam 6a is
formed.
Scheme
5
Proposed mechanism for the formation of pyri-
do[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones 6a
and C6a positions, respectively. Furthermore, the signal at
d = 126.39 was definitely assigned to the carbon C11b
because of its HMBC correlation to H2 and its 13C con-
nectivity to C1 in the INADEQUATE spectrum. Unfortu-
nately, strong signal overlap between the aromatic protons
H2¢, H4¢, and H6¢ prevents the 13C assignment by HMBC
methods. Nevertheless, it was possible to deduce the miss-
ing assignment by evaluating the 13C-13C INADEQUATE
(Figure 2).
The structures of all the pyrido[2¢,1¢:2,3]imidazo[4,5-
c]isoquinolin-5(6H)-ones 6 described here have been elu-
1
cidated by MS, H, 13C, COSY, HSQC, HMBC, and
INADEQUATE spectroscopic methods. The complete
1H, 13C NMR spectral assignment, especially of quaterna-
ry carbons C11a, C11b, and C6a of compound 6n, is
shown in Figure 2. In the HMBC spectra long-range cor-
relations between the protons H1 (3JCH), H2 (4JCH), H9
(5JCH) and the carbon signal at d = 123.66 along with cor-
relations between H7 (3JCH), H8 (4JCH), H2 (5JCH) and the
carbon at d = 123.62 unambiguously established the C11a
The structural assignments based on NMR spectroscopic
methods were unambiguously confirmed by the results of
the X-ray crystal structure analysis of 6n (Figure 3).8–13
Table 2 Synthesis of Pyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones 6 from Different 2-Aminopyridines 1, Isocyanides 3, and
2-Carboxybenzaldehydes 5
Entry
1
Pyridine
1a
R1
Isocyanide R2
Benzaldehyde R3
R4
Product
6a
Yield (%)
56
H
3a
3a
3b
3c
3d
3e
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
Bn
5a
5a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
5b
5b
5b
5b
H
H
2
1b
1a
5-Br
H
Bn
H
H
6b
6c
66
3
Cy
H
H
46
4
1a
H
i-Pr
Bu
H
H
6d
6e
48
5
1a
H
H
H
51
6
1a
H
CH2CO2Me
Bn
H
H
6f
46
7
1c
5-Cl
3-Me
5-Me
4-Et
H
H
H
6g
64
8
1d
1e
Bn
H
H
6h
6i
53
9
Bn
H
H
60
10
11
12
13
14
15
16
1f
Bn
H
H
6j
50
1a
Bn
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
3-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
4-OMe
6k
6l
35
1b
1c
5-Br
5-Cl
3-Me
5-Me
3-OBn
Bn
43
Bn
6m
6n
6o
42
1d
1e
Bn
68
Bn
38
1g
Bn
6p
50
Synthesis 2008, No. 22, 3649–3656 © Thieme Stuttgart · New York

3652
F. Mert-Balci et al.
PAPER
corded using CHEMPACK 4.0 pulse sequences. Melting points
were determined on a Kofler melting point apparatus (Reichert,
Austria) and are uncorrected. Mass spectra were recorded on a
MAT95 with 70 eV ionization energy. IR spectra were taken on a
Spectrum One FT-IR spectrophotometer. UV spectra were mea-
sured using a CARY 4E UV-Visible spectrophotometer. Elemental
analyses were carried out by F. Hambloch, Institute of Organic and
Biomolecular Chemistry, University of Göttingen.
H
H
H
H
H
H
H
H
H
O
2
3
1
11
N
4
4a
10a
11a
11b
10
9
8
13C - 13C correlation
HMBC
OMe
5
6
N
7
6a
6b
H
N
O
H
H
7'
H
2'
5'
3'
4'
1'
6'
Microwave-Assisted 3CR of 2-Aminopyridines 1, Isocyanides 3,
and Carboxybenzaldehydes 5; General Procedure
Figure 2 Important 3J, 4J, and 5J 1H-13C HMBC and 13C-13C corre-
lations in compound 6n
Compounds 1 (1 mmol), 3 (2.25 mmol), and 5 (1.09 mmol) were
suspended in toluene (2 mL) and placed in a 10-mL reaction vial
that had been heated and cooled under argon. After the addition of
MeSO3H (0.2 mmol), the vial was sealed with a septum and irradi-
ated with microwaves (Discover by CEM; 2450 MHz; 300 W) at
160 °C for 7 min. The mixture was allowed to cool to r.t., diluted
with CH2Cl2 (100 mL), and then washed with NaHCO3 soln (2 ×
100 mL). The residue obtained after drying the organic phase
(MgSO4) and concentration in vacuo was purified by column chro-
matography (silica gel, EtOAc or EtOAc–CH2Cl2) to yield 6.
6-Benzylpyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one
(6a)
Pale brown solid; yield: 56%; mp 234–236 °C (Lit.7d mp 228–229
°C).
IR (ATR): 1642, 1618, 1559, 1495, 1425, 1385, 1300, 1258, 1153,
1128, 979, 772, 730, 710, 702, 681 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.91 (s, 2 H, 7¢-CH2), 6.57 (ddd,
J = 1.3 Hz, J = 6.7 Hz, J = 7.2 Hz, 1 H, H8), 7.05 (ddd, J = 1.1 Hz,
J = 6.8 Hz, J = 9.4 Hz, 1 H, H9), 7.20–7.27 (m, 2 H, H2¢, H6¢),
7.27–7.31 (m, 1 H, H4¢), 7.31–7.39 (m, 2 H, H3¢, H5¢), 7.62 (ddd,
J = 1.4 Hz, J = 7.3 Hz, J = 8.1 Hz, 1 H, H3), 7.67 (dt, J = 1.3 Hz,
J = 9.3 Hz, 1 H, H10), 7.84 (ddd, J = 1.3 Hz, J = 7.2 Hz, J = 8.1 Hz,
1 H, H2), 8.13 (dt, J = 1.1 Hz, J = 7.3 Hz 1 H, H7), 8.44 (ddd,
J = 0.7 Hz, J = 1.3 Hz, J = 8.0 Hz, 1 H, H1), 8.55 (ddd, J = 0.6 Hz,
J = 1.3 Hz, J = 8.1 Hz, 1 H, H4).
13C NMR (75 MHz, CDCl3): d = 46.8 (C7¢), 112.5 (C8), 118.7
(C10), 121.9 (C1), 123.1 (C7), 123.7 (C9), 123.9 (C4a), 124.7
(C11a), 125.1 (C6a), 125.4 (C2¢, C6¢), 127.2 (C3), 127.8 (C4¢),
129.4 (C3¢, C5¢), 129.5 (C4), 131.9 (C11b), 133.3 (C2), 135.9 (C1¢),
143.0 (C10a), 161.7 (C5).
Figure 3 Solid state structure of compound 6n; anisotropic dis-
placement parameters are depicted at the 50% probability level; the
second molecule of the asymmetric unit and H atoms are omitted for
reasons of clarity.
To summarize, pyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquino-
lin-5(6H)-ones can be obtained in a few minutes with
yields ranging from 35% to 68% by means of a micro-
wave-assisted three-component reaction between 2-ami-
nopyridines, isocyanides, and 2-carboxybenzaldehydes.
The transformation is easy to perform, robust, and highly
efficient, as this process allows the formation of two het-
erocyclic rings and four new bonds in a single synthetic
operation.
MS (El, 70 eV): m/z (%) = 325 (37) [M+], 234 (100), 130 (15), 78
(12), 51 (2).
UV/Vis (MeCN): lmax (log e) = 377 (4.15), 309 (3.61), 259 (4.57),
240 (4.47), 227 nm (4.58).
6-Benzyl-8-bromopyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-
5(6H)-one (6b)
Yellow solid; yield: 66%; mp 270–272 °C.
IR (ATR): 3055, 1640, 1618, 1524, 1405, 1340, 1316, 1303, 1267,
933, 796, 765, 732, 713, 698, 660 cm–1.
Starting materials were purchased from chemical companies and
used without purification. Reactions were performed using a Dis-
cover Explorer microwave synthesizer (CEM Corp.), producing
continuous irradiation at 2450 MHz. All experiments were conduct-
ed under argon. Anhyd toluene was distilled from Na. TLC was per-
formed on TLC aluminum roll silica gel 60 F254 (MERCK).
Compounds were visualized with UV light (l = 254 nm) and/or im-
mersion in KMnO4 soln followed by heating. NMR spectra were re-
corded in CDCl3 on 300 MHz and 500 MHz spectrometers. The 1H
and 13C chemical shifts were referenced to residual solvent signals
at dH = 7.26 and dC = 77 relative to TMS. 1H, 13C{1H}, gDQFCOSY,
gHSQC, INADEQUATE (300 MHz, 90 mg of 6n, 5 mm Shigemi
tube) spectra were measured with standard Varian pulse sequences.
Adiabatic broadband and band selective gHMBC spectra were re-
1H NMR (300 MHz, CDCl3): d = 5.88 (s, 2 H, 7¢-CH2), 7.08 (dd,
J = 1.3 Hz, J = 9.6 Hz, 1 H, H9), 7.22–7.29 (m, 2 H, H2¢, H6¢),
7.29–7.34 (m, 1 H, H4¢), 7.34–7.42 (m, 2 H, H3¢, H5¢), 7.48 (dd,
J = 0.9 Hz, J = 9.7 Hz, 1 H, H10), 7.60 (ddd, J = 1.2 Hz, J = 7.3 Hz,
J = 8.1 Hz, 1 H, H3), 7.84 (ddd, J = 1.3 Hz, J = 7.2 Hz, J = 8.5 Hz,
1 H, H2), 8.32 (dd, J = 0.9 Hz, J = 1.7 Hz, 1 H, H7), 8.40 (ddd,
J = 0.6 Hz, J = 1.2 Hz, J = 8.0 Hz, 1 H, H1), 8.55 (ddd, J = 0.6 Hz,
J = 1.3 Hz, J = 8.1 Hz, 1 H, H4).
13C NMR (75 MHz, CDCl3): d = 46.7 (C7¢), 107.2 (C8), 119.0
(C10), 121.9 (C1), 123.2 (C7), 124.1 (C4a), 124.7 (C11a), 125.5
(C2¢, C6¢), 125.8 (C6a), 126.9 (C9), 127.6 (C3), 128.1 (C4¢), 129.5
Synthesis 2008, No. 22, 3649–3656 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones
3653
(C3¢, C5¢), 129.7 (C4), 131.6 (C11b), 133.4 (C2), 135.7 (C1¢), 141.2
(C10a), 161.7 (C5).
IR (ATR): 2950, 2868, 1639, 1617, 1574, 1558, 1498, 1387, 1303,
1262, 773, 734, 703, 682 cm–1.
MS (EI, 70 eV): m/z (%) = 403 (55) [M+], 312 (100), 233 (5), 204
(3), 156 (13), 130 (47), 91 (16), 76 (6), 65 (3).
1H NMR (300 MHz, CDCl3): d = 1.02 (t, J = 7.4 Hz, 3 H, 4¢-CH3),
1.49–1.64 (m, 2 H, 3¢-CH2), 1.80–1.96 (m, 2 H, 2¢-CH2), 4.56–4.68
(m, 2 H, 1¢-CH2), 6.84 (ddd, J = 1.3 Hz, J = 6.7 Hz, J = 7.3 Hz, 1
H, H8), 7.15 (ddd, J = 1.1 Hz, J = 6.6 Hz, J = 9.2 Hz, 1 H, H9), 7.53
(ddd, J = 1.3 Hz, J = 7.2 Hz, J = 8.1 Hz, 1 H, H3), 7.68 (dt, J = 1.2
Hz, J = 9.2 Hz, 1 H, H10), 7.77 (ddd, J = 1.3 Hz, J = 7.2 Hz, J = 8.1
Hz, 1 H, H2), 8.31 (dt, J = 1.1 Hz, J = 7.3 Hz, 1 H, H7), 8.38 (ddd,
J = 0.7 Hz, J = 1.3 Hz, J = 8.1 Hz, 1 H, H1), 8.46 (ddd, J = 0.7 Hz,
J = 1.3 Hz, J = 8.1 Hz, 1 H, H4).
13C NMR (75 MHz, CDCl3): d = 13.8 (C4¢), 19.9 (C3¢), 32.1 (C2¢),
42.7 (C1¢), 112.9 (C8), 118.9 (C10), 121.9 (C1), 122.8 (C7), 123.6
(C9), 124.0 (C4a), 124.5 (C6a), 124.8 (C11a), 127.1 (C3), 129.2
(C4), 131.3 (C11b), 132.9 (C2), 142.8 (C10a), 161.2 (C5).
UV/Vis (MeCN): lmax (log e) = 403 (4.02), 383 (4.17), 318 (3.70),
266 (4.52), 245 (4.50), 231 (4.60), 208 nm (4.56).
Anal. Calcd for C21H14BrN3O: C, 62.39; H, 3.49; N, 10.39. Found:
C, 62.65; H, 3.70; N, 10.16.
6-Cyclohexylpyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-
one (6c)
Yellow solid; yield: 46%; mp 224–226 °C.
IR (ATR): 2935, 2850, 1645, 1617, 1298, 1268, 1131, 772, 746,
724, 704, 689 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.27–2.14 (m, 8 H, H2¢b, 2 H3¢, 2
H4¢, 2 H5¢, H6¢b), 2.81–3.09 (m, 2 H, H2¢a, H6¢a), 4.43 (tt, J = 3.6
Hz, J = 11.9 Hz, 1 H, H1¢), 6.87 (dt, J = 1.2 Hz, J = 7.1 Hz, 1 H,
H8), 7.17 (ddd, J = 1.2 Hz, J = 6.7 Hz, J = 9.2 Hz, 1 H, H9), 7.53
(ddd, J = 1.3 Hz, J = 7.3 Hz, J = 8.1 Hz, 1 H, H3), 7.71 (dt, J = 1.2
Hz, J = 9.2 Hz, 1 H, H10), 7.78 (ddd, J = 1.3 Hz, J = 7.2 Hz, J = 8.1
Hz, 1 H, H2), 8.14 (br d, J = 7.4 Hz, 1 H, H7), 8.36 (ddd, J = 0.6 Hz,
J = 1.2 Hz, J = 7.8 Hz, 1 H, H1), 8.43 (ddd, J = 0.6 Hz, J = 1.3 Hz,
J = 8.1 Hz, 1 H, H4).
13C NMR (75 MHz, CDCl3): d = 25.0 (C4¢), 26.4 (C3¢, C5¢), 29.8
(C2¢, C6¢), 60.3 (C1¢), 112.8 (C8), 119.1 (C10), 121.8 (C1), 123.3
(C7), 123.4 (C9), 125.3 (C6a), 125.7 (C11a), 125.9 (C4a), 127.1
(C3), 128.8 (C4), 131.6 (C11b), 132.8 (C2), 142.8 (C10a), 162.8
(C5).
MS (EI, 70 eV): m/z (%) = 291 (95) [M+], 235 (100), 206 (15), 130
(23), 78 (27), 51 (6).
UV/Vis (MeCN): lmax (log e) = 379 (4.12), 309 (3.54), 260 (4.53),
241 (4.40), 227 (4.50), 205 nm (4.46).
Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88; N, 14.42. Found: C,
76.16; H, 5.76; N, 13.89.
6-[(Methoxycarbonyl)methyl]pyrido[2¢,1¢:2,3]imidazo[4,5-
c]isoquinolin-5(6H)-one (6f)
Yellow solid; yield: 46%; mp 221–223 °C.
IR (ATR): 1748, 1736, 1644, 1619, 1558, 1388, 1365, 1318, 1227,
1145, 967, 770, 739, 728, 702 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.81 (s, 3 H, OCH3), 5.46 (s, 2 H,
2¢-CH2), 6.78 (ddd, J = 1.3 Hz, J = 6.7 Hz, J = 7.2 Hz, 1 H, H8),
7.13 (ddd, J = 1.2 Hz, J = 6.7 Hz, J = 9.2 Hz, 1 H, H9), 7.55 (ddd,
J = 1.3 Hz, J = 7.3 Hz, J = 8.1 Hz, 1 H, H3), 7.67 (dt, J = 1.2 Hz,
J = 9.2 Hz, 1 H, H10), 7.81 (ddd, J = 1.3 Hz, J = 7.2 Hz, J = 8.0 Hz,
1 H, H2), 8.13 (dt, J = 1.0 Hz, J = 7.3 Hz, 1 H, H7), 8.39 (ddd,
J = 0.6 Hz, J = 1.2 Hz, J = 8.0 Hz, 1 H, H1), 8.46 (ddd, J = 0.7 Hz,
J = 1.3 Hz, J = 8.1 Hz, 1 H, H4).
MS (EI, 70 eV): m/z (%) = 317 (22) [M+], 235 (100), 206 (7), 130
(2), 78 (6).
UV/Vis (MeCN): lmax (log e) = 381 (4.06), 309 (3.52), 261 (4.52),
229 (4.49), 207 nm (4.46).
Anal. Calcd for C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C,
75.43; H, 5.85; N, 13.01.
13C NMR (75 MHz, CDCl3): d = 44.7 (C2¢), 53.2 (OCH3), 113.0
(C8), 119.0 (C10), 121.9 (C1), 121.9 (C7), 123.5 (C4a), 123.7 (C9),
123.9 (C6a), 125.0 (C11a), 127.3 (C3), 129.4 (C4), 131.9 (C11b),
133.5 (C2), 142.9 (C10a), 161.3 (C5), 168.7 (C1¢).
MS (EI, 70 eV): m/z (%) = 307 (100) [M+], 275 (4), 248 (61), 234
(72), 220 (16), 130 (17), 78 (21), 51 (4).
6-Isopropylpyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-
one (6d)
Pale green solid; yield: 48%; mp 180–182 °C.
IR (ATR): 1628, 1617, 1574, 1556, 1403, 1302, 1272, 1096, 763,
731, 711, 698, 683 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.86 [d, J = 6.8 Hz, 6 H, 1¢-
(CH3)2], 5.01 (hept, J = 6.8 Hz, 1 H, H1¢), 6.85 (dt, J = 1.3 Hz,
J = 6.9 Hz, 1 H, H8), 7.17 (ddd, J = 1.2 Hz, J = 6.6 Hz, J = 9.2 Hz,
1 H, H9), 7.53 (ddd, J = 1.2 Hz, J = 7.1 Hz, J = 8.2 Hz, 1 H, H3),
7.71 (dt, J = 1.2 Hz, J = 9.2 Hz, 1 H, H10), 7.77 (ddd, J = 1.3 Hz,
J = 7.2 Hz, J = 8.2 Hz, 1 H, H2), 8.26 (br d, J = 7.3 Hz, 1 H, H7),
8.37 (ddd, J = 0.6 Hz, J = 1.0 Hz, J = 7.9 Hz, 1 H, H1), 8.43 (dd,
J = 1.7 Hz, J = 8.1 Hz, 1 H, H4).
HRMS (ESI): m/z [M + H]+ calcd for C17H13N3O3: 308.1035; found:
308.1030.
UV/Vis (MeCN): lmax (log e) = 376 (4.09), 309 (3.57), 258 (4.52),
240 (4.41), 228 nm (4.51).
6-Benzyl-8-chloropyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-
5(6H)-one (6g)
Yellow solid; yield: 64%; mp 273–274 °C.
13C NMR (125 MHz, CDCl3): d = 20.7 (1¢-CH3), 51.3 (C1¢), 112.8
(C8), 119.0 (C10), 121.9 (C1), 123.5 (C7), 123.6 (C9), 125.2 (C6a),
125.6 (C11a), 125.8 (C4a), 127.2 (C3), 128.8 (C4), 131.6 (C11b),
132.9 (C2), 142.8 (C10a), 162.7 (C5).
MS (El, 70 eV): m/z (%) = 277 (34) [M+], 235 (100), 206 (14), 130
(10), 78 (13), 51 (3).
IR (ATR): 3057, 1642, 1618, 1515, 1493, 1302, 1266, 1066, 941,
811, 765, 732, 724, 696, 681 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.89 (s, 2 H, 7¢-CH2), 7.00 (dd,
J = 1.7 Hz, J = 9.6 Hz, 1 H, H9), 7.22–7.29 (m, 2 H, H2¢, H6¢),
7.29–7.34 (m, 1 H, H4¢), 7.34–7.42 (m, 2 H, H3¢, H5¢), 7.55 (dd,
J = 1.0 Hz, J = 9.7 Hz, 1 H, H10), 7.62 (ddd, J = 1.3 Hz, J = 7.2 Hz,
J = 8.2 Hz, 1 H, H3), 7.84 (ddd, J = 1.3 Hz, J = 7.2 Hz, J = 8.1 Hz,
1 H, H2), 8.21 (br dd, J = 0.8 Hz, J = 2.0 Hz, 1 H, H7), 8.41 (ddd,
J = 0.7 Hz, J = 1.3 Hz, J = 8.0 Hz, 1 H, H1), 8.55 (ddd, J = 0.6 Hz,
J = 1.3 Hz, J = 8.1 Hz, 1 H, H4).
UV/Vis (MeCN): lmax (log e) = 380 (4.05), 309 (3.51), 260 (4.50),
228 (4.48), 205 nm (4.44).
Anal. Calcd for C17H15N3O: C, 73.63; H, 5.45; N, 15.15. Found: C,
73.65; H, 5.16; N, 15.03.
13C NMR (75 MHz, CDCl3): d = 46.7 (C7¢), 118.8 (C10), 120.7
(C8), 121.0 (C7), 121.9 (C1), 124.0 (C4a), 124.9 (C6a), 124.9 (C9),
125.5 (C2¢, C6¢), 126.0 (C11a), 127.6 (C3), 128.1 (C4¢), 129.5 (C3¢,
6-Butylpyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one
(6e)
Yellow solid; yield: 51%; mp 134–135 °C.
Synthesis 2008, No. 22, 3649–3656 © Thieme Stuttgart · New York

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F. Mert-Balci et al.
PAPER
C5¢), 129.7 (C4), 131.6 (C11b), 133.4 (C2), 135.7 (C1¢), 141.2
(C10a), 161.7 (C5).
IR (ATR): 1639, 1623, 1561, 1496, 1448, 1427, 1386, 1307, 1267,
1150, 980, 861, 772, 728, 703, 682 cm–1.
MS (EI, 70 eV): m/z (%) = 359 (31) [M+], 268 (100), 130 (21), 112
(9), 91 (9), 76 (4), 65 (2).
1H NMR (300 MHz, CDCl3): d = 1.23 (t, J = 7.5 Hz, 3 H, 1¢¢-CH3),
2.61 (q, J = 7.5 Hz, 2 H, 1¢¢-CH2), 5.89 (s, 2 H, 7¢-CH2), 6.43 (dd,
J = 1.4 Hz, J = 7.3 Hz, 1 H, H8), 7.19–7.26 (m, 2 H, H2¢, H6¢),
7.26–7.30 (m, 1 H, H4¢), 7.30–7.38 (m, 2 H, H3¢, H5¢), 7.39 (br s, 1
H, H10), 7.56 (ddd, J = 1.4 Hz, J = 7.1 Hz, J = 8.1 Hz, 1 H, H3),
7.82 (ddd, J = 1.4 Hz, J = 7.2 Hz, J = 8.3 Hz, 1 H, H2), 8.02 (dd,
J = 0.8 Hz, J = 7.3 Hz, 1 H, H7), 8.42 (ddd, J = 0.6 Hz, J = 1.2 Hz,
J = 8.0 Hz, 1 H, H1), 8.54 (ddd, J = 0.6 Hz, J = 1.3 Hz, J = 8.1 Hz,
1 H, H4).
13C NMR (75 MHz, CDCl3): d = 13.8 (1¢¢-CH3), 28.1 (C1¢¢), 46.8
(C7¢), 114.3 (C8), 115.3 (C10), 121.8 (C1), 122.5 (C7), 123.8 (C4a),
124.4 (C6a), 124.9 (C11a), 125.5 (C2¢, C6¢), 126.9 (C3), 127.8
(C4¢), 129.4 (C3¢, C5¢), 129.5 (C4), 132.1 (C11b), 133.2 (C2), 135.9
(C1¢), 140.8 (C9), 143.8 (C10a), 161.6 (C5).
UV/Vis (MeCN): lmax (log e) = 403 (3.98), 383 (4.13), 317 (3.67),
265 (4.51), 244 (4.45), 230 (4.57), 206 nm (4.55).
Anal. Calcd for C21H14ClN3O: C, 70.10; H, 3.92; N, 11.68. Found:
C, 69.85; H, 3.79; N, 11.50.
6-Benzyl-10-methylpyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-
5(6H)-one (6h)
Yellow solid; yield: 53%; mp 242–244 °C.
IR (ATR): 1647, 1621, 1557, 1387, 1306, 1269, 1157, 1132, 983,
772, 732, 707, 700, 682 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.68 (s, 3 H, 10-CH3), 5.92 (s, 2
H, 7¢-CH2), 6.53 (t, J = 7.0 Hz, 1 H, H8), 6.91 (d, J = 6.7 Hz, 1 H,
H9), 7.22–7.27 (m, 2 H, H2¢, H6¢), 7.27–7.31 (m, 1 H, H4¢), 7.31–
7.39 (m, 2 H, H3¢, H5¢), 7.59 (ddd, J = 1.2 Hz, J = 7.2 Hz, J = 8.1
Hz, 1 H, H3), 7.85 (ddd, J = 1.4 Hz, J = 7.2 Hz, J = 7.9 Hz, 1 H,
H2), 8.06 (br d, J = 7.1 Hz, 1 H, H7), 8.56 (dd, J = 1.5 Hz, J = 8.2
Hz, 1 H, H4), 8.59 (dd, J = 1.1 Hz, J = 8.1 Hz, 1 H, H1).
13C NMR (75 MHz, CDCl3): d = 17.3 (10-CH3), 46.7 (C7¢), 112.6
(C8), 121.1 (C7), 122.2 (C1), 122.6 (C9), 123.9 (C4a), 124.5
(C11a), 125.1 (C6a), 125.5 (C2¢, C6¢), 127.1 (C3), 127.8 (C4¢),
128.5 (C10), 129.3 (C3¢, C5¢), 129.5 (C4), 131.9 (C11b), 133.1
(C2), 136.0 (C1¢), 143.4 (C10a), 161.8 (C5).
MS (EI, 70 eV): m/z (%) = 353 (23) [M+], 262 (100), 130 (10), 106
(7).
UV/Vis (MeCN): lmax (log e) = 378 (4.09), 261 (4.57), 240 (4.43),
227 (4.53), 206 nm (4.60).
Anal. Calcd for C23H19N3O: C, 78.16; H, 5.42; N, 11.89. Found: C,
77.97; H, 5.19; N, 12.13.
6-Benzyl-3,4-dimethoxypyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquin-
olin-5(6H)-one (6k)
Yellow solid; yield: 35%; mp 281–286 °C.
IR (ATR): 1641, 1615, 1577, 1385, 1294, 1252, 1232, 1080, 1072,
1043, 1030, 988, 943, 852, 811, 732, 718, 691 cm–1.
MS (EI, 70 eV): m/z (%) = 339 (29) [M+], 248 (100), 130 (12), 92
(12), 65 (6).
1H NMR (300 MHz, CDCl3): d = 3.99 (s, 3 H, 3-OCH3), 4.01 (s, 3
H, 4-OCH3), 5.86 (s, 2 H, 1¢-CH2), 6.59 (t, J = 6.8 Hz, 1 H, H8),
7.08 (dd, J = 6.9 Hz, J = 8.8 Hz, 1 H, H9), 7.22–7.31 (m, 3 H, H2¢,
H4¢, H6¢), 7.31–7.40 (m, 2 H, H3¢, H5¢), 7.51 (d, J = 8.9 Hz, 1 H,
H2), 7.65 (br d, J = 9.1 Hz, 1 H, H10), 8.10 (br d, J = 7.2 Hz, 1 H,
H7), 8.25 (d, J = 8.9 Hz, 1 H, H1).
13C NMR (75 MHz, CDCl3): d = 46.4 (C7¢), 56.7 (3-OCH3), 61.5
(4-OCH3), 112.7 (C8), 118.1 (C10), 118.2 (C1), 118.6 (C4a), 119.1
(C2), 123.1 (C7), 123.7 (C6a), 123.9 (C9), 124.1 (C11a), 125.5
(C2¢, C6¢), 126.1 (C11b), 127.8 (C4¢), 129.3 (C3¢, C5¢), 136.1 (C1¢),
142.5 (C10a), 150.9 (C4), 152.9 (C3), 159.5 (C5).
UV/Vis (MeCN): lmax (log e) = 373 (4.07), 260 (4.56), 243 (4.42),
229 (4.48), 205 nm (4.60).
Anal. Calcd for C22H17N3O: C, 77.86; H, 5.05; N, 12.38. Found: C,
77.51; H, 4.82; N, 12.62.
6-Benzyl-8-methylpyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-
5(6H)-one (6i)
Pale yellow solid; yield: 60%; mp 257–259 °C.
IR (ATR): 1646, 1616, 1557, 1451, 1407, 1300, 1263, 973, 783,
773, 736, 704 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.14 (d, J = 1.1 Hz, 3 H, 8-CH3),
5.93 (br s, 2 H, 7¢-CH2), 7.01 (dd, J = 1.5 Hz, J = 9.3 Hz, 1 H, H9),
7.21–7.30 (m, 3 H, H2¢, H4¢, H6¢), 7.30–7.39 (m, 2 H, H3¢, H5¢),
7.61 (dd, J = 1.0 Hz, J = 9.2 Hz, 1 H, H10), 7.64 (ddd, J = 1.3 Hz,
J = 7.1 Hz, J = 8.2 Hz, 1 H, H3), 7.87 (ddd, J = 1.4 Hz, J = 7.2 Hz,
J = 8.2 Hz, 1 H, H2), 8.02 (q, J = 1.3 Hz, 1 H, H7), 8.51 (ddd,
J = 0.7 Hz, J = 1.3 Hz, J = 8.0 Hz, 1 H, H1), 8.57 (ddd, J = 0.7 Hz,
J = 1.3 Hz, J = 8.1 Hz, 1 H, H4).
MS (EI, 70 eV): m/z (%) = 385 (56) [M+], 294 (100), 279 (18), 251
(14), 190 (7), 91 (6), 78 (18).
UV/Vis (MeCN): lmax (log e) = 389 (4.13), 266 (4.36), 229 nm
(4.61).
Anal. Calcd for C23H19N3O3: C, 71.67; H, 4.97; N, 10.90. Found: C,
71.39; H, 4.70; N, 11.18.
6-Benzyl-8-bromo-3,4-dimethoxypyrido[2¢,1¢:2,3]imidazo[4,5-
c]isoquinolin-5(6H)-one (6l)
Yellow solid; yield: 43%; mp 262–264 °C.
13C NMR (75 MHz, CDCl3): d = 18.5 (8-CH3), 46.9 (C7¢), 117.7
(C10), 120.7 (C7), 121.9 (C1), 122.1 (C8), 123.8 (C4a), 124.4
(C6a), 124.8 (C11a), 125.5 (C2¢, C6¢), 127.1 (C9), 127.2 (C3),
127.8 (C4¢), 129.3 (C3¢, C5¢), 129.5 (C4), 131.8 (C11b), 133.2 (C2),
136.2 (C1¢), 142.1 (C10a), 161.8 (C5).
IR (ATR): 1651, 1399, 1274, 1258, 1246, 1083, 1074, 1031, 990,
976, 810, 798, 786, 780, 747, 697 cm–1.
MS (EI, 70 eV): m/z (%) = 339 (27) [M+], 248 (100), 130 (13), 92
(9), 65 (6).
1H NMR (300 MHz, CDCl3): d = 3.99 (s, 3 H, 3-OCH3), 4.02 (s, 3
H, 4-OCH3), 5.83 (s, 2 H, 7¢-CH2), 7.08 (dd, J = 1.3 Hz, J = 9.5 Hz,
1 H, H9), 7.23–7.29 (m, 2 H, H2¢, H6¢), 7.29–7.33 (m, 1 H, H4¢),
7.33–7.42 (m, 2 H, H3¢, H5¢), 7.48 (dd, J = 0.8 Hz, J = 9.6 Hz, 1 H,
H10), 7.51 (d, J = 8.8 Hz, 1 H, H2), 8.19 (d, J = 8.7 Hz, 1 H, H1),
8.27 (dd, J = 0.9 Hz, J = 1.8 Hz, 1 H, H7).
13C NMR (75 MHz, CDCl3): d = 46.3 (C7¢), 56.7 (3-OCH3), 61.5
(4-OCH3), 107.2 (C8), 118.2 (C1), 118.5 (C10), 118.7 (C4a), 119.1
(C2), 123.1 (C7), 123.7 (C6a), 125.1 (C11a), 125.6 (C2¢, C6¢),
125.8 (C11b), 126.8 (C9), 127.9 (C4¢), 129.5 (C3¢, C5¢), 135.9
(C1¢), 140.8 (C10a), 150.9 (C4), 153.2 (C3), 159.5 (C5).
UV/Vis (MeCN): lmax (log e) = 377 (4.11), 315 (3.68), 261 (4.54),
244 (4.44), 228 (4.54), 205 nm (4.56).
Anal. Calcd for C22H17N3O: C, 77.86; H, 5.05; N, 12.38. Found: C,
77.62; H, 4.75; N, 12.10.
6-Benzyl-9-ethylpyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-
5(6H)-one (6j)
Yellow solid; yield: 50%; mp 222–224 °C.
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Synthesis of Pyrido[2¢,1¢:2,3]imidazo[4,5-c]isoquinolin-5(6H)-ones
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MS (EI, 70 eV): m/z (%) = 463 (51) [M+], 372 (100), 357 (28), 344
(22), 329 (18), 190 (11), 158 (17), 91 (24), 76 (9), 65 (6).
6.88 (dd, J = 1.5 Hz, J = 9.3 Hz, 1 H, H9), 7.22–7.30 (m, 3 H, H2¢,
H4¢, H6¢), 7.30–7.40 (m, 2 H, H3¢, H5¢), 7.47 (d, J = 8.8 Hz, 1 H,
H2), 7.50 (d, J = 9.3 Hz, 1 H, H10), 7.85–7.92 (m, 1 H, H7), 8.19
(d, J = 8.6 Hz, 1 H, H1).
UV/Vis (MeCN): lmax (log e) = 416 (4.14), 394 (4.25), 274 (4.39),
234 nm (4.69).
13C NMR (75 MHz, CDCl3): d = 18.5 (8-CH3), 46.5 (C7¢), 56.7 (3-
OCH3), 61.5 (4-OCH3), 117.3 (C2), 117.9 (C1), 118.5 (C4a), 119.1
(C10), 120.7 (C7), 121.9 (C8), 123.5 (C6a), 124.3 (C11a), 125.6
(C2¢, C6¢), 126.5 (C11b), 126.9 (C9), 127.7 (C4¢), 129.2 (C3¢, C5¢),
136.5 (C1¢), 141.8 (C10a), 150.9 (C4), 152.7 (C3), 159.6 (C5).
Anal. Calcd for C23H18BrN3O3: C, 59.50; H, 3.91; N, 9.05. Found:
C, 59.35; H, 3.94; N, 8.75.
6-Benzyl-8-chloro-3,4-dimethoxypyrido[2¢,1¢:2,3]imidazo[4,5-
c]isoquinolin-5(6H)-one (6m)
Yellow solid; yield: 42%; mp 278–279 °C.
MS (EI, 70 eV): m/z (%) = 399 (45) [M+], 308 (100), 393 (13), 265
(13), 190 (6), 92 (13), 65 (9).
IR (ATR): 3082, 1652, 1462, 1400, 1291, 1276, 1259, 1247, 1083,
1053, 1035, 991, 976, 953, 810, 799, 787, 748, 698 cm–1.
UV/Vis (MeCN): lmax (log e) = 389 (4.17), 267 (4.40), 253 (4.40),
230 nm (4.65).
1H NMR (300 MHz, CDCl3): d = 4.00 (s, 3 H, 3-OCH3), 4.02 (s, 3
H, 4-OCH3), 5.83 (s, 2 H, 7¢-CH2), 7.01 (dd, J = 1.5 Hz, J = 9.6 Hz,
1 H, H9), 7.23–7.29 (m, 2 H, H2¢, H6¢), 7.29–7.33 (m, 1 H, H4¢),
7.33–7.42 (m, 2 H, H3¢, H5¢), 7.50 (d, J = 8.7 Hz, 1 H, H2), 7.56 (br
d, J = 9.8 Hz, 1 H, H10), 8.17 (br d, J = 2.1 Hz, 1 H, H7), 8.21 (d,
J = 8.7 Hz, 1 H, H1).
Anal. Calcd for C24H21N3O3: C, 72.16; H, 5.30; N, 10.52. Found: C,
72.06; H, 5.57; N, 10.30.
6-Benzyl-10-(benzyloxy)-3,4-dimethoxypyrido[2¢,1¢:2,3]imida-
zo[4,5-c]isoquinolin-5(6H)-one (6p)
Yellow solid; yield: 50%; mp 215–217 °C.
13C NMR (75 MHz, CDCl3): d = 46.3 (C7¢), 56.7 (3-OCH3), 61.6
(4-OCH3), 118.2 (C10), 118.3 (C1), 118.7 (C4a), 119.1 (C2), 120.8
(C8), 120.9 (C7), 123.9 (C6a), 124.9 (C9), 125.2 (C11a), 125.5
(C2¢, C6¢), 125.8 (C11b), 128.0 (C4¢), 129.5 (C3¢, C5¢), 135.9 (C1¢),
140.8 (C10a), 150.9 (C4), 153.2 (C3), 159.5 (C5).
MS (EI, 70 eV): m/z (%) = 419 (54) [M+], 328 (100), 312 (29), 285
(21), 190 (7), 112 (19), 91 (16), 76 (7), 65 (4).
IR (ATR): 1647, 1545, 1535, 1394, 1268, 1254, 1236, 1195, 1068,
1049, 999, 970, 818, 752, 725, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.98 (s, 3 H, 3-OCH3), 4.00 (s, 3
H, 4-OCH3), 5.38 (s, 2 H, 7¢¢-CH2), 5.81 (br s, 2 H, 7¢-CH2), 6.32
(dd, J = 1.3 Hz, J = 7.6 Hz, 1 H, H9), 6.37 (dd, J = 6.6 Hz, J = 7.5
Hz, 1 H, H8), 7.19–7.25 (m, 2 H, H2¢, H6¢), 7.28–7.41 (m, 6 H, H3¢,
H4¢, H5¢, H3¢¢, H4¢¢, H5¢¢), 7.48 (d, J = 8.9 Hz, 1 H, H2), 7.47–7.52
(m, 2 H, H2¢¢, H6¢¢), 7.70 (dd, J = 1.3 Hz, J = 6.7 Hz, 1 H, H7), 8.40
(d, J = 8.6 Hz, 1 H, H1).
13C NMR (75 MHz, CDCl3): d = 46.4 (C7¢), 56.7 (3-OCH3), 61.5
(4-OCH3), 70.8 (C7¢¢), 101.9 (C9), 112.2 (C8), 116.2 (C7), 118.5
(C4a), 118.6 (C1), 118.9 (C2), 123.8 (C11a), 124.5 (C6a), 125.5
(C2¢, C6¢), 126.5 (C11b), 127.1 (C2¢¢, C6¢¢), 127.6 (C4¢), 128.1
(C4¢¢), 128.6 and 129.2 (C3¢, C5¢; C3¢¢, C5¢¢), 136.0 and 136.2 (C1¢,
C1¢¢), 137.3 (C10a), 147.9 (C10), 150.7 (C4), 152.6 (C3), 159.6
(C5).
UV/Vis (MeCN): lmax (log e) = 415 (4.13), 394 (4.25), 273 (4.39),
234 nm (4.69).
Anal. Calcd for C23H18ClN3O3: C, 65.79; H, 4.32; N, 10.01. Found:
C, 65.44; H, 4.18; N, 9.85.
6-Benzyl-3,4-dimethoxy-10-methylpyrido[2¢,1¢:2,3]imida-
zo[4,5-c]isoquinolin-5(6H)-one (6n)
Yellow solid; yield: 68%; mp 202–204 °C.
IR (ATR): 1650, 1470, 1418, 1385, 1297, 1271, 1249, 1077, 1046,
999, 828, 722, 715, 696 cm–1.
UV/Vis (MeCN): lmax (log e) = 381 (4.09), 269 (4.52), 219 (4.64),
210 nm (4.65).
1H NMR (500 MHz, CDCl3): d = 2.67 (s, 3 H, 10-CH3), 3.99 (s, 3
H, 3-OCH3), 4.02 (s, 3 H, 4-OCH3), 5.85 (s, 2 H, 7¢-CH2), 6.50 (t,
J = 7.0 Hz, 1 H, H8), 6.87 (d, J = 6.7 Hz, 1 H, H9), 7.21–7.29 (m, 3
H, H2¢, H4¢, H6¢), 7.29–7.38 (m, 2 H, H3¢, H5¢), 7.50 (d, J = 8.7 Hz,
1 H, H2), 7.98 (d, J = 7.2 Hz, 1 H, H7), 8.34 (d, J = 8.8 Hz, 1 H,
H1).
13C NMR (125 MHz, CDCl3): d = 16.9 (10-CH3), 45.9 (C7¢), 56.3
(3-OCH3), 61.1 (4-OCH3), 111.8 (C8), 117.7 (C1), 118.0 (C4a),
118.4 (C2), 120.5 (C7), 121.8 (C9), 123.6 (C6a), 123.7 (C11a),
125.2 (C2¢, C6¢), 126.4 (C11b), 127.2 (C4¢), 127.6 (C10), 128.8
(C3¢, C5¢), 136.1 (C1¢), 142.7 (C10a), 150.3 (C4), 152.1 (C3), 159.0
(C5).
Anal. Calcd for C30H25N3O4: C, 73.30; H, 5.13; N, 8.55. Found: C,
73.03; H, 4.90; N, 8.32.
Acknowledgment
We thank Dr. R. Frank, Ms. I. Klaiber, Dr. H. Leutbecher, and Ms.
S. Mika for recording UV, MS and NMR spectra. Financial support
by the BMBF (01RI05181) is greatly acknowledged.
References
MS (El, 70 eV): m/z (%) = 399 (47) [M+], 308 (100), 293 (14), 265
(1) (a) For a monograph, see: Multicomponent Reactions; Zhu,
J.; Bienaymé, H., Eds.; Wiley-VCH: Weinheim, 2005.
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(12), 190 (6), 92 (15), 65 (8).
UV/Vis (MeCN): lmax (log e) = 386 (4.13), 266 (4.44), 230 (4.59),
219 nm (4.60).
Anal. Calcd for C24H21N3O3: C, 72.16; H, 5.30; N, 10.52. Found: C,
71.85; H, 4.97; N, 10.39.
(2) (a) For a review, see: Dömling, A. Chem. Rev. 2006, 106,
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Paola, S.; Menegotto, I. G.; Pirali, T. Angew. Chem. Int. Ed.
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6-Benzyl-3,4-dimethoxy-8-methylpyrido[2¢,1¢:2,3]imidazo[4,5-
c]isoquinolin-5(6H)-one (6o)
Dark yellow solid; yield: 38%; mp 241–245 °C.
IR (ATR): 1639, 1578, 1400, 1292, 1263, 1240, 1070, 1040, 1029,
985, 850, 813, 788, 712, 693 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.07 (d, J = 1.0 Hz, 3 H, 8-CH3),
3.98 (s, 3 H, 3-OCH3), 4.01 (s, 3 H, 4-OCH3), 5.84 (s, 2 H, 7¢-CH2),
(3) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 661.
Synthesis 2008, No. 22, 3649–3656 © Thieme Stuttgart · New York

3656
F. Mert-Balci et al.
PAPER
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experimental work we learned about a similar domino
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(8) (a) X-ray crystal structure analysis for 6n: formula
C24H21N3O3, M = 399.44, orange crystal 0.10 × 0.03 × 0.02
mm3, monoclinic, space group P21/n, a = 22.673(2),
b = 7.2566(7), c = 24.348(2) Å, b = 107.4740(10)°,
V = 3821.1(6) Å3, rcalcd = 1.389 mg/m3, absorption
coefficient m = 0.093 mm–1, Z = 8, reflections collected
41880, qmax = 28.49°, independent reflections 9106
[Rint = 0.0678], final R1 [I > 2s(I)] = 0.0454, wR2
[I > 2s(I)] = 0.0977, R1 (all data) = 0.1016, wR2 (all
data) = 0.1172, GOF = 1.016, extinction parameter =
0.0012(2), largest diff. peak and hole 0.252 and –0.249
eÅ–3. (b) X-ray data were collected at 100(2) K on an
INCOATEC Microsource device with mirror-
(e) Elhakmaoui, A.; Gueiffier, A.; Milhavet, J.-C.; Blache,
Y.; Chapat, J.-P.; Chavignon, O.; Teulade, J.-C.; Snoeck, R.;
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monochromated Mo-Ka radiation (l = 0.71073 Å). The
device is equipped with a SMART APEX II area detector.
The data were integrated with SAINT9 and an empirical
absorption correction (SADABS)10 was applied. The
structure was solved by using direct methods with SHELXS-
97 and refined by full-matrix least-squares on F2 for all data
with SHELXL-97.11–13 All non-hydrogen atoms were
refined with anisotropic displacement parameters. A riding
model with idealized geometry was employed for all
hydrogen atoms. CCDC-674626 contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
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Tetrahedron Lett. 2007, 48, 4079. (b) Shaabani, A.;
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Crystallographic Data Centre via www.ccdc.cam.ac.uk/
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(6) Mert-Balci, F.; Beifuss, U. unpublished results.
(7) Other approaches to this and related ring systems:
(a) Veljkovic, I.; Zimmer, R.; Reissig, H.-U.; Brüdgam, I.;
Hartl, H. Synthesis 2006, 2677. (b) Paolini, J. P.; Palopoli,
F. P.; Lendvay, L. J.; Huffman, J. J. Heterocycl. Chem. 1987,
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(13) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
Synthesis 2008, No. 22, 3649–3656 © Thieme Stuttgart · New York