Intramolecular arylation reactions: first efficient synthesis of novel fused pyridoimidazoquinolinones or pyridoimidazoazepinones libraries

Article abstract of DOI:10.1016/j.tet.2009.12.049

An efficient method for the synthesis of new polycyclic skeletons: pyrido[2′,1′:2,3]imidazo[5,4-c]quinolin-6(5H)-ones and pyrido[2′,1′:2,3]imidazo[5,4-c]azepin-7(6H)-ones libraries is described via Pd-catalyzed intramolecular arylation involving C(sp2)-H activation. This method permits the synthesis of polycyclic derivatives in good yield. The process tolerates a variety of aryl substituents as well as alkyl imidazo[1,2-a]pyridine-2-carboxamide structures. The resultant compounds, 10(11)-chloro-pyrido[2′,1′:2,3]imidazo[5,4-c]quinolinones or azepinones are functionalized under Suzuki cross-coupling conditions to give polyfunctional compounds.

Full text of DOI:10.1016/j.tet.2009.12.049

Tetrahedron 66 (2010) 1937–1946
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Tetrahedron
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Intramolecular arylation reactions: first efficient synthesis of novel fused
pyridoimidazoquinolinones or pyridoimidazoazepinones libraries
,
,
b
a
J. Koubachi a b, S. Berteina-Raboin a , A. Mouaddib , G. Guillaumet
*
a Institut de Chimie Organique et Analytique, Universite´ d’Orle´ans, UMR CNRS 6005, BP 6759, 45067 Orle´ans Cedex 2, France
b Faculte´ des Sciences et Techniques de Beni-Mellal, Universite´ Sultan Moulay Slimane, BP 523, 23000 Beni-Mellal, Morocco
a r t i c l e i n f o
a b s t r a c t
An efficient method for the synthesis of new polycyclic skeletons: pyrido[20,10:2,3]imidazo[5,4-c]qui-
nolin-6(5H)-ones and pyrido[20,10:2,3]imidazo[5,4-c]azepin-7(6H)-ones libraries is described via Pd-
catalyzed intramolecular arylation involving C(sp2)-H activation. This method permits the synthesis of
polycyclic derivatives in good yield. The process tolerates a variety of aryl substituents as well as alkyl
imidazo[1,2-a]pyridine-2-carboxamide structures. The resultant compounds, 10(11)-chloro-pyr-
ido[20,10:2,3]imidazo[5,4-c]quinolinones or azepinones are functionalized under Suzuki cross-coupling
conditions to give polyfunctional compounds.
Article history:
Received 27 July 2009
Received in revised form 22 December 2009
Accepted 30 December 2010
Available online 7 January 2010
Ó 2010 Published by Elsevier Ltd.
1. Introduction
H
O
H
N
O
N
3
R
R
Significant efforts have been devoted to new synthetic methods
regarding quinolinone and azepinone skeleton1 because of many
biologically active compounds of containing these ring systems.1 For
2
1
N
NH2
N
X
X
H
N
instance, carteolol has been used clinically as a b-adrenergic block-
I
Paullone
R
ing agent.1d Paullone derivatives (Fig. 1) have been described as
potent cyclin-dependent kinase as well as glycogen synthase kinase
inhibitors.2 Latondines A and B (Fig. 1) have been isolated from In-
donesian sponge Stylissa carteri.3 Recently, newcompounds I (Fig.1)
were reported as most potent cytotoxic agents4 and are described as
potential Pfmrk inhibitors.5 In 2005, compound II (Fig.1), which was
found to be an active molecule, induces S and G2/M arrests of cell
cycle, leading to apoptosis.6 Interestingly, all these compounds show
Br
3
R 3
2
4
NH
MeOOC
Br
( )n5
N
H
1
O
N
R 4
6
Latondine A and B
13
NH
N
7
12
O
N
R 511
9
O
10
S
III, n = 0, 1
a
strong analogy with pyrido[20,10:2,3]imidazo[5,4-c]quinolin-
II
6(5H)-ones and pyrido[20,10:2,3]imidazo[5,4-c]azepin-7(6H)-ones
derivatives III (Fig. 1). Our protocol provides a more efficient alter-
native tothe preparations of compounds III, using intramolecular C–
H arylation of heteroaromatic compounds. The method reported
herein opens up a modular access to pyrido[20,10:2,3]imidazo[5,4-
c]quinolin-6(5H)-ones or pyrido[20,10:2,3]imidazo[5,4-c]azepin-
7(6H)-ones.
The introduction of functionalized aryl moieties into heterocyclic
compounds is also an important task in organic synthesis. Palla-
dium-catalyzed direct coupling of (hetero)aryl halides offers an at-
tractive alternative to cross-coupling reactions (Kumada, Negishi,
Stille, Suzuki)7 for the construction of complex polycyclic systems.8
Figure 1. Some literature examples of active quinolinone and azepinone derivatives.
In this context, the overall goal of our research is to develop
efficient synthesis of original imidazo[1,2-a]pyridine derivatives9 to
the design of therapeutic agents.10 Some of our latest work in the
area from the development of new synthetic methods includes
direct and regioselective palladium-catalyzed intermolecular
(hetero)arylation11 and C–H alkenylation12 at C-3 of imidazo[1,2-
a]pyridines. Indeed we have described the first examples of one-
pot Suzuki cross-coupling/direct arylation and one-pot cyclization/
Suzuki cross-coupling/regioselective arylation.13 These results
prompted us to explore selective intramolecular arylation of
N,N,di-substituted imidazo[1,2-a]pyridine-2-carboxamide for the
synthesis of a library of pyrido[20,10:2,3]imidazo[5,4-c]quinolin-
6(5H)-ones and pyrido[20,10:2,3]imidazo[5,4-c]azepin-7(6H)-ones
* Corresponding author. Tel.: þ33 238494856; fax: þ33 238417281.
E-mail address: sabine.berteina-raboin@univ-orleans.fr (S. Berteina-Raboin).
0040-4020/$ – see front matter Ó 2010 Published by Elsevier Ltd.
doi:10.1016/j.tet.2009.12.049

1938
J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
III (Fig. 1), which was then used in Suzuki palladium cross-coupling
in order to access various polyfunctional compounds.
Then, a first attempt of the cyclization, carried out with amide
2a using our conditions,11 gave the starting material (entry 1, Table
1). Next, we used recently described various conditions16,17 in order
to avoid the protection of amide. Unfortunately, all these tests failed
and resulted in the recovery of the starting material (entries 2 and
3, Table 1). The intramolecular CH arylation reaction conditions of
2a are summarized in Table 1.
Recently, some examples of the formation of pyr-
ido[20,10:2,3]imidazo[5,4-c]isoquinolin-5(6H)-one
analogs
by
three-component reaction were reported in literature.14 However,
the synthesis of polyfunctional heteroaromatics III (Fig. 1) is very
difficult using similar methodology. In order to prepare heterocyclic
system III (Fig. 1), the application of intramolecular arylation re-
action seems promising. As far as we know, this is the first example
of intramolecular arylation of imidazo[1,2-a]pyridines as sub-
strates. Such a strategy would furnish novel libraries of polycyclic
frameworks derived from privileged structures that, in turn, could
be used as a source for new chemical entities in medical and bi-
ological research.
Table 1
Palladium-catalyzed cyclization of 2a
Me
Me
Br
NH
H
Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv)
DMA
NH
O
N
O
N
2. Results and discussion
N
N
The resulting original structures were obtained applying the
retrosynthetic scheme shown in Scheme 1, in a few steps from
alkylimidazo[1,2-a]pyridine-2-carboxylate derivatives and in-
volved as key steps (i) condensation reaction with aniline de-
rivatives, (ii) protection of the amide and (iii) palladium-catalyzed
intramolecular arylation at C-3 imidazopyridine ring.
2a
Entry
Additives
K2CO3, 100 ꢀC, 48 h
CsOAc, NH(iPr)2, 100 ꢀC, 48 h
MgO, CuI, 100 ꢀC, 48 h
Yield (%)
1
2
3
0
0
0
R 3
Br
This failure was probably caused by the presence of the free NH
group.11,12,18 For this reason, we decided to perform the reaction
using alkylated amide. Alkylation of the amide N-atom with benzyl
and p-methoxybenzyl groups was done by the exposure of NaH and
benzyl bromide or p-methoxybenzyl chloride, which afforded fully
protected derivatives 3a and 3b in 85 and 76% yield, respectively.
These intermediates were used as precursors for the intramolecular
arylation reaction (Scheme 3).
H
( )n
(i) and (ii)
H
CO2R 1
N
R 4
N
N
N
R 2
O
N
R 2
R 3
(iii)
R1 = Me, Et
R2 = H, Cl, Me, OMe
( )n
Me
H
Me
H
N
R 4
Me
R
R
3 = H, Me
4 = H, Bn, PMB, Boc
N
Br
Direct Intramolecular
Arylation (n = 0, 1)
Br
(i)
O
R 2
N
R 2
N
(ii)
N
R 2
NH
O
N
Scheme 1. Retrosynthetic scheme.
O
N
N
O
N
N
N
2a
3a, R2 = Bn, 85 %
3b, R2 = PMB, 76 %
4a, 80 %(a) 78 %(b)
4b, 82 %(a) 80 %(b)
Our effort to design the cyclization precursor and the intra-
molecular palladium-catalyzed C–H arylation is described in
Scheme 2. In the first case, we proposed the introduction of an aryl
bromide on the imidazole moiety of the bicyclic ring to convert the
alkylimidazo[1,2-a]pyridine-2-carboxylate structures into intra-
molecular arylation substrates and facilitate it. The precursor 2a,
required as key intermediate for the intramolecular arylation
reaction, was carried out by treatment of ethyl and methyl
imidazo[1,2-a]pyridine-2-carboxylates 1a and 1b with 2-bromo-4-
methylaniline in the presence of Me3Al15 to afford the amide 2a in
88 and 86% yield, respectively (Scheme 2).
Scheme 3. (i) PMBCl or BnBr, NaH, THF, reflux, 24–36 h; (ii) (a) Pd(OAc)2 (0.1 equiv),
PPh3 (0.2 equiv), K2CO3 (2 equiv), DMA, 100 ꢀC, oil bath; (b) Pd(OAc)2 (0.1 equiv), PPh3
(0.2 equiv), K2CO3 (2 equiv), DMA, 130 ꢀC, M.W.
Having the N,N-di-substituted imidazo[1,2-a]pyridine-2-car-
boxamides 3a and 3b in hand, we next examined Pd-catalyzed
intramolecular arylation. Gratifyingly, the compounds 3a and 3b
could be efficiently functionalized at 3-position. The reaction was
carried out in the presence of 10 mol % of Pd(OAc)2/20 mol % PPh3
and K2CO3 (2 equiv) in DMA.11 The original 5-benzyl-2-methyl-
pyrido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-one derivatives 4a
and 4b were isolated in excellent yield (Scheme 3). We next applied
these last conditions [i.e., 10 mol % of Pd(OAc)2/20 mol % PPh3,
K2CO3 (2 equiv), DMA] under microwave irradiation; after 1 h
30 min at 130 ꢀC, the desired compound 4a was isolated without
any difficulty in 78% yield (Scheme 3). In order to complete our
studies, each step was optimized in the presence of p-methoxy-
benzyl protecting group. Thus, compound 4b was isolated in 80%
yield (Scheme 3).
Me
NH2
Me
Br
H
Br
H
NH
O
(i)
CO2R 1
N
+
N
N
N
1a, R1 = Et
1b, R1 = Me
2a, 88 %
2a, 86 %
We then turned our attention to remove the p-methoxybenzyl
and benzyl groups. Thus, exposure of 5-benzyl-2-methyl-pyr-
ido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-one 4a to a catalytic
Scheme 2. (i) Me3Al, CH2Cl2, 0 ꢀC then reflux, 4 h.

J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
1939
amount of Pd/C in DMF under an atmosphere of hydrogen resulted
in clean reduction of the pyridine nucleus (Scheme 4). Under these
conditions, corresponding 5 was obtained in 84% yield (Scheme 4).
This result is comparable with literature.19
and palladium(II) acetate/triphenylphosphine as catalyst under
conventional heating. In this case, the novel pyr-
ido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-one derivatives 4(c–f)
were isolated in excellent yield ranging between 83 and 98%
(entries 1–4, Table 4).
Me
Me
Table 3
Preparation of cyclization precursor
Bn
NH2
Bn
H2 (100 psi), Pd/C
DMF, r.t., 4 days
( )n
R 3
N
N
X
N
X
N
O
O
N
5
N
( )n
NH
H
H
4a
84 %
R 3
(i)
CO2R 1
N
Scheme 4. Hydrogenation reaction (partial reduction) of 4a.
N
N
O
R 2
N
R 2
1a, R1 = Et, R2 = H
2(b-h)
(ii)
The other assay performed with 5-(p-methoxybenzyl)-2-
methylpyrido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-ones 4a was
realized in the presence of TFA under reflux for 48 h with
conventional heating.20 Unfortunately, only the starting material
4b was recovered (entry 1, Table 2). Compound 6a was obtained
in 90% yield (entry 2, Table 2) using microwave irradiation at
130 ꢀC for 2 h, under the same reaction conditions. Interestingly,
when the irradiation time was increased to 3 h at 130 ꢀC, the
desired 2-methylpyrido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-
one 6a was isolated in excellent yield (entry 3, Table 2). Similar
results were observed after two hours and 30 min at 150 ꢀC
(entry 4, Table 2).
1c, R1 = Me, R2 = 6-Cl
1d, R1 = Me, R2 = 7-Me
1e, R1 = Et, R2 = 6-OMe
R 3
X
( )n
H
N
R 4
N
O
N
R 2
3(c-j)
Entry
1
X
n
R3
2
R4
3
3c, 85%(a)
3d, 79%(a)
3e, 82%(a)
3f, 74%(a)
3g, 85%(a)
3h, 83%(a)
3i, 84%(b)
3h, 83%(a)
3j, 78%(a)
Table 2
Deprotection of PMB group
1
2
3
4
5
6
7
8
9
1a
1c
1d
1e
1a
1a
1a
1a
1c
Br
Br
Br
Br
Br
Br
Br
H
0
0
0
0
1
1
1
1
1
H
2b, 81%
2c, 83%
2d, 85%
2e, 72%
2f, 72%
2f
2f
2g, 80%
2h, 76%
PMB
PMB
PMB
PMB
Bn
PMB
Boc
2-Br-Bn
2-Br-Bn
Me
Me
Me
H
H
H
Me
Me
PMB
NH
TFA
N
OMe
OMe
H
N
O
N
Reaction conditions
O
N
(i) Me3Al, CH2Cl2, 0 ꢀCdrtdreflux, 4–6 h; (ii) (a) PMBCl, BnBr or 2-Br-BnBr, NaH,
THF, rt then reflux, 24–48 h; (b) DMAP, Et3N, (Boc)2O, THF, 0 ꢀC-rt then reflux, 32 h.
N
4b
6a
Encouraged by these successful attempts with six-member li-
braries, we extended our studies to seven-membred ring of the
azepinone by intramolecular arylation reaction. Our first attempt
with 3g, using conventional heating, afforded the desired pyr-
ido[20,10:2,3]imidazo[5,4-c]benzazepin-7(6H)-one 4g in 75% yield
(entry 5, Table 4). Utilizing microwave irradiation at 130 ꢀC for 1 h
30 min, under the same conditions gave compound 4g in 87% yield
(entry 6, Table 4). With these reaction conditions, we evaluated the
scope and limitations of our method using various precursors 3
(Table 4).
The reaction with 3(h–j) afforded the desired pyr-
ido[20,10:2,3]imidazo[5,4-c]benzazepin-7(6H)-one 4(h–j) in good
yield (entries 7–9, Table 4). The reaction from 3j, using microwave
irradiation, afforded compound 4j in 78% yield after two hours
(entry 10, Table 4). Unfortunately, when using 20 mol % of Pd(OAc)2
and 40 mol % of PPh3 for 2 h, under the same reaction conditions,
the coupling reaction of 3j led to two different compounds 4j and
dehalogenated product 4h in 51% and 25% yield, respectively (entry
11, Table 4). The intramolecular C–H arylation reaction of 3(c–j) was
summarized in Table 4.
Entry
Reaction conditions
Yield (%)
1
2
3
4
Reflux, 48 h
0
90
98
97
M.W, 130 ꢀC, 2 h
M.W, 130 ꢀC, 3 h
M.W, 150 ꢀC, 2 h 30 min
With these results in hand, we thought that this methodology
could be extended to the synthesis of different pyr-
ido[20,10:2,3]imidazo[5,4-c]heterocycles. Thus, starting material 1a,
1(c–e), treated with various amine derivatives in the presence of
Me3Al in the optimal conditions, led to the original compounds
2(b–h) in good yield (entries 1–9, Table 3). Protection of the amide
N-atom with benzyl, p-methoxybenzyl and Boc group gave func-
tionalized substrates 3(c–j) suitable for intramolecular coupling
reactions (Table 3).
In order to explore the scope and limitation of the Pd-cata-
lyzed intramolecular arylation method, we applied the optimized
reaction conditions to precursor (3c–3j). The results (Table 4)
showed that compounds (3c–3j) could be efficiently functional-
ized at position 3, the reaction being performed in dimethyla-
cetamide (DMA) as solvent, with potassium carbonate as base
We further expanded the diversity of derivatives using various 5-
(p-methoxybenzyl)-pyrido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-

1940
J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
Table 4
Table 4 (continued )
Palladium-catalyzed intramolecular CH arylation reaction of various cyclization
precursors 3
Entry
3
Reaction time
Product 4
Yield
R 3
11
3j
2 hc
51% (4j)þ25% (4h)c
X
N
O
PMB
R 3
Cl
N
N
Pd(OAc) 2 (0.1 equiv.)
PPh 3 (0.2 equiv.)
( )n
( )n
H
N
R 4
a
100 ꢀC, oil bath.
130 ꢀC, M.W.
N
R 4
b
c
N
K2CO3 (2 equiv.), DMA
N
Pd(OAc)2 (0.2 equiv), PPh3 (0.4 equiv), K2CO3 (2 equiv), DMA 130 ꢀC, M.W.
O
O
N
R 2
N
R 2
3(c-j)
4(c-j)
Yield
ones. Thus, the treatment of compounds 4(c–f) with TFA under
microwave irradiation at 130 ꢀC for 3 h afforded the desired pyr-
ido[20,10:2,3]imidazo[5,4-c] quinolin-6(5H)-ones 6(b–e) in good
yield (entries 1–4, Table 5).
Entry
3
Reaction time
22 ha
Product 4
PMB
1
3c
N
4c, 95%
Table 5
N
Deprotection
of
PMB
group
of
various
10-(p-methoxybenzyl)pyr-
O
N
ido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-ones 4
R 3
R 3
Me
3d 30 ha
4d, 88%
PMB
NH
2
PMB
N
TFA, 130 °C, 3 h
M.W
N
Cl
N
N
O
N
O
O
N
N
N
R 2
R 2
Me
4(c-f)
6(b-e)
PMB
3
3e
3f
24 ha
4e, 98%
N
Entry
Reagent 4
Product 6
Yield
N
O
N
Me
1
4c
NH
6b, 88%
Me
N
O
N
4
5
36 ha
4f, 83%
PMB
N
MeO
N
Me
O
N
2
4d
4e
4f
6c, 81%
6d, 85%
6e, 94%
NH
Cl
N
3g
3g
48 ha
4g, 75%a
Bn
Bn
N
O
N
N
N
O
N
N
Me
6
7
8
1 h 30 minb
4g, 87%b
4h, 82%
4i, 75%
N
O
3
NH
O
N
N
Me
Me
3h 1 h 30 min
N
PMB
N
O
N
4
NH
MeO
N
O
N
3i
3j
3j
2 hb
48 ha
2 hb
Boc
N
O
N
N
In this work, we have demonstrated the compatibility of the
intramolecular arylation conditions with the presence of a chloro
substituent at position 10 and 11, which could be used to introduce
various substitutions using Suzuki cross-coupling reaction. The
potential of this approach was explored: After optimization studies,
we found the best reaction conditions:11,13,21 Thus, 10-chloro-2-
methyl-5-(p-methoxybenzyl)-pyrido[20,10:2,3]imidazo[5,4-c]quino-
lin-6(5H)-one 4d and 11-chloro-6-(p-methoxybenzyl)-pyr-
ido[20,10:2,3]imidazo[5,4-c]azepin-7(6H)-one 4j were reacted with
various aryl boronic acids (1.2 equiv), Pd(PPh3)4 (0.1 equiv), and
K2CO3 (2 equiv) in a mixture of dioxane/EtOH (3/1: v/v) under
9
4j, 72%a
N
PMB
PMB
Cl
Cl
N
O
N
N
10
4j, 78%b
N
O
N

J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
1941
microwave irradiation at 150 ꢀC for 2 h. These conditions afforded
by an IR sensor. Melting points were determined with a Bu¨chi SMP-
20 melting point apparatus and were uncorrected. 1H and 13C NMR
were recorded on a Bruker Avance DPX 250 spectrometer
polysubstituted
pyrido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-
ones and pyrido[20,10:2,3]imidazo[5,4-c]azepin-7(6H)-ones 7(a–e)
in good yield (Table 6).
(250.19 MHz 1H, 62.89 MHz 13C) and DPX-400 spectrometer
(400 MHz 1H, 100.6 MHz 13C) using TMS as the internal standard,
multiplicities were determined by the DEPT 135 sequence. HRMS
were recorded with a TOF spectrometer (ESI mode) or with a Fin-
nigan MAT 95 XL (CI mode) at the Regional Center of Physical
Measurement University Blaise Pascal, Clermont Ferrand. All
commercial solvents were used without further purification. Col-
umn chromatography was carried out using Silica gel 60N (spher-
ical, neutral, 40–63 mm, Merck). TLC was carried out on Merck
silica gel 60F254 precoated plates and visualized with UV light.
Table 6
Suzuki cross-coupling of 10(11)-chloro-pyrido[20,10:2,3]imidazo[5,4-c]heterocycles
4d and 4j under microwave irradiation
R 3
R 3
R5-B(OH)2, K2CO3
Pd(PPh 3)4, dioxane/ EtOH
( )n
( )n
N
PMB
N
PMB
150 °C, 2h, M.W
R 5
N
N
Cl
O
O
N
N
n = 0, 4d
n = 1, 4j
7(a-e)
4.2. N-substituted imidazo[1,2-a]pyridine-2-carboxamides
(2); General procedure
Entry
1
Reagent 4
Product 7
Yield
Under N2 atmosphere at ꢁ5–0 ꢀC, Me3Al (2 M soln in toluene,
2 equiv) was added to a soln of 2-bromoaniline or p-methoxy-
benzylamine (1.5 equiv) in anhyd CH2Cl2 (20 ml) was added drop-
wise at ꢁ5 ꢀC, and the mixture was stirred for 30 min at this
temperature. The mixture was then slowly warmed to 0 ꢀC over
30 min, and a soln of 1 (1 g, 1 equiv) in anhyd CH2Cl2 (10 ml) was
added dropwise. The mixture was stirred for 4–6 h at reflux, and
then carefully quenched with 1 N aq HCl (10 ml) at 0 ꢀC. The mix-
ture was extracted with CH2Cl2 (3ꢂ). The combined organic layers
were dried over MgSO4 and concentrated under vacuum. The res-
idue was purified by column chromatography on silica gel (EtOAc–
PE) to give the desired product 2.
Me
4d
7a, 88%
MeO
PMB
N
N
O
N
Me
2
3
4d
4d
7b, 97%
7c, 88%
PMB
N
S
N
O
N
Me
O
PMB
N
H
4.2.1. N-(2-Bromo-4-methylphenyl)-imidazo[1,2-a]pyridine-2-car-
N
boxamide (2a). White solid (88%); mp¼215–217 ꢀC; 1H NMR
O
N
(CDCl3, 250 MHz):
d
2.32 (s, 3H, CH3), 6.83–6.89 (m,1H, HAr), 7.16 (d,
0
0
1H, H5 , J¼8.5 Hz), 7.24–7.30 (m, 1H, HAr), 7.41 (s, 1H, H3 ), 7.63–7.67
0
(m, 1H, HAr), 8.15–8.18 (m, 1H, HAr), 8.21 (s, 1H, H3), 8.44 (d, 1H, H6 ,
4
5
4j
4j
7d, 82%
7e, 85%
N
J¼8.5 Hz), 9.79 (s, 1H, NH); 13C NMR (CDCl3, 60.9 MHz):
d
20.7(CH3),
PMB
S
N
113.7 (CH), 114.7 (CH), 118.7 (CH), 121.5 (CH), 126.2 (CH), 126.5 (CH),
129.0 (CH), 132.8 (CH), 133.5 (C), 135.1 (C), 140.2 (C), 144.8 (C), 160.7
(CO); HRMS: m/z [M]þ calcd for C15H13N3OBr: 330.0233, found
330.0242.
O
N
N
O
N
O
PMB
H
4.2.2. N-(2-Bromophenyl)-imidazo[1,2-a]pyridine-2-carboxamide
N
(2b). Yellow solid (81%); mp¼177–178 ꢀC; 1H NMR (CDCl3,
400 MHz):
d 6.84–6.88 (m, 1H, HAr), 6.97–7.02 (m, 1H, HAr), 7.24–
3. Conclusion
7.28 (m, 1H, HAr), 7.34–7.38 (m, 1H, HAr), 7.58–7.66 (m, 2H, HAr),
8.14–8.16 (m, 1H, HAr), 8.22 (s, 1H, H3), 8.58–8.61 (m, 1H, HAr), 9.72
(s, 1H, NH); 13C NMR (CDCl3, 100.6 MHz):
d 113.7 (CH), 113.8 (CH),
We developed
a
straightforward preparation of original
pyrido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-ones and pyrido-
[20,10:2,3]imidazo[5,4-c]azepin-7(6H)-ones library via palladium-
catalyzed intramolecular arylation at the C-3 imidazopyridinic
position. This method can be used with a wide range of cyclization
precursors allowing the synthesis of novel pyrido[20,10:2,3]-
imidazo[5,4-c]heterocycles. We also reported the compatibility of
the synthesis with the presence of chloro groups, which was used
to the synthesis of polyfunctional compounds. Additional studies
are in progress to apply this method for the design of potent bio-
active molecules.
114.7 (C), 118.7 (CH), 121.6 (CH), 125.0 (CH), 126.2 (CH), 126.5 (CH),
128.4 (CH), 132.5 (CH), 136.1 (C), 140.1 (C), 144.6 (C), 160.9 (CO); SM
(IS): m/z [MþH]þ¼316 [79Br], 318 [81Br].
4.2.3. N-(2-Bromo-4-methylphenyl)-6-chloroimidazo[1,2-a]pyri-
dine-2-carboxamide (2c). White solid (83%); mp>250 ꢀC; 1H NMR
0
(CDCl3, 250 MHz):
d
2.32 (s, 3H, CH3), 7.17 (d, 1H, H5 , J¼8.2 Hz),
0
6.21–6.23 (m, 1H, H7), 7.41 (s, 1H, H3 ), 7.60 (d, 1H, H8, J¼9.7 Hz),
0
8.19–8.23 (m, 2H, H3, H5), 8.43 (d, 1H, H6 , J¼8.2 Hz), 9.74 (s, 1H,
NH); 13C NMR (CDCl3, 60.9 MHz):
d 20.6 (CH3), 113.6 (C), 114.8 (CH),
119.0 (CH), 121.4 (CH), 122.0 (C), 124.2 (CH), 127.8 (CH), 128.9 (CH),
132.7 (CH), 133.3 (C), 135.2 (C), 141.0 (C), 142.9 (C), 160.2 (CO); SM
(IS): m/z [MþH]þ¼365 [35Cl], 367 [37Cl], 364 [79Br], 366 [81Br].
4. Experimental section
4.1. General method
4.2.4. N-(2-Bromo-4-methylphenyl)-7-methylimidazo[1,2-a]pyri-
All reagents were purchased from Sigma–Aldrich, Acros Or-
ganics, and Alfa Aesar and used without further purification. Mi-
crowave-assisted reactions were carried out in a Biotage Initiator
microwave synthesis instrument and temperatures were measured
dine-2-carboxamide (2d). Yellow solid (85%); mp¼198–199 ꢀC; 1H
NMR (CDCl3, 250 MHz):
d
2.31 (s, 3H, CH3), 2.39 (s, 3H, CH3), 6.66
0
(dd, 1H, H6, J¼1.5, 7 Hz), 7.15 (dd, 1H, H5 , J¼1.2, 8.5 Hz), 7.26–7.40
0
(m, 2H, H3 and H8), 8.01 (d, 1H, H5, J¼7 Hz), 8.12 (s, 1H, H3), 8.42 (d,

1942
J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
1H, H6 , J¼8.5 Hz), 9.76 (s, 1H, NH); 13C NMR (CDCl3, 60.9 MHz):
(m, 5H, HAr), 7.43–7.49 (m, 2H, H3, HAr), 7.86 (d, 1H, H6 , J¼5 Hz); 13C
0
0
d
20.7(CH3), 21.5(CH3), 113.6 (C), 114.1 (CH), 116.4 (CH), 116.7 (CH),
NMR (CDCl3, 100.6 MHz): d 20.9 (CH2), 52.6 (CH3), 113.2 (CH), 114.1
121.4 (CH), 125.6 (CH), 128.9 (CH), 132.7 (CH), 133.6 (C), 135.0 (C),
(CH), 118.9 (CH), 123.6 (C), 125.2 (CH), 126.0 (CH), 127.6 (CH), 128.4
(CH), 128.8 (CH), 129.7 (CH), 131.8 (CH), 134.0 (C), 136.9 (C), 138.8
(CH), 140.0 (C), 144.2 (C), 163.9 (CO); HRMS: m/z [M]þ calcd for
C22H19N3OBr: 420.0711, found 420.0722.
137.2 (C), 139.9 (C), 145.1 (C), 160.9 (CO); SM (IS): m/z [MþH]þ¼344
[
79Br], 346 [81Br].
4.2.5. N-(2-Bromo-4-methylphenyl)-6-methoxyimidazo[1,2-a]pyri-
dine-2-carboxamide (2e). Brown solid (72%); mp¼125–127 ꢀC; 1H
4.2.11. N-(2-Bromo-4-methylphenyl)-N-(4-methoxybenzyl)-imi-
NMR (CDCl3, 250 MHz):
d
2.32 (s, 3H, CH3), 3.83 (s, 3H, OCH3), 7.05
dazo[1,2-a]pyridine-2-carboxamide (3b). Brown oil (76%); 1H NMR
0
(dd, 1H, H7, J¼2.25, 9.76 Hz), 7.16 (d, 1H, H5 , J¼8.5 Hz), 7.41 (s, 1H,
(CDCl3, 400 MHz): d 2.31 (s, 3H, CH3), 3.77 (s, 3H, OCH3), 4.21 (d, 1H,
0
H3 ), 7.60 (d, 1H, H8, J¼9.76 Hz), 7.64 (d, 1H, H5, J¼2 Hz), 8.17 (s, 1H,
CH2, J¼9 Hz), 5.78 (d,1H, CH2, J¼9 Hz), 6.67–6.69 (m, 2H, HAr), 6.76–
H3), 8.43 (d, 1H, H6 , J¼8.5 Hz), 9.72 (s, 1H, NH); 13C NMR (CDCl3,
7.79 (m, 2H, HAr), 6.91 (d, 1H, HAr, J¼5 Hz), 7.02 (s, 1H, H3 ), 7.06–7.10
0
0
60.9 MHz):
d
20.7 (CH3), 20.7 (OCH3), 107.5 (CH), 113.7 (C), 115.6
(m, 1H, HAr), 7.22–7.24 (m, 2H, HAr), 7.43–7.49 (m, 2H, H3, HAr), 7.85
(d, 1H, H6 , J¼5 Hz); 13C NMR (CDCl3, 100.6 MHz):
d 21.0(CH3),
0
(CH), 118.8 (CH), 121.5 (CH), 122.1 (CH), 129.0 (CH), 132.8 (CH), 133.6
(C), 135.0 (C), 140.0 (C), 141.9 (C), 150.1 (C), 160.9 (CO); HRMS: m/z
[M]þ calcd for C16H15N3O2Br: 330.0348, found 360.0336.
51.9(CH2), 55.3(CH3), 113.2 (CH), 113.8 (2ꢂCH), 114.1 (CH), 118.9
(CH), 123.6 (C), 125.2 (CH), 126.0 (CH), 128.9 (CH), 129.2 (C), 131.1
(2ꢂCH), 131.9 (CH), 133.9 (CH), 138.7 (C), 139.6 (C), 139.9 (C), 144.2
(C), 159.1 (C), 163.9 (CO); HRMS: m/z [M]þ calcd for C23H21N3O2Br:
450.0817, found 450.0811.
4.2.6. N-(2-Bromobenzyl)-imidazo[1,2-a]pyridine-2-carboxamide
(2f). Yellow solid (72%); mp¼179–182 ꢀC; 1H NMR (CDCl3,
400 MHz):
d
4.75 (d, 2H, CH2, J¼6.4 Hz), 6.83 (t, 1H, HAr, J¼6.8 Hz),
7.10–7.15 (m, 1H, HAr), 7.21–7.29 (m, 2H, HAr), 7.47 (d, 1H, HAr
J¼7.2 Hz), 7.46–7.56 (m, 2H, HAr), 7.84 (t, 1H, NH, J¼6.4 Hz), 8.12–
8.16 (m, 2H, HAr); 13C NMR (CDCl3, 100.6 MHz):
43.5 (CH2), 113.5
,
4.2.12. N-(2-Bromophenyl)-N-(4-methoxybenzyl)-imidazo[1,2-
a]pyridine-2-carboxamide (3c). Yellow oil (85%); mp¼122–124 ꢀC;
d
1H NMR (CDCl3, 250 MHz):
d 3.73 (s, 3H, OCH3), 4.27 (d, 1H, CH2,
(CH), 114.4 (CH), 118.3 (CH), 123.8 (C), 126.1 (CH), 126.5 (CH), 127.7
(CH),129.1 (CH),130.1 (CH),132.8 (CH),137.4 (C),139.9 (C),144.6 (C),
162.7 (CO); HRMS: m/z [M]þ calcd for C15H13N3OBr: 330.0242,
found 330.0241.
J¼14.3 Hz), 5.78 (d, 1H, CH2, J¼14.3 Hz), 6.63 (t, 1H, HAr, J¼6.6 Hz),
00
00
6.76 (d, 2H, H4 , H6 , J¼8.5 Hz), 6.84 (dd, 1H, HAr, J¼2.4, 7.1 Hz),
00
00
6.99–7.11 (m, 2H, HAr), 7.13–7.18 (m, 2H, HAr), 7.22 (d, 2H, H3 , H7 ,
J¼8.5 Hz), 7.40 (d, 1H, HAr, J¼9.3 Hz), 7.57–7.61 (m, 1H, HAr), 7.83 (d,
1H, HAr, J¼6.6 Hz); 13C NMR (CDCl3, 60.9 MHz):
d 51.5(CH2), 55.9
4.2.7. N-(4-Methoxybenzyl)–imidazo[1,2-a]pyridine-2-carboxamide
(OCH3), 112.9 (CH), 113.4 (2ꢂCH), 114.0 (CH), 118.2 (CH), 123.7 (C),
125.0 (CH), 125.77 (CH), 127.8 (CH), 128.6 (C), 129.3 (CH), 130.7
(2ꢂCH), 131.9 (CH), 133.2 (CH), 139.1 (C), 141.0 (C), 143.8 (C), 158.8
(C), 163.4 (CO); SM (IS): m/z [MþH]þ¼436 [79Br], 438 [81Br].
(2g). Yellow solid (80%); mp¼121–123 ꢀC; 1H NMR (CDCl3,
250 MHz):
d
3.79 (s, 3H, OCH3), 4.60 (d, 2H, CH2, J¼6.0 Hz), 6.80–
0
0
0
0
6.89 (m, 3H, HAr, H4 , H6 ), 7.18–7.33 (m, 3H, HAr, H3 , H7 ), 7.52 (dd,
1H, HAr, J¼0.8, 9.3 Hz), 7.66 (t, 1H, NH, J¼6.0 Hz), 8.12–8.17 (m, 2H,
HAr); 13C NMR (CDCl3, 60.9 MHz):
d
42.8 (CH2), 55.4 (CH3), 113.4
4.2.13. N-(2-Bromo-4-methylphenyl)-6-chloro-N-(4-methoxy-
(CH), 114.1 (2ꢂCH), 114.4 (C), 118.2 (CH), 126.1 (CH), 126.5 (CH),
129.4 (2ꢂCH), 130.4 (CH), 140.1 (C), 144.6 (C), 159.1 (C), 162.6 (CO);
SM (IS): m/z [MþH]þ¼282.
benzyl)-imidazo[1,2-a]pyridine-2-carboxamide (3d). Yellow solid
(79%); mp¼122–125 ꢀC; 1H NMR (CDCl3, 250 MHz):
d 2.32 (s, 3H,
CH3), 3.77 (s, 3H, OCH3), 4.23 (d, 1H, CH2, J¼14.2 Hz), 5.76 (d, 1H,
00
00
CH2, J¼14.2 Hz), 6.69 (d, 1H, HAr, J¼8.0 Hz), 6.79 (d, 2H, H4 , H6 ,
J¼8.5 Hz), 6.69 (d, 1H, H6, J¼7.2 Hz), 7.01–7.08 (m, 2H, HAr), 7.23 (d,
4.2.8. 6-Chloro-N-(4-methoxybenzyl)-imidazo[1,2-a]pyridine-2-car-
boxamide (2h). Yellow solid (76%); mp¼151–153 ꢀC; 1H NMR
2H, H3 , H7 , J¼8.5 Hz), 7.41–7.44 (m, 2H, HAr), 7.93 (s, 1H, H5); 13C
00
00
(CDCl3, 400 MHz):
d
3.77 (s, 3H, OCH3), 4.58 (d, 2H, CH2, J¼5.6 Hz),
NMR (CDCl3, 60.9 MHz): d 20.9(CH3), 51.9 (CH2), 55.3 (OCH3), 113.7
0
0
6.84 (d, 2H, H4 , H6 , J¼8.4 Hz), 7.15 (d, 2H, H7, J¼9.6 Hz), 7.27 (d, 2H,
(2ꢂCH), 114.3 (CH), 119.1 (CH), 121.4 (C), 123.5 (C), 123.7 (CH), 126.8
(CH), 128.9 (C), 128.9 (CH), 131.1 (2ꢂCH), 131.7 (CH), 133.9 (CH),
138.4 (C), 140.1 (C), 140.4 (C), 142.5 (C), 159.1 (C), 163.3 (CO); HRMS:
m/z [M]þ calcd for C23H20N3O2BrCl: 484.0427, found 484.0423.
0
0
H3 , H7 , J¼8.4 Hz), 7.42 (d, 1H, H8, J¼9.6 Hz), 7.71 (t, 1H, NH,
J¼5.6 Hz), 8.14 (s, 1H, H3), 8.19 (s, 1H, H5); 13C NMR (CDCl3,
100.6 MHz):
d
42.7 (CH2), 55.3 (CH3), 114.0 (2ꢂCH), 114.6 (CH), 118.4
(CH), 121.6 (C), 124.3 (CH), 127.5 (CH), 129.2 (2ꢂCH), 130.3 (C), 140.8
(C), 142.8 (C), 159.0 (C), 162.1 (CO); SM (IS): m/z [MþH]þ¼316.
4.2.14. N-(2-Bromo-4-methylphenyl)-N-(4-methoxybenzyl)-7-meth-
ylimidazo[1,2-a]pyridine-2-carboxamide (3e). Brown oil (82%); 1H
4.2.9. N,N-di-substituted
imidazo[1,2-a]pyridine-2-carboxamides
NMR (CDCl3, 250 MHz):
3H, OCH3), 4.21 (d, 1H, CH2, J¼14.5 Hz), 5.76 (d, 1H, CH2, J¼14.5 Hz),
6.47 (d,1H, H6, J¼6.8 Hz), 6.69 (d,1H, HAr, J¼8.0 Hz), 6.76 (d, 2H, HAr
d 2.26 (s, 3H, CH3), 2.29 (s, 3H, CH3), 3.72 (s,
(3); General procedure. At 0 ꢀC and under N2 atmosphere, NaH (60%
dispersion in oil; 2 equiv) was added to a stirred soln of 2 (0.4 g,
1 equiv) in anhyd THF (10 ml). The mixture was stirred for 30 min
at 0 ꢀC, and a soln of benzyl bromide, 2-bromobenzyl bromide or
p-methoxybenzyl chloride (1.4 equiv) in anhyd THF (10 ml) was
added dropwise. The mixture was stirred for 4–6 h at reflux, for
24–48 h, and then the mixture was cooled to rt and extracted with
CH2Cl2 (3ꢂ). The combined organic layers were dried over MgSO4
and concentrated under vacuum. The residue was purified by
column chromatography on silica gel (EtOAc–PE) to afford the
desired product 3.
,
00
00
H4 , H6 , J¼8.8 Hz), 6.86–6.91 (m, 1H, HAr), 7.20–7.34 (m, 3H, HAr
,
H3 , H7 ), 7.41 (s, 1H, H3), 7.70 (d, 1H, H5, J¼6.8 Hz); 13C NMR (CDCl3,
00
00
60.9 MHz):
d 20.3 (CH3), 21.1 (CH3), 51.5 (CH2), 54.91 (OCH3), 113.3
(CH), 113.4 (2ꢂCH), 115.7 (CH), 116.3 (CH), 123.2 (C), 124.9 (CH),
128.6 (CH), 128.8 (C), 130.7 (2ꢂCH), 131.5 (CH), 133.6 (CH), 135.9 (C),
138.3 (C), 138.8 (C), 139.7 (C), 144.3 (C), 158.7 (C), 163.6 (CO); SM
(IS): m/z [MþH]þ¼464 [79Br], 466 [81Br].
4.2.15. N-(2-Bromo-4-methylphenyl)-N-(4-methoxybenzyl)-6-me-
thoxyimidazo[1,2-a]pyridine-2-carboxamide
(3f). Brown
solid
4.2.10. N-Benzyl-N-(2-bromo-4-methylphenyl)-imidazo[1,2-a]pyri-
(74%); mp¼72–74 ꢀC; 1H NMR (CDCl3, 400 MHz):
d
2.31 (s, 3H, CH3),
dine-2-carboxamide (3a). Yellow solid (85%); mp¼134–135 ꢀC; 1H
3.71 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.20 (d, 1H, CH2, J¼14.3 Hz),
5.76 (d, 1H, CH2, J¼14.3 Hz), 6.69 (d, 1H, HAr, J¼8.5 Hz), 6.77 (d, 2H,
NMR (CDCl3, 400 MHz):
d 2.30 (s, 3H, CH3), 4.26 (d, 1H, CH2,
00
00
J¼8.7 Hz), 5.86 (d, 1H, CH2, J¼8.7 Hz), 6.76–6.73 (m, 2H, HAr), 6.9 (d,
H4 , H6 , J¼8.5 Hz), 6.84–6.94 (m, 3H, HAr), 7.20–7.24 (m, 2H, HAr),
1H, H5 , J¼5 Hz), 7.04 (s, 1H, H3 ), 7.06–7.10 (m, 1H, HAr), 7.23–7.33
7.32–7.36 (m, 2H, HAr), 7.44 (s, 1H, H5); 13C NMR (CDCl3,
0
0

J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
1943
100.6 MHz):
d
20.9 (CH3), 51.8(CH2), 55.2 (OCH3), 56.1 (OCH3), 107.0
4.4. Pyrido[20,10:2,3]imidazo[5,4-c]heterocycles analogs (4);
General procedure
(CH), 113.6 (2ꢂCH), 115.1 (CH), 118.8 (CH), 121.0 (CH), 123.5 (C),
128.8 (CH), 129.1 (C), 131.0 (2ꢂCH), 131.8 (CH), 133.9 (CH), 138.6 (C),
139.2 (C), 139.8 (C), 141.3 (C), 149.7 (C), 159.0 (C), 163.7 (CO); SM
(IS): m/z [MþH]þ¼480 [79Br], 482 [81Br].
By coventional heating: a mixture of N,N-di-substituted imi-
dazo[1,2-a]pyridine-2-carboxamide (3) (200 mg, 1 equiv), K2CO3
(2 equiv), PPh3 (0.2 equiv), and Pd(OAc)2 (0.1 equiv) in DMA (2 mL)
was heated to 100 ꢀC. The reaction was stirred for 48 h, and then
the mixture was cooled to rt and extracted with CH2Cl2 (3ꢂ). The
combined organic layers were dried over MgSO4 and concentrated
under vacuum. The residue was purified by column chromatogra-
phy on silica gel (EtOAc–PE) to give the desired product pyr-
ido[20,10:2,3]imidazo[5,4-c]heterocycles analogs (4).
4.2.16. N-Benzyl-N-(2-bromobenzyl)-imidazo[1,2-a]pyridine-2-car-
boxamide (3g). Yellow solid (85%); mp¼127–129 ꢀC; 1H NMR
(CDCl3, 250 MHz):
d 4.72 (s, 1H, CH2), 4.80 (s, 1H, CH2), 5.45 (s, 1H,
CH2), 5.50 (s, 1H, CH2), 6.76–6.79 (m, 2H, HAr), 7.10–7.33 (m, 9H,
HAr), 7.51–7.54 (m, 2H, HAr), 8.09–8.21 (m, 2H, HAr); 13C NMR
(CDCl3, 100.6 MHz):
d 48.7 (CH2), 51.3 (CH2), 113.4 (CH), 113.9 (CH),
116.9 (CH), 118.6 (CH), 123.3 (C), 125.4 (CH), 126.0 (CH), 127.4 (CH),
127.7 (CH), 128.5 (CH), 128.6 (2ꢂCH), 128.7 (CH), 128.9 (CH), 132.8
(CH),136.0 (C),137.0 (C),137.6 (C),140.8 (C),144.1 (C),165.0 (CO); m/
z [MþH]þ¼421.
Under microwave irradiation: to a soln of N,N-di-substituted
imidazo[1,2-a]pyridine-2-carboxamide (3) (200 mg, 1 equiv) dis-
solved in DMA (2 mL) in a vial microwave tube was added, under
argon, a stirrer bar, K2CO3 (2 equiv), PPh3 (0.2 equiv), and Pd(OAc)2
(0.1 equiv). The vial was sealed with a silicon septum and subjected
to microwave irradiation [4(a–h): at 130 ꢀC for 1 h 30 min; 4i and
4j: at 130 ꢀC for 2 h] with stirring. The reaction vessel was allowed
to cool to rt, diluted with CH2Cl2 (15 mL) and extracted (3ꢂ). The
combined organic layers were dried (MgSO4) and concentrated
under vacuum. The residue was purified by column chromatogra-
phy (silica gel, EtOAc–PE) to give the desired product.
4.2.17. N-(2-Bromobenzyl)-N-(4-methoxybenzyl)-imidazo[1,2-a]pyr-
idine-2-carboxamide (3h). Yellow solid (83%); mp¼125–127 ꢀC;
1H NMR (CDCl3, 400 MHz):
d 3.76 (s, 3H, CH3), 4.65 (s, 1H, CH2),
4.78 (s, 1H, CH2), 5.36 (s, 1H, CH2), 5.46 (s, 1H, CH2), 6.65–6.85 (m,
00
00
00
00
3H, HAr, H4 , H6 ), 7.06–7.46 (m, 6H, HAr, H3 , H7 ), 7.51–7.58 (m,
2H, HAr), 8.05–8.21 (m, 3H, HAr); 13C NMR (CDCl3, 100.6 MHz):
d
48.4 (CH2), 51.0 (CH2), 55.3 (CH3), 113.4 (CH), 113.9 (2ꢂCH),
116.7 (CH), 118.5 (CH), 123.6 (C), 125.4 (CH), 126.0 (CH), 127.6
(CH), 128.6 (CH), 128.8 (CH), 129.1 (CH), 129.9 (CH), 132.8 (CH),
136.0 (C), 137.0 (C), 140.9 (C), 144.1 (C), 159.0 (C), 164.8 (CO); m/z
[MþH]þ¼451.
4.4.1. 5-Benzyl-2-methyl-pyrido[20,10:2,3]imidazo[5,4-c]quinolin-
6(5H)-one (4a). Yellow solid (80%); mp>250 ꢀC; 1H NMR (CDCl3,
250 MHz):
d 2.48 (s, 3H, CH3), 5.75 (s, 2H, CH2), 7.11 (t, 1H, HAr,
J¼6.5 Hz), 7.18–7.27 (m, 6H, HAr), 7.34 (d, 1H, HAr, J¼8.5 Hz), 7.45 (t,
1H, HAr, J¼7.7 Hz), 7.90–7.94 (m, 2H, HAr), 8.90 (d,1H, HAr, J¼6.5 Hz);
4.2.18. N-(2-Bromobenzyl)-6-chloro-N-(4-methoxybenzyl)-imidazo
13C NMR (CDCl3, 60.9 MHz):
d 21.2(CH2), 46.3 (CH3), 114.1 (CH),
[1,2-a]pyridine-2-carboxamide (3j). White solid (78%); mp¼152–
114.2 (CH), 116.9 (CH), 120.1 (CH), 120.3 (CH), 125.1 (C), 126.6 (CH),
126.7 (CH), 127.2 (CH), 128.8 (CH), 128.9 (CH), 132.3 (C), 134.4 (C),
134.5 (C),136.8 (CH),147.7 (C),158.9 (CO); HRMS: m/z [M]þ calcd for
C22H18N3OBr: 340.1450, found 340.1457.
155 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 3.78 (s, 3H, CH3), 4.63 (s, 1H,
CH2), 4.76 (s, 1H, CH2), 5.31 (s, 1H, CH2), 5.40 (s, 1H, CH2), 6.81–
6.86 (m, 2H, HAr), 7.10–7.18 (m, 3H, HAr), 7.24–7.34 (m, 3H, HAr),
7.42–7.54 (m, 2H, HAr), 8.11–8.19 (m, 2H, HAr); 13C NMR (CDCl3,
100.6 MHz):
d
48.2 (CH2), 50.5 (CH2), 55.0 (CH3), 113.6 (2ꢂCH),
4.4.2. 5-(4-Methoxybenzyl)-2-methylpyrido[20,10:2,3]imidazo [5,4-c]
116.8 (CH), 118.6 (CH), 121.4 (C), 123.3 (C), 123.4 (CH), 126.7 (CH),
127.3 (CH), 128.3 (CH), 128.5 (CH), 128.7 (CH), 129.6 (CH), 132.6
(CH), 135.6 (C), 136.6 (C), 141.5 (C), 142.1 (C), 158.7 (C), 164.1 (CO);
HRMS: m/z [M]þ calcd for C23H20N3O2BrCl: 484.0427, found
484.0432.
quinolin-6(5H)-one (4b). Yellow solid (82%); mp>250 ꢀC; 1H NMR
(CDCl3, 400 MHz): d 2.50 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 5.70 (s, 2H,
CH2), 6.77–6.81 (m, 2H, HAr), 7.10–7.27 (m, 4H, HAr), 7.40–7.48 (m,
2H, HAr), 7.92–7.96 (m, 2H, HAr), 8.93 (d, 1H, HAr, J¼7.2 Hz); 13C NMR
(CDCl3, 100.6 MHz):
d 21.24(CH3), 45.8(CH2), 55.36 (CH3), 114.1
(CH), 114.2 (2ꢂCH), 114.3 (C), 117.0 (CH), 120.1 (CH), 120.3 (CH),
125.1 (C), 126.6 (CH), 127.2 (CH), 128.1 (2ꢂCH), 128.9 (C), 128.9 (CH),
132.2 (C), 134.4 (C), 134.6 (C), 147.7 (C), 158.8 (C), 159.0 (CO); HRMS:
m/z [M]þ calcd for C23H20N3O2: 370.1556, found 370.1552.
4.3. Procedure for synthesis of tert-butyl-N-(2-bromobenzyl)-
{(imidazo[1,2-a]pyridinyl)carbonyl} carbamate (3i)
At rt and under N2 atmosphere, DMAP (0.44 g, 3.63 mmol), Et3N
(0.51 ml, 3.63 mmol) were added to a stirred solution of amide (2f)
(0.6 g, 1.8 mmol) in anhyd THF (10 ml). The mixture was stirred at
rt, and a soln of (Boc)2O (0.59 g, 2.7 mmol) in anhyd THF (5 ml) was
added dropwise. The mixture was stirred for 36 h at reflux, and
then the mixture was cooled to rt and extracted with CH2Cl2 (3ꢂ).
The combined organic layer was dried over MgSO4 and concen-
trated under vacuum. The residue was purified by column
chromatography on silica gel (EtOAc–PE) to give tert-butyl-N-(2-
bromobenzyl)-{(imidazo[1,2-a]pyridinyl) carbonyl}carbamate (3i)
as white solid (0.65 g, 84% yield).
4.4.3. 5-(4-Methoxybenzyl)-pyrido[20,10:2,3]imidazo[5,4-c] quinolin-
6(5H)-one (4c). Yellowish solid (95%); mp¼242–244 ꢀC; 1H NMR
(CDCl3, 400 MHz):
d 2.54 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 5.70 (s,
0
0
2H, CH2), 6.82 (d, 2H, H4 , H6 , J¼8.8 Hz), 7.10 (dt, 1H, HAr, J¼3.5,
0
0
9.5 Hz), 7.20 (d, 2H, H3 , H7 , J¼8.8 Hz), 7.30–7.51 (m, 4H, HAr), 6.91
(d, 1H, HAr, J¼9.5 Hz), 8.14 (dd, 1H, HAr, J¼1.2, 8.0 Hz), 8.86 (d, 1H,
HAr, J¼7.2 Hz); 13C NMR (CDCl3, 100.6 MHz):
d 45.8(CH2), 55.3
(OCH3), 114.2 (3ꢂCH), 114.3 (C), 117.0 (CH), 120.0 (CH), 120.2 (CH),
122.6 (CH), 125.2 (C), 126.5 (CH), 127.3 (CH), 127.8 (CH), 128.1
(2ꢂCH), 128.7 (C), 134.5 (C), 136.4 (C), 147.8 (C), 158.8 (C), 159.1
(CO); HRMS: m/z [M]þ calcd for C15H13N3OBr: 356.1404, found
356.1399.
Mp¼157–159 ꢀC; 1H NMR (CDCl3, 250 MHz):
d 1.21 (s, 9H,
OC(CH3)3), 5.10 (s, 2H, CH2), 6.84 (dt, 1H, HAr, J¼3.4, 9.5 Hz), 7.10
(dt, 1H, HAr, J¼3.9, 10.5 Hz), 7.20–7.32 (m, 2H, HAr), 7.45 (d, 1H, HAr
,
J¼7.75 Hz), 7.53–7.63 (m, 2H, HAr), 8.07 (s, 1H, H3), 8.13 (dt, 1H, HAr
,
4.4.4. 10-Chloro-5-(4-methoxybenzyl)-2-methyl-pyrido[20,10:2,3]
J¼1.06, 6.92 Hz); 13C NMR (CDCl3, 60.9 MHz):
d
27.5 (OC(CH3)3),
imidazo[5,4-c]quinolin-6(5H)-one (4d). Yellowish solid (88%);
49.5 (CH2), 83.2 (OC(CH3)3), 113.6 (CH), 115.1 (CH), 118.8 (CH),
122.5 (C), 125.9 (CH), 126.3 (CH), 127.4 (CH), 127.7 (CH), 128.5 (CH),
132.7 (CH), 137.0 (C), 141.4 (C), 144.1 (C), 153.5 (CO), 168.1 (CO);
HRMS: m/z [M]þ calcd for C20H21N3O3Br: 430.0766, found
430.0773.
mp>250 ꢀC; 1H NMR (CDCl3, 400 MHz):
d 2.54 (s, 3H, CH3), 3.76 (s,
0
0
3H, OCH3), 5.70 (s, 2H, CH2), 6.88–6.85 (m, 2H, H4 , H6 ), 7.18–7.29
00
00
(m, 3H, HAr), 7.42–7.47 (m, 2H, H3 , H7 ), 7.89–7.93 (m, 2H, HAr), 8.94
(s, 1H, H11); 13C NMR (CDCl3, 100.6 MHz):
21.2(CH3), 45.8(CH2),
55.4 (OCH3), 113.8 (C), 114.3 (2ꢂCH), 117.1 (CH), 120.2 (C), 120.3
d

1944
J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
(CH), 120.4 (CH), 122.4 (C), 124.3 (CH), 125.3 (C), 128.1 (2ꢂCH), 128.7
(CH), 129.5 (CH), 132.5 (C), 134.6 (C), 135.2 (C), 145.9 (C), 158.7 (C),
158.9 (CO); HRMS: m/z [M]þ calcd for C23H19N3O2Cl: 404.1166,
found 404.1167.
(C), 128.8 (2ꢂCH), 129.7 (CH), 136.9 (C), 138.6 (C), 145.9 (C), 151.2
(CO), 162.6 (CO); HRMS: m/z [M]þ calcd for C20H20N3O3: 350.1505,
found 350.1513.
4.4.10. 11-Chloro-6-(4-methoxybenzyl)-pyrido[20,10:2,3]imidazo [5,4-
4.4.5. 5-(4-Methoxybenzyl)-2,9-di-methyl-pyrido[20,10:2,3] imidazo
c]benzazepin-7(6H)-one (4j). Brown solid (78%); mp¼132–134 ꢀC;
[5,4-c]quinolin-6(5H)-one (4e). Yellowish solid (98%); mp>250 ꢀC;
1H NMR (CDCl3, 400 MHz):
d 3.80 (s, 3H, CH3), 4.08 (d, 1H, CH2,
1H NMR (CDCl3, 400 MHz):
d
2.44 (s, 3H, CH3), 2.45 (s, 3H, CH3), 3.71
J¼14.8 Hz), 4.26 (d,1H, CH2, J¼14.8 Hz), 4.53 (d, 1H, CH2, J¼14.8 Hz),
0
0
0
0
(s, 3H, OCH3), 5.62 (s, 2H, CH2), 6.77 (m, 2H, H4 , H6 , J¼8.8 Hz), 6.86
5.03 (d, 1H, CH2, J¼14.8 Hz), 6.84 (d, 2H, H4 , H6 , J¼8.3 Hz), 7.15 (d,
1H, HAr, J¼7.5 Hz), 7.25–7.37 (m, 4H, HAr), 7.50–7.56 (m, 1H, HAr),
7.74–7.82 (m, 2H, HAr), 8.61 (s, 1H, H12); 13C NMR (CDCl3,
0
0
(dd, 1H, H6, J¼1.2, 7.2 Hz), 7.13–7.17 (m, 3H, HAr, H3 , H7 ), 7.32 (d, 1H,
HAr, J¼9.0 Hz), 7.59 (s, 1H, H1), 7.80 (s, 1H, H5), 8.67 (d, 1H, H5,
J¼7.2 Hz); 13C NMR (CDCl3, 100.6 MHz):
d
21.23 (CH3), 21.69 (CH3),
100.6 MHz):
d
49.8 (CH2), 50.3 (CH2), 55.4 (CH3), 114.1 (2ꢂCH),
45.7 (CH2), 55.4 (OCH3), 114.2 (2ꢂCH), 114.2 (C), 116.8 (CH), 116.9
(CH), 117.9 (CH), 120.1 (CH), 124.8 (C), 125.8 (CH), 128.1 (2ꢂCH),
128.6 (CH), 129.0 (C), 132.1 (C), 134.2 (C), 134.6 (C), 138.5 (C), 148.2
(C), 158.8 (C), 159.0 (CO); HRMS: m/z [M]þ calcd for C24H22N3O2:
384.1712, found 384.1710.
120.0 (CH), 122.2 (CH), 122.4 (C), 124.2 (C), 124.3 (CH), 127.1 (CH),
127.2 (C), 128.0 (CH), 128.8 (CH), 129.1 (CH), 129.2 (C), 130.1 (2ꢂCH),
137.0 (C), 140.1 (C), 144.2 (C), 159.3 (C), 163.5 (CO); HRMS: m/z [M]þ
calcd for C23H19N3O2Cl: 404.1166, found 404.1158.
4.5. Procedure synthesis of 5-benzyl-2-methyl-
8,9,10,11-tetrahydropyrido[20,10:2,3]imidazo[5,4-c]quinolin-
7(6H)-one (5)
4.4.6. 10-Methoxy-5-(4-methoxybenzyl)-2-methyl-pyrido
[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-one (4f). Yellow solid (83%);
mp¼242–244 ꢀC; 1H NMR (CDCl3, 250 MHz):
d 2.49 (s, 3H, CH3),
3.73 (s, 3H, CH3), 4.0 (s, 3H, OCH3), 5.64 (s, 2H, CH2), 6.78 (d, 2H,
A solution of compound (4a) in DMF was hydrogenated with
10% palladium on carbon under H2 (100 psi) for four days. After
the catalyst was filtered off, the filtrate was concentrated
under vacuum. The residue was purified by column chromatog-
raphy on silica gel (CH2Cl2–MeOH) to give 2-methyl-8,9,10,11-
tetrahydropyrido[20,10:2,3] imidazo[5,4-c]quinolin-7(6H)-one (5)
yellow solid (84%); mp>250 ꢀC; 1H NMR (CDCl3, 400 MHz): 2.01–
2.04 (m, 2H, CH2, H9), 5.18–2.24 (m, 2H, CH2, H10), 2.40 (s, 3H,
CH3), 3.13 (t, 2H, CH2, H8, J¼3.8 Hz), 4.51 (t, 2H, CH2, H11,
J¼3.8 Hz), 5.61 (s, 2H, CH2), 7.10–7.27 (m, 7H, HAr), 7.92 (s, 1H,
0
0
H4 , H6 , J¼8.5 Hz), 7.15–7.27 (m, 4H, HAr), 7.37 (d, 1H, HAr
,
J¼8.8 Hz), 7.77–7.81 (m, 2H, HAr), 8.26 (d, 1H, HAr, J¼2 Hz); 13C
NMR (CDCl3, 62.9 MHz):
d 21.4 (CH3), 45.7 (CH2), 55.3 (OCH3),
55.6(OCH3), 108.3 (CH), 114.2 (2ꢂCH), 114.4 (C), 116.9 (CH), 119.9
(CH), 120.0 (CH), 122.6 (CH), 125.6 (C), 128.0 (2ꢂCH), 128.7 (CH),
128.9 (C), 132.0 (C), 134.4 (C), 134.7 (C), 145.0 (C), 150.2 (C), 158.8
(C), 159.0 (CO); HRMS: m/z [M]þ calcd for C24H22N3O3: 400.1661,
found 400.1667.
4.4.7. 6-(Benzyl)-pyrido[20,10:2,3]imidazo[5,4-c]benzazepin-7(6H)-
H1); 13C NMR (CDCl3, 100.6 MHz):
d 19.8 (CH2), 21.1 (CH3), 23.2
one (4g). Yellow solid (87%); mp¼194–196 ꢀC; 1H NMR (CDCl3,
(CH2), 25.9 (CH2), 45.8 (CH2), 46.6 (CH2), 114.3 (C), 116.6 (CH),
121.14 (CH), 126.61 (2ꢂCH), 126.66 (C), 127.03 (2ꢂCH), 128.67
(CH), 128.89 (CH), 130.56 (C), 131.35 (C), 132.54 (C), 135.03 (C),
137.14 (C), 150.15 (C), 150.18 (C), 158.23 (CO); HRMS: m/z [M]þ
calcd for C22H22N3O: 344.1763, found 344.1765.
400 MHz):
d
4.08 (d, 1H, CH2, J¼14.8 Hz), 4.31 (d, 1H, CH2,
J¼14.8 Hz), 4.60 (d, 1H, CH2, J¼14.8 Hz), 5.12 (d, 1H, CH2, J¼14.8 Hz),
6.97 (dt, 1H, HAr, J¼2.2, 5.9 Hz), 7.13 (d, 1H, HAr, J¼4.5 Hz), 7.27–7.36
(m, 7H, HAr), 8.63 (dt, 1H, HAr, J¼2.4, 6.6 Hz), 7.82–7.84 (m, 2H, HAr),
8.6 (d, 1H, HAr, J¼4.5 Hz); 13C NMR (CDCl3, 100.6 Hz):
d 50.4 (CH2),
50.6 (CH2), 114.0 (CH), 119.6 (CH), 123.9 (C), 124.3 (CH), 124.4 (CH),
126.5 (CH), 127.6 (C), 127.6 (CH), 128.4 (CH), 128.5 (CH), 128.6
(2ꢂCH), 128.7 (2ꢂCH), 128.9 (CH), 136.7 (C), 137.3 (C), 139.4 (C),
145.9 (C), 163.9 (CO); HRMS: m/z [M]þ calcd for C22H18N3O:
340.1450, found 340.1462.
4.6. Deprotection of PMB group of various 10-
(p-methoxybenzyl)pyrido[20,10:2,3]imidazo[5,4-c]quinolin-
6(5H)-ones (6); General procedure
To a soln of 10-(p-methoxybenzyl)pyrido [20,10:2,3]imidazo[5,4-
c]quinolin-6(5H)-one 4 dissolved in TFA (5 mL) in a vial microwave
tube was added, under argon. The vial was sealed with a silicon
septum and subjected to microwave irradiation at 130 ꢀC for 3 h,
with stirring. The reaction vessel was allowed to cool to rt, con-
centrated in vacuo to dryness, water was added to the residue and
then extracted with CH2Cl2 (15 mL). The organic layer was washed
successively with saturated aqueous NaHCO3, water and brine, and
dried over MgSO4. The solvent was concentrated in vacuo. The
residue was purified by column chromatography (silica gel, CH2Cl2–
MeOH) to give the desired product (6).
4.4.8. 6-(4-Methoxybenzyl)-pyrido[20,10:2,3]imidazo[5,4-c] benzaze-
pin-7(6H)-one (4h). Yellow oil (82%); 1H NMR (CDCl3, 250 MHz):
d
3.80 (s, 3H, CH3), 4.08 (d, 1H, CH2, J¼15.0 Hz), 4.27 (d, 1H, CH2,
J¼15.0 Hz), 4.52 (d, 1H, CH2, J¼15.0 Hz), 5.08 (d, 1H, CH2,
0
0
J¼15.0 Hz), 6.84 (m, 2H, H4 , H6 ), 7.13 (dt, 1H, HAr, J¼4.8, 15.4 Hz),
7.15 (d, 1H, HAr, J¼7.5 Hz), 7.27–7.36 (m, 4H, HAr), 7.46–7.52 (m, 1H,
H
Ar), 7.79–7.84 (m, 2H, HAr), 8.59 (d, 1H, HAr, J¼7 Hz); 13C NMR
(CDCl3, 62.9 MHz):
d 49.7 (CH2), 50.3 (CH2), 55.4 (CH3), 114.0
(2ꢂCH), 114.0 (CH), 119.6 (CH), 123.8 (C), 124.3 (CH), 124.4 (CH),
126.5 (CH), 127.6 (C), 128.4 (CH), 128.5 (CH), 128.9 (CH), 129.4 (C),
130.0 (2ꢂCH), 136.7 (C), 136.8 (C), 139.4 (C), 145.9 (C), 159.2 (C),
163.8 (CO); HRMS: m/z [M]þ calcd for C23H20N3O2: 370.1556,
found 370.1546.
4.6.1. 2-Methyl-pyrido[20,10:2,3]imidazo[5,4-c]quinolin-6-one
(6a). Yellowish solid (98%); mp>250 ꢀC; 1H NMR (DMSO-d6,
400 MHz):
d 2.48 (s, 3H, CH3), 7.27–7.35 (m, 2H, HAr), 7.46 (d, 1H,
0
H5 , J¼8.5 Hz), 7.66–7.69 (m, 1H, HAr), 7.89–7.90 (m, 1H, HAr), 8.30 (s,
4.4.9. tert-Butyl-7-oxo-pyrido[20,10:2,3]imidazo[5,4-c] benzazepine-
1H, H3 ), 9.48–9.49 (m, 1H, HAr), 11.92 (s, 1H, CONH); 13C NMR
0
6-carboxylate (4i). Yellow Solid (75%); mp¼180–183 ꢀC; 1H NMR
(DMSO-d6,100.6 MHz): d 20.56(CH3), 99.45 (C), 111.8 (C), 114.5 (CH),
(CDCl3, 250 MHz):
d
1.53 (s, 9H, OC(CH3)3), 4.28 (d, 1H, CH2,
116.2 (CH), 117.8 (CH), 120.3 (CH), 128.5 (CH), 128.8 (CH), 128.9 (CH),
131.7 (C), 132.8 (C), 144.4 (C), 133.5 (C), 157.3 (CO); HRMS: m/z [M]þ
calcd for C15H12N3O: 250.0980, found 250.0992.
J¼14.8 Hz), 5.25 (d, 1H, CH2, J¼14.8 Hz), 6.97 (dt, 1H, HAr, J¼3.5,
9.4 Hz), 7.34 (dt, 1H, HAr, J¼2.2, 7.0 Hz), 7.38–7.65 (m, 3H, HAr), 7.81–
7.91 (m, 2H, HAr), 8.63 (d, 1H, HAr, J¼7.0 Hz); 13C NMR (CDCl3,
62.9 MHz):
d
28.13 (OC(CH3)3), 48.1 (CH2), 83.4 (OC(CH3)3), 114.4
4.6.2. Pyrido[20,10:2,3]imidazo[5,4-c]quinolin-6-one
solid (88%); mp>250 ꢀC; 1H NMR (DMSO-d6, 250 MHz):
(6b). Brown
7.20–7.26
(CH), 119.9 (CH), 124.4 (CH), 124.5 (C), 124.8 (CH), 126.9 (CH), 127.3
d

J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
1945
(m, 1H, HAr), 7.33–7.39 (m, 1H, HAr), 7.50–7.62 (m, 3H, HAr), 7.88 (d,
(CO); HRMS: m/z [M]þ calcd for C30H26N3O3: 476.1974, found
1H, HAr, J¼7.5 Hz), 8.49–7.52 (m, 1H, HAr), 9.36–9.39 (m, 1H, HAr),
476.1988.
11.90 (s, 1H, CONH); 13C NMR (DMSO-d6, 100.6 MHz):
d 99.9 (C),
112.2 (C), 114.1 (CH), 116.3 (CH), 118.6 (CH), 120.6 (CH), 122.2 (CH),
127.4 (CH), 127.9 (CH), 128.0 (CH), 134.3 (C), 135.5 (C), 154.5 (C),
158.1 (CO); HRMS: m/z [M]þ calcd for C14H10N3O: 236.0824, found
236.0821.
4.6.8. 5-(4-Methoxybenzyl)-2-methyl-10-(thiophen-3-yl)-pyrido
[20,10:2,3] imidazo[5,4-c]quinolin-6(5H)-one (7b). Yellow solid
(97%); mp¼241–243 ꢀC; NMR 1H (CDCl3, 400 MHz):
d 2.46 (s, 3H,
0
0
CH3), 3.71 (s, 3H, OCH3), 5.60 (s, 2H, CH2), 6.76 (d, 2H, H4 , H6 ,
0
0
J¼8.8 Hz), 7.14 (d, 2H, H3 and H7 , J¼8.8 Hz), 7.17–7.18 (m, 1H, HAr),
7.32 (d, 1H, HAr, J¼9.0 Hz), 7.42 (dd, 1H, HAr, J¼1.2, 5.2 Hz), 7.42 (dd,
1H, HAr, J¼3.0, 5.2 Hz), 7.58–7.63 (m, 2H, HAr), 7.83–7.87 (m, 2H,
4.6.3. 10-Chloro-2-methylpyrido[20,10:2,3]imidazo[5,4-c] quinolin-6-
one (6c). Brown solid (81%); mp>250 ꢀC; 1H NMR (DMSO-d6,
250 MHz):
d
2.50 (s, 3H, CH3), 7.33 (d, 1H, HAr, J¼8.5 Hz), 7.41–7.45
HAr), 8.90 (s, 1H, H12); NMR 13C (CDCl3, 100.6 MHz):
d 21.1(CH3),
(m, 1H, HAr), 7.65–7.69 (m, 1H, HAr), 7.90–7.94 (m, 1H, HAr), 8.35 (s,
45.4 (CH2), 55.1 (OCH3), 113.9 (C), 114.0 (2ꢂCH), 116.7 (CH), 119.4
(CH), 119.9 (CH), 121.9 (CH), 122.6 (CH), 123.4 (C), 125.0 (C), 125.7
(CH), 127.5 (CH), 127.5 (CH), 127.8 (2ꢂCH), 128.6 (C), 128.7 (CH),
132.0 (C), 134.2 (C), 134.7 (C), 137.5 (C), 146.6 (C), 158.5 (C), 158.6
(CO); HRMS: m/z [M]þ calcd for C27H22N3O2S: 452.1433, found:
452.1450.
1H, H1), 9.54 (s, 1H, H11), 8.24 (s, 1H, CONH); 13C NMR (DMSO-d6,
100.6 MHz):
d 20.40(CH3), 94.7 (C), 111.5 (C), 116.2 (CH), 119.6 (C),
120.6 (CH), 121.4 (CH), 122.2 (C), 127.8 (CH), 129.1 (CH), 129.4 (CH),
131.8 (C), 133.6 (C), 157.2 (CO); HRMS: m/z [M]þ calcd for
C15H11N3OCl: 284.0591, found 284.0593.
4.6.4. 2,9-Dimethyl-pyrido[20,10:2,3]imidazo[5,4-c]quinolin-6-one
4.6.9. {5-(4-Methoxybenzyl)-2-methyl-pyrido[20,10:2,3] imidazo [5,4-
(6d). Brown solid (85%); mp>250 ꢀC; 1H NMR (DMSO-d6,
c]quinolin-6(5H)-on-10-yl}benzaldehyde (7c). Yellow solid (88%);
250 MHz):
d
2.48 (s, 3H, CH3), 2.57 (s, 3H, CH3), 7.33 (d, 1H, H10
,
mp¼241–243 ꢀC; NMR 1H (CDCl3, 250 MHz):
d 2.49 (s, 3H, CH3),
3.72 (s, 3H, OCH3), 5.63 (s, 2H, CH2), 6.75–6.78 (m, 2H, HAr), 7.14–
J¼4.5 Hz), 7.37 (d, 1H, H3, J¼5.3 Hz), 7.46 (d, 1H, H4, J¼5.3 Hz), 7.73
(s, 1H, H1), 8.27 (s, 1H, H8), 9.44 (d, 1H, H11, J¼4.5 Hz), 12.19 (s, 1H,
7.28 (m, 3H, HAr), 7.39 (d, 1H, HAr, J¼10.0 Hz), 7.67 (d, 1H, HAr
J¼7.5 Hz), 7.84–8.07 (m, 6H, HAr), 9.05 (s, 1H, H12), 10.09 (s, 1H,
CHO); NMR 13C (CDCl3, 60.9 MHz):
21.3(CH3), 45.7(CH2),
,
CONH); 13C NMR (DMSO-d6, 100.6 MHz):
d 20.5(CH3), 21.1(CH3),
111.0 (C), 113.6 (CH), 116.5 (CH), 118.5 (CH), 120.5 (CH), 125.8 (C),
128.1 (C), 128.4 (CH), 129.6 (CH), 132.3 (C), 133.7 (C), 144.2 (C), 155.4
(C), 158.3 (CO); HRMS: m/z [M]þ calcd for C16H14N3O: 264.1137,
found 264.1150.
d
55.3(OCH3), 114.0 (C), 114.16 (2ꢂCH), 117.0 (CH), 120.0 (CH), 120.3
(CH), 124.5 (CH), 125.4 (C), 127.4 (C), 127.5 (CH), 128.0 (4ꢂCH), 128.7
(C), 129.2 (CH), 130.7 (2ꢂCH), 132.4 (C), 134.5 (C), 135.1 (C), 136.0
(C), 142.9 (C), 146.8 (C), 158.6 (C), 158.8 (CO), 191.5 (CHO); HRMS: m/
z [M]þ calcd for C30H24N3O3: 474.1818, found 474.1812.
4.6.5. 10-Methoxy-2-methyl-pyrido[20,10:2,3]imidazo[5,4-c] quino-
lin-6-one (6e). Yellowish solid (94%); mp>250 ꢀC; 1H NMR
(DMSO-d6, 250 MHz):
7.32 (m, 1H, HAr), 7.39–7.44 (m, 2H, HAr), 7.46 (d, 1H, HAr
J¼9.8 Hz), 8.16 (s, 1H, HAr), 8.60–8.62 (m, 1H, HAr), 11.73 (s, 1H,
NH); 13C NMR (DMSO-d6, 60.9 MHz):
20.7(CH3), 56.7(OCH3),
d
2.48 (s, 3H, CH3), 4.0 (s, 3H, OCH3), 7.28–
4.6.10. 6-(4-Methoxybenzyl)-11-(thiophen-3-yl)-pyrido[20,10:2,3]
imidazo[5,4-c]benzazepin-7(6H)-one (7d). Yellow solid (82%);
,
mp¼143–145 ꢀC; NMR 1H (CDCl3, 250 MHz):
d 3.80 (s, 3H, OCH3),
d
4.09 (d,1H, CH2, J¼15.0 Hz), 4.30 (d,1H, CH2, J¼15.0 Hz), 4.52 (d,1H,
0
109.3 (CH), 112.1 (C), 116.1 (CH), 118.9 (CH), 120.2 (CH), 122.9 (CH),
126.2 (CH), 128.5 (CH), 131.3 (C), 133.4 (C), 134.5 (C), 143.9 (C),
149.5 (C), 157.8 (CO); HRMS: m/z [M]þ calcd for C16H14N3O2:
280.1086, found 280.1089.
CH2, J¼15.0 Hz), 5.06 (d, 1H, CH2, J¼15.0 Hz), 6.85 (d, 2H, H4 and
0
H6 , J¼8.5 Hz), 7.16 (d, 1H, HAr, J¼7.25 Hz), 7.27–7.37 (m, 4H, HAr),
7.44–7.61 (m, 4H, HAr), 7.81–7.89 (m, 2H, HAr), 8.75 (s, 1H, H12);
NMR 13C (CDCl3, 60.9 MHz):
d 49.7(CH2), 50.3(CH2), 55.4(CH3),114.0
(2ꢂCH), 119.5 (CH), 120.7 (CH), 121.6 (CH), 123.5 (C), 124.2 (C), 124.4
(CH), 125.8 (CH), 127.0 (CH), 127.5 (CH), 127.6 (C), 128.4 (CH), 128.7
(CH), 129.0 (CH), 129.4 (C), 130.1 (2ꢂCH), 136.8 (C), 137.8 (C), 139.8
(C), 145.1 (C), 159.2 (C), 163.7 (CO); HRMS: m/z [M]þ calcd for
C27H22N3O2S: 452.1433, found 452.1444.
4.6.6. 10(11)-Aryl-pyrido[20,10:2,3]imidazo[5,4-c]heterocycles (7) un-
der microwaves irradiation; general procedure. To a soln of 10-
chloro-5-(4-methoxybenzyl)-2-methyl-pyrido[20,10:2,3]imidazo[5,4-
c]quinolin-6(5H)-one (4d) and 11-chloro-6-(4-methoxybenzyl)-
pyrido[20,10:2,3] imidazo[5,4-c]benzazepin-7(6H)-one (4j) (0.1 g)
dissolved in dioxane–EtOH (2:1, 2 mL) in a vial microwave tube were
added under argon a stirrer bar, aryl boronic acid (1.2 equiv), K2CO3
(2 equiv), and Pd(PPh3)4 (0.1 equiv). The reaction vessel was sealed
with a silicon septum and subjected to microwave irradiation at
150 ꢀC for 2 hwithstirring. The mixturewas then allowed tocoolto rt,
diluted with CH2Cl2 (15 mL) and extracted (3ꢂ). The combined or-
ganic layers were dried (MgSO4)and concentratedundervacuum. The
crude material obtained was purified by column chromatography
(silica gel, EtOAc–PE) to give the desired product (7).
4.6.11. {6-(4-methoxybenzyl)-pyrido[20,10:2,3]imidazo[5,4-c]benza-
zepin-7(6H)-on-11-yl}benzaldehyde (7e). Brown solid (85%);
mp¼241–243 ꢀC; 1H NMR (CDCl3, 250 MHz):
d 3.80 (s, 3H, OCH3),
4.11 (d, 1H, CH2, J¼15.0 Hz), 4.30 (d, 1H, CH2, J¼15.0 Hz), 4.54 (d, 1H,
CH2, J¼15.0 Hz), 5.05 (d,1H, CH2, J¼15.0 Hz), 6.83–6.86 (m, 2H, HAr),
7.18 (d, 1H, HAr, J¼7.5 Hz), 7.27–7.39 (m, 3H, HAr), 7.52–7.64 (m, 2H,
HAr), 7.74–7.77 (m, 2H, HAr), 7.87–7.93 (m, 2H, HAr), 7.99–8.02 (m,
2H, HAr), 8.81 (s, 1H, H12), 10.07 (s, 1H, CHO); NMR 13C (CDCl3,
60.9 MHz):
d
49.8(CH2), 50.3(CH2), 55.4(CH3), 114.0 (2ꢂCH), 119.8
(CH), 122.3 (CH), 124.4 (CH), 126.7 (CH), 127.2 (C), 127.4 (C), 127.7
(2ꢂCH), 128.7 (CH), 128.8 (CH), 129.1 (CH), 129.2 (C), 130.0 (2ꢂCH),
130.6 (2ꢂCH), 135.9 (C), 136.9 (C), 140.1 (C), 142.9 (C), 145.2 (C),
159.2 (C), 163.5 (C), 163.6 (CO), 191.5 (CHO); HRMS: m/z [M]þ calcd
for C30H24N3O3: 474.1818, found 474.1815.
4.6.7. 10-(4-Methoxyphenyl)-5-(4-methoxybenzyl)-2-methyl-pyr-
ido[20,10:2,3]imidazo[5,4-c]quinolin-6(5H)-one (7a). Brown solid
(88%); mp¼134–136 ꢀC; 1H NMR (CDCl3, 250 MHz):
d 2.50 (s, 3H,
CH3), 3.73 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 5.67 (s, 2H, CH2), 6.79
(d, 2H, HAr, J¼9.8 Hz), 7.07–7.25 (m, 5H, HAr), 7.41 (d, 2H, HAr
J¼8.8 Hz), 7.58–7.67 (m, 3H, HAr), 7.93–7.96 (m, 2H, HAr), 8.92 (s,
1H, H12); NMR 13C (CDCl3, 62.9 MHz):
21.3(CH3), 45.8 (CH2), 55.3
,
References and notes
d
1. (a) Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.; Henderson, C. G.; Roberts,
D. A.; Ruddock, K. S.; Samuels, G. M. R.; Stefaniak, M. H. J. Med. Chem. 1988, 31,
2048; (b) Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.; Henderson, C. G.;
Morris, D. S.; Roberts, D. A.; Ruddock, K. S.; Samuels, G. M. R.; Stefaniak, M. H.
J. Med. Chem. 1989, 32, 575; (c) Fujioka, T.; Teramoto, S.; Mori, T.; Hosokawa, T.;
(OCH3), 55.6(OCH3), 114.2 (2ꢂCH), 114.3 (C), 115.0 (2ꢂCH), 117.0
(CH), 119.6 (CH), 120.3 (CH), 123.0 (CH), 125.3 (C), 128.1 (2ꢂCH),
128.5 (CH), 128.6 (2ꢂCH), 128.8 (C), 129.0 (CH), 129.5 (C), 132.1 (C),
132.3 (C), 134.4 (C), 134.8 (C), 146.9 (C), 158.8 (C), 158.9 (C), 160.1

1946
J. Koubachi et al. / Tetrahedron 66 (2010) 1937–1946
Sumida, T.; Tominaga, M.; Yabuuchi, Y. J. Med. Chem. 1992, 35, 3607; (d)
Lipworth, B. J.; Grove, A. Br. J. Clin. Pharmacol. 1997, 43, 9.
Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1036; (e) Campeau, L.-C.;
Fagnou, K. Chem. Commun. 2006, 1253 and references therein.
9. (a) El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Tetrahedron
Lett. 2003, 44, 6265; (b) El Kazzouli, S.; Berthault, A.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Lett. Org. Chem. 2005, 2, 184.
10. Guillaumet, G.; Berteina-Raboin, S.; El Kazzouli, S.; Delagrange, P.; Caignard, D.-H.
PCT, Int. Appl., WO 2,006,027,474, 2006. Chem. Abstr. 144 :254132
11. Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G.
Synlett 2006, 3237.
12. (a) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet,
G. Synthesis 2008, 2537; (b) Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Synthesis 2009, 271.
13. Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G.
J. Org. Chem. 2007, 72, 7650.
14. (a) Paolini, J. P.; Palopoli, F. P.; Lendvay, L. J. Heterocycl. Chem. 1987, 24, 549; (b)
Meng, T.; Zhang, Z.; Hu, D.; Lin, L.; Ding, J.; Wang, X.; Shen, J. J. Comb. Chem.
2007, 9, 739; (c) Che, C.; Xiang, J.; Wang, G.-X.; Fathi, R.; Quan, J.-M.; Yang, Z.
J. Comb. Chem. 2007, 9, 982.
15. (a) Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R. Tetrahedron 2006, 62,
11100; (b) De Mel, V. S. J.; Kumar, R.; Oliver, J. P. Organometallics 1990, 9, 1303.
16. Wang, X.; Gribkov, D. V.; Sames, D. J. Org. Chem. 2007, 72, 1476.
17. Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897.
18. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron 1999, 55, 6917.
19. Kercher, T.; Rao, C.; Bencsik, J. R.; Josey, J. A. J. Comb. Chem. 2007, 9, 1177.
20. (a) Bouissane, L.; El Kazzouli, S.; Le´once, S.; Pfeiffer, B.; Rakib, E. M.; Khouili, M.;
Guillaumet, G. Bioorg. Med. Chem. 2006, 14, 1078; (b) Miki, Y.; Hachiken, H.;
Kashima, Y.; Sugimura, W.; Yanase, N. Heterocycles 1998, 48, 1; (c) Joseph, B.;
Be´hard, A.; Lesur, B.; Guillaumet, G. Synlett 2003, 1542.
2. (a) Meijer, L.; Leost, M.; Lozach, O.; Schmitt, S.; Kunick, C. In Handbook of Ex-
perimental Pharmacology; Pinna, L. A., Cohen, P. T. W., Eds.; Springer: Berlin,
2005; vol. 167, pp 47–64; (b) Kunick, C.; Lauenroth, K.; Leost, M.; Meijer, L.;
Lemcke, T. Bioorg. Med. Chem. Lett. 2004, 14, 413; (c) Kunick, C.; Schultz, C.;
Lemcke, T.; Zaharevitz, D. W.; Gussio, R.; Jalluri, R. K.; Sausville, E. A.; Leost, M.;
Meijer, L. Bioorg. Med. Chem. Lett. 2000, 10, 567; (d) Schultz, C.; Link, A.;
Leost, M.; Zaharevitz, D. W.; Gussio, R.; Sausville, E. A.; Meijer, L.; Kunick, C. L.
J. Med. Chem. 1999, 42, 2909; (e) Gussio, R.; Zaharevitz, D. W.; McGraph, C. F.;
Pattabiraman, N.; Kellog, G. E.; Schultz, C.; Link, A.; Kunick, C.; Meijer, L.;
Sausville, E. A. Anti Cancer Drug Des. 2000, 15, 53; (f) Wieking, K.; Knockaert, M.;
Leost, M.; Zaharevitz, D. W.; Meijer, L.; Kunick, C. Arch. Pharm. Pharm. Med.
Chem. 2002, 7, 311; (g) Lahusen, T.; De Siervi, A.; Kunick, C.; Senderowicz, A. M.
Mol. Carcinog. 2003, 36, 183; (h) Zaharevitz, D. W. Cancer Res. 1999, 59, 2566; (i)
Kunick, C. Curr. Pharm. Des. 1999, 5, 181; (m) Bleeker, C.; Kunick, C. Pharmazie
1999, 54, 645; (n) Meijer, L. Brevet EP 1,106,180 2001. Chem. Abstr.: 135: 41041.
3. Linington, R. G.; Williams, D. E.; Tahir, A.; van Soest, R.; Andersen, R. J. Org. Lett.
2003, 5, 2735.
4. Chen, Y.-L.; Chung, C.-H.; Chen, I.-L.; Chen, P.-H.; Jeng, H.-Y. Bioorg. Med. Chem.
Lett. 2002, 10, 2705.
5. Xiao, Z.; Waters, N. C.; Woodard, C. L.; Lib, Z.; Lia, P.-K. Bioorg. Med. Chem. Lett.
2001, 11, 2875.
´
6. Jarak, I.; Kralj, M.; Sy¨uman, L.; Pavlovice, G.; Dogan, J.; Piantanida, I.; Mladen
Zyinice´, M.; Pavelice´, K.; Karminski-Zamola, G. J. Med. Chem. 2005, 48, 2346.
7. Negishi, I. In Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., de Meijere, A., Eds.; Wiley: New York, NY, 2002; Vol. I, Chapter III.
8. Some recent reviews of direct arylation of heteroarenes, see: (a) Alberico, D.;
Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174; (b) Satoh, T.; Miura, M. Chem.
Lett. 2007, 36, 200; (c) Fairlamb, I. J. S. Chem. Soc. Rev. 2007, 36, 1036; (d)
21. Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G.
J. Mar. Chim. Heterocycl. 2008, 7, 1.