Synthesis of pyrido[2′,1′:2,3]imidazo[4,5-b]quinoline and pyrido[1′,2′:1,2]imidazo[4,5-b]quinoline and their benzo and aza analogs via tandem catalysis

Article abstract of DOI:10.1016/j.tet.2007.06.011

In this paper we report regioselective tandem metal-catalyzed aminations on dihaloquinolines (2-chloro-3-iodoquinoline and 2,3-dibromoquinoline) with amino(benzo)(di)azines. Eight new heterocyclic scaffolds of the dipyridoimidazole type could be synthesized. By controlling the reaction temperature selective C-2 intermolecular Pd-catalyzed amination on 2,3-dibromoquinoline with amino(benzo)(di)azines can be achieved.

Full text of DOI:10.1016/j.tet.2007.06.011

Tetrahedron 63 (2007) 8954–8961
0
0
Synthesis of pyrido[2 ,1 :2,3]imidazo[4,5-b]quinoline
0
0
and pyrido[1 ,2 :1,2]imidazo[4,5-b]quinoline and their benzo
and aza analogs via tandem catalysis
*
Kristof T. J. Loones, Bert U. W. Maes and Roger A. Dommisse
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
Received 8 May 2007; revised 28 May 2007; accepted 2 June 2007
Available online 9 June 2007
Abstract—In this paper we report regioselective tandem metal-catalyzed aminations on dihaloquinolines (2-chloro-3-iodoquinoline and 2,3-
dibromoquinoline) with amino(benzo)(di)azines. Eight new heterocyclic scaffolds of the dipyridoimidazole type could be synthesized. By
controlling the reaction temperature selective C-2 intermolecular Pd-catalyzed amination on 2,3-dibromoquinoline with amino(benzo)(di)-
azines can be achieved.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
C–N and aryl C–N bond formation with 2-(2-(pseudo)ha-
loalkenyl)aryl halides. In 2004 our group reported the first
regioselective auto-tandem inter- and intramolecular Pd-cat-
1
4
Arylamines are important entities with several important
applications (pharmaceuticals, agrochemicals, polymers,
and materials for the electronics and xerographic indus-
try). The most important method hitherto available to syn-
thesize these arylamines is via metal-catalyzed C–N bond
formation. One of the most popular and best explored repre-
sentatives of this group is the Pd-catalyzed amination, auto-
1
5
alyzed amination protocol. 2-Chloro-3-iodopyridine was
coupled with a set of amino(benzo)(di)azines upon which
1
,2
0
0
dipyrido[1,2-a:3 ,2 -d]imidazole and its benzo and aza ana-
logs were formed. More recently, we developed an orthogo-
nal (Pd- and Cu-catalyst) and an auto-tandem (Pd-catalyst)
regioselective inter- and intramolecular amination protocol
on 2,3-dibromopyridine by which regioisomers of the dipyr-
3
nomously developed by the groups of Buchwald and
Hartwig in the mid 1990s. The Buchwald–Hartwig reaction
4
0 0
ido[1,2-a:3 ,2 -d]imidazole analogs could be obtained.
16
has made tremendous progress, especially by the refinement
of the ligands.
1
,2,5–7
Since the beginning of this decade the
We wondered if our tandem amination procedures could be
extended to the benzo-analogs of the substrates 2-chloro-3-
iodopyridine and 2,3-dibromopyridine; 2-chloro-3-iodoqui-
noline (1) and 2,3-dibromoquinoline (5) (Scheme 1). This
Cu-catalyzed amination revives due to the introduction of
Cu–ligand complexes through which the harsh conditions,
necessary for the Ullmann-type C–N bond formation, can
8
,9
be substituted for milder coupling conditions. One of the
most daring challenges in this research field is the develop-
ment of tandem metal-catalyzed amination protocols. Via
these one-pot processes complex structures can be obtained
starting from easily available building blocks. Until now,
only a few examples of tandem metal-catalyzed aminations
(
a)
H
N
I
N
PdLn
2
PdLn
(
N)
N
N
N
N
Cl
N
N
Cl
N
N
N (N)
1
3
4
1
0
have been reported in the literature. Most of them focused
on the formation of the pyrrole ring of carbazoles, con-
structed via a double N-arylation of primary amines with
(b)
Br
Br
Br
N (N)
N
PdLn
2
PdLn
or
CuX
(N)
0
11–13
N
H
2
substituted indoles can be synthesized via a tandem alkenyl
,2 -di(pseudo)halobiaryls.
Also the pyrrole ring of
5
6
7
N
N
N
H2N
N
2a
H2N
N
H2N
N
2d
H2N
N
Keywords: Tandem catalysis; Buchwald–Hartwig reaction; Dihaloquino-
lines.
2b
NH2
2e
2c
*
Corresponding author. Tel.: +32 32653205; fax: +32 32653233; e-mail:
bert.maes@ua.ac.be
Scheme 1. Orthogonal and auto-tandem inter- and intramolecular amination
on dihaloquinolines (1, 5) with amino(benzo)(di)azines (2).
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.011

K. T. J. Loones et al. / Tetrahedron 63 (2007) 8954–8961
8955
extension would show the generality of our optimized
tandem inter- and intramolecular regioselective amination
protocols in terms of substrate scope. To the best of our
knowledge pyridoimidazoquinoline derivatives, except
compound 4a were obtained. To increase the yield of 4a the
reaction temperature was elevated to 140 C. Using these
ꢀ
21
modified reaction conditions [Pd(OAc) , XANTPHOS,
2
ꢀ
There was no 3a left in the reaction mixture, but surprisingly
a substantial amount of N,N -di(pyridin-2-yl)quinolin-2,3-
Cs CO , toluene, 140 C] 82% of 4a could be isolated.
2
3
0
0
17
pyrido[2 ,1 :2,3]imidazo[4,5-b]quinoline (4a) and pyrido-
0
0
18
0
[
1 ,2 :1,2]imidazo[4,5-b]quinoline (7a) have not been
described in the literature yet. So our concise tandem
methodologies would allow to access eight hitherto un-
known heterocyclic scaffolds of the dipyridoimidazole type.
diamine was formed. This competing reaction can be com-
pletely suppressed by decreasing the amount of 2a from
the standardly used 1.2 equiv to 1.0 equiv. In this way 4a
was obtained in an excellent yield (96%). The second
auto-tandem Pd-catalyzed amination examined was the
coupling of 1 with 2-aminoquinoline (2b). Gratifyingly,
using the original reaction conditions for the coupling of
2
. Results and discussion
Starting material 1 is not commercially available and there-
fore it had to be synthesized first. The synthesis starts with
the diazotization of readily available 3-aminoquinoline (8)
followed by reaction with KI. 3-Iodoquinoline (9) is easily
transformed into its N-oxide (10) with m-chloroperoxybenz-
oic acid (Scheme 2). Subsequently, a rearrangement of 10
to 3-iodoquinolin-2(1H)-one (11) could be obtained through
the reaction of 10 with benzoyl chloride and hydroxide. The
transformation of 9 to 11 is based on a method of Erickson
for the synthesis of 2,3-dichloroquinoline starting from 3-
2-chloro-3-iodopyridine with 2b [Pd(OAc) , rac-BINAP,
2
0
imidazole (4b) was isolated. The same reaction conditions
0
Cs CO , toluene, reflux], 97% of diquino[1,2-a:3 ,2 -d]-
3
2
were then used to perform the coupling with 1-aminoisoqui-
0
0
noline (2c) yielding isoquino[1 ,2 :2,3]imidazo[4,5-b]quino-
line (4c) in 98%. Reaction of 1 with aminopyrazine (2d)
0
0
gave 81% of pyrazino[2 ,1 :2,3]imidazo[4,5-b]quinoline
(4d) and only traces of 2-chloro-N-(pyrazin-2-yl)quinolin-
3-amine (3d) intermediate were left. Auto-tandem Pd-cata-
lyzed amination of 1 with 3-aminopyridazine (2e) gave
1
9
0
0
bromoquinoline. Finally, treatment of 11 with POCl3
gave the desired compound 1 in an overall yield of 50%
93% of pyridazino[6 ,1 :2,3]imidazo[4,5-b]quinoline (4e).
In this case XANTPHOS was used as ligand as on substrate
2-chloro-3-iodopyridine as reported previously. In conclu-
2
0
15
(
Scheme 2). It is important to mention that the developed
procedure is very efficient as the transformation of 3-iodo-
quinoline (9) into 1 only requires one column chromato-
graphic separation in the last step. Starting material 5 is
commercially available.
sion, except for the reaction with 2-aminopyridine (2a), 1
can be coupled with all the amino(benzo)(di)azines (2b–
2e) using the reaction conditions earlier developed for the
auto-tandem Pd-catalyzed amination on 2-chloro-3-iodopyr-
idine (see Table 1). The desired compounds were isolated
in high yields, proving the general applicability of our auto-
tandem amination protocol.
1
5
Subsequently, the applicability of 1 as substrate was exam-
ined. Using exactly the same reaction conditions as
described for the auto-tandem Pd-catalyzed amination
of 2-chloro-3-iodopyridine with 2-aminopyridine (2a)
Subsequently, 2,3-dibromoquinoline (5) was tackled as sub-
0
0
[
binaphthyl), Cs CO , toluene, reflux] 1 was coupled with
Pd(OAc) , rac-BINAP (2,2 -bis(diphenylphosphino)-1,1 -
strate. The optimized reaction conditions [Pd (dba) ,
2
2
3
1
5
ꢀ
XANTPHOS, CuI, Cs CO , DME at 140 C ] for the or-
2 3
21
2
3
2
a. After a reaction time of 17 h the desired pyrido-
thogonal tandem amination of 2,3-dibromopyridine with 2
were tested on 5. For the coupling with 2a 80% of pyri-
0
0
16
[
2 ,1 :2,3]imidazo[4,5-b]quinoline (4a) was formed but
unfortunately only as minor compound. Mainly 1 and
-chloro-N-(pyridin-2-yl)quinolin-3-amine (3a) were ob-
0
0
do[1 ,2 :1,2]imidazo[4,5-b]quinoline (7a) was isolated, nei-
ther 5 nor 3-bromo-N-(pyridin-2-yl)quinolin-2-amine (6a)
remained in the reaction mixture. A similar yield was ob-
2
served. The presence of 1 in the reaction mixture was an in-
dication that rac-BINAP should be replaced by another
ligand for the C–N coupling process. Because we earlier
found that XANTPHOS (9,9-dimethyl-4,5-bis(diphenyl-
phosphino)-9H-xanthene) is a more general ligand for
tandem aminations, we decided to replace rac-BINAP
by XANTPHOS, keeping the other reaction conditions
unchanged. Encouragingly, 1 could not be detected
anymore in the reaction mixture. Unfortunately, 60% of
the intermediate 3a and only 15% of the desired tetracyclic
0
0
tained for the synthesis of diquino[1,2-a:2 ,3 -d]imidazole
(7b) (85%) using 2b as amidine. The orthogonal tandem
amination of 5 with 2c yielded 90% of isoquino-
0
0
[2 ,1 :1,2]imidazo[4,5-b]quinoline (7c). Coupling of 5 with
0
0
2d gave pyrazino[1 ,2 :1,2]imidazo[4,5-b]quinoline (7d) in
rather low yield (14%). No remaining or
a
5
1
5,16
3-bromo-N-(pyrazin-2-yl)quinolin-2-amine (6d) could be
observed in the reaction mixture. This low yield is not
entirely surprising knowing that the coupling of
1
) HBF , i-amyl nitrite
I
NH2
4
acetone, -8 °C
2) KI, -8 °C -> 10 °C
N
86%
N
9
8
I
I
I
m-CPBA
benzoyl chloride
POCl3
CH2Cl2
RT
NaOH
toluene
reflux
N
O
N
H
O
N
1 59%
Cl
H2O / CH2Cl2
10
11
Scheme 2. Synthesis of 2-chloro-3-iodoquinoline (1).

8956
K. T. J. Loones et al. / Tetrahedron 63 (2007) 8954–8961
0
0
0
0
Table 1. Synthesis of pyrido[2 ,1 :2,3]imidazo[4,5-b]quinoline and its
benzo and aza analogs via auto-tandem amination on 1 with amino(benzo)-
Table 2. Synthesis of pyrido[1 ,2 :1,2]imidazo[4,5-b]quinoline and its
benzo and aza analogs via orthogonal tandem (Pd-catalyst and Cu-catalyst)
amination on 5 with amino(benzo)(di)azines
a
a
(di)azines
Pd(OAc)2
Pd (dba)
2
3
I
rac. BINAP or XANTPHOS
N
XANTPHOS
CuI
2
+
2
Br
Br
N
N
Cs2CO3
toluene
reflux
+
N (N)
N
Cl
N
Cs2CO3
DME
140 °C
N (N)
N
1
4
5
7
2
2
Ligand
3
4
(%)
4
(
%)
2
Ligand
6 (%)
7 (%)
7
N
N
N
N
N
N
b,c
96
a
XANTPHOS
0
2a
XANTPHOS
XANTPHOS
0
80
N
N
N
N
N
N
2
b
0
0
85
90
2
2
2
b
c
rac-BINAP
rac-BINAP
0
0
97
98
N
N
N
N
2c
XANTPHOS
N
N
N
N
N
N
N
N
d
e
rac-BINAP
Traces
0
81
93
2d
XANTPHOS
XANTPHOS
0
0
14
70
N
N
N
N
N
N
N
N
2
XANTPHOS
2
e
N
N
a
Pd(OAc)
1.5 mmol), 2 (1.8 mmol), Cs
7 h.
One equivalent of compound 2 was used instead of 1.2 equiv.
2
(4 mol %), rac-BINAP (4 mol %) or XANTPHOS (4 mol %), 1
a
(
1
2
CO (6.0 mmol), toluene (15 mL), reflux,
3
2 3
Pd (dba) (2 mol %), XANTPHOS (4.4 mol %), CuI, 1 (1.5 mmol), 2
2 3
(1.8 mmol), Cs CO (6.0 mmol), DME (15 mL), reaction temperature:
b
c
ꢀ
21
140 C (80 mL pressure tube), 24 h.
ꢀ
21
Reaction temperature: 140 C (80 mL pressure tube).
intermediate 3-bromo-N-(quinolin-2-yl)quinolin-2-amine
(6b) and 66% of 7b. We also detected a significant
amount of N-(quinolin-2-yl)quinolin-2-amine, presumably
formed by Pd-catalyzed hydrodebromination of 6b. The
auto-tandem Pd-catalyzed amination of 5 with 2c yielded
3-bromo-N-(isoquinolin-1-yl)quinolin-2-amine (6c) in
13% and 7c in 72%. Compound 7d could not be synthe-
sized via this auto-tandem Pd-catalyzed amination proto-
col. The coupling of 5 with 2e gave 35% of 7e. Neither
5 nor 6e could be recovered, but 17% of hydrodebromi-
nated 6e could be isolated. All the results are summarized
in Table 3. Looking at the results presented in Tables 2
and 3, one can easily conclude that the orthogonal tandem
protocol on 5 is a generally more suitable methodology to
2,3-dibromopyridine with 2d yielded only 44% of the corre-
sponding ring closed product pyrido[2 ,3 :4,5]imidazo[1,2-
0
a]pyrazine. We found that the reason for the low yield is
0
ꢀ
ence of CuI. Finally, the orthogonal tandem amination of
the instability of the intermediate 6d at 140 C in the pres-
2
2
0 0
5
with 2e gave 70% of pyridazino[1 ,6 :1,2]imidazo[4,5-
b]quinoline (7e). Neither 5 nor 3-bromo-N-(pyridazin-3-yl)-
quinolin-2-amine (6e) could be detected. In view of these
results we can conclude that also the earlier developed
orthogonal tandem amination protocol on 2,3-dibromopyri-
dine shows generality and can be extended to 2,3-dibromo-
quinoline, preserving the good yields (see Table 2).
0
0
During the optimization of the tandem inter- and intramo-
lecular amination of 2,3-dibromopyridine with amino-
prepare the desired pyrido[1 ,2 :1,2]imidazo[4,5:b]quino-
line and its benzo and aza analogs.
(
benzo)(di)azines we noticed that, for some amidines, the
orthogonal tandem Pd- and Cu-catalyzed amination proto-
col could be simplified to an auto-tandem Pd-catalyzed
protocol. Therefore we decided to investigate whether
such an auto-tandem Pd-catalyzed amination would also
be feasible when 5 was used as substrate instead of 2,3-di-
bromopyridine. When the auto-tandem amination condi-
tions developed for the coupling of 2,3-dibromopyridine
with 2 [Pd (dba) , XANTPHOS, Cs CO , DME at
When the auto-tandem Pd-catalyzed inter- and intramole-
cular amination protocol (2 mol % Pd (dba) , 4.4 mol %
2
3
ꢀ
the previous paragraph, was used at a lower temperature
(85 C) the corresponding N-(3-bromoquinolin-2-yl)azahe-
XANTPHOS, Cs CO , DME, 140 C, 24 h), described in
2
3
ꢀ
teroarylamines were obtained as the sole reaction products.
For 2b, 2c, 2d, and 2e a loading of 4 mol % Pd-catalyst
was sufficient, while for 2a a double loading was required
to get complete conversion of 5 in 7 h. The desired com-
pounds 6 were in all cases obtained in a good yield. The
results are presented in Table 3.
2
3
2
3
ꢀ
16
1
40 C] were used to couple 5 with 2a, 66% of 6a
and 15% of the desired 7a was isolated. No remaining 5
was detected. The coupling with 2b gave no 5, 10% of

K. T. J. Loones et al. / Tetrahedron 63 (2007) 8954–8961
8957
Table 3. Attempted auto-tandem Pd-catalyzed inter- and intramolecular amination and Pd-catalyzed intermolecular amination on 5 with amino(benzo)(di)-
azines
a
Pd2(dba)3
Pd2(dba)3
Br
Br
Br
(N)
N
N
N
XANTPHOS
XANTPHOS
(N)
+
2
Cs CO
Cs2CO3
DME
140 °C
2
3
N
N
H
N
N
DME
6
reflux
5
7
ꢀ
2
Pd loading (mol %)
Reaction time (h)
Reaction temperature ( C)
5 (%)
6 (%)
7 (%)
b
2
2
2
2
2
2
2
2
2
2
2
a
a
a
b
b
c
4
8
4
4
4
4
4
4
4
4
4
24
7
24
7
24
7
24
7
Reflux
Reflux
9
Traces
0
Traces
0
Traces
0
Traces
82
85
66
87
10
86
13
79
78
84
0
0
0
15
0
66
0
72
0
b
c
140
Reflux
b
c
140
Reflux
b
c
c
140
Reflux
b
d
d
e
c
24
7
24
140
Reflux
140
0
0
0
0
0
35
b
c
e
a
b
c
2 3 2 3
Pd (dba) (x mol %), XANTPHOS (2.2x mol %), 1 (1.5 mmol), 2 (1.8 mmol), Cs CO (6.0 mmol), DME (15 mL).
The experiments were carried out in a 100 mL flask.
The experiments were carried out in an 80 mL pressure tube.
21
3. Conclusion
purchased from Aldrich, Pd(OAc) , Pd (dba) , and DME
2 2 3
from Acros and rac-BINAP was obtained from Rhodia. 3-
Aminopyridazine was prepared from 3-amino-6-chloropyrid-
azine via hydrogenolysis. All other reagents are obtained
from commercial sources and used without extra purifi-
cation. Flash column chromatography was performed on
Kieselgel 60 (ROCC SI 1721, 40–60 mm).
In this paper we showed that the earlier developed tan-
dem metal-catalyzed aminations on dihalopyridines with
amino(benzo)(di)azines can be smoothly extended to di-
haloquinolines, namely 2-chloro-3-iodoquinoline (1) and
2
3
2
,3-dibromoquinoline (5). Selective C-2 intermolecular Pd-
catalyzed amination on 5 can be achieved for all amidines
2) if the reaction temperature is controlled. Eight hitherto
unknown heteroaromatic skeletons were synthesized.
(
4.1.1. Synthesis of 3-iodoquinoline (9). In a flask of 100 mL
3
-aminoquinoline (4.85 mmol, 0.7 g) was dissolved in ace-
ꢀ
a cold HBF solution (1.2 mL HBF in 1.0 mL acetone)
tone (7.5 mL) and cooled to ꢁ8 C. To this stirred solution
4
. Experimental
.1. General information
All melting points were determined on a B €u chi apparatus
4
4
was slowly added. Next a cold isoamyl nitrite solution
(1.0 mL isoamyl nitrite in 1.0 mL acetone) was added in
small portions to the reaction mixture. The reaction mixture
4
was stirred for 1 h allowing the reaction mixture to reach
ꢀ
1
13
and are uncorrected. The H NMR and C NMR spectra
were obtained on a Bruker Avance II 400 spectrometer
with TMS as the internal standard. All coupling constants
are given in hertz and the chemical shifts are given in parts
per million. Multiplicity is indicated using the following ab-
breviations: br for broad, d for doublet, t for triplet, m for
multiplet and s for singlet. For mass spectrometric analysis,
10 C. Subsequently KI (12 mmol, 2.0 g) dissolved in H O
2
(2.5 mL) was added to the reaction mixture in small portions
and stirred for another 2 h. Next the solvent was evaporated.
Water (40 mL) and 3 N NaOH (3 mL) was added to the res-
idue. Then the basic solution was extracted with CH Cl
2
2
(8ꢂ40 mL). The organic fractions were combined and
washed with saturated Na S O solution (80 mL) and subse-
2
2 4
samples were dissolved in CH OH containing 0.1% formic
3
quently dried over MgSO and evaporated to dryness. The
4
acid and diluted to a concentration of approximately
residue was purified by column chromatography using
CH Cl as eluant.
ꢁ
5
1
0
mol/L. Injections (1 mL) were directed to the mass
spectrometer at a flow rate of 5 mL/min (CH OH and 0.1%
2
2
3
ꢀ
1
formic acid), using a CapLC HPLC system (Waters-Micro-
mass). Accurate mass data were acquired on a Qq-TOF 2
mass spectrometer (Waters-Micromass) equipped with
a standard electrospray ionization (ESI) interface. Cone volt-
age (approx. 35 V) and capillary voltage (approx. 3.3 kV)
were optimized on one compound and used for all others.
For the determination of the accurate mass of the molecular
Yield 1.064 g (86%); white solid; mp: 58 C; H NMR
(400 MHz, CDCl ): d 9.03 (1H, d, J¼1.9 Hz, H ), 8.51
3
2
(1H, d, J¼1.9 Hz, H ), 8.06 (1H, d, J¼8.5 Hz, H ), 7.72
4
8
(1H, dd, J¼8.5, 6.9 Hz, H ), 7.69 (1H, d, J¼8.2 Hz, H ),
7
5
1
3
7.54 (1H, dd, J¼8.2, 6.9 Hz, H ); C NMR (100 MHz,
6
CDCl ): d 155.5, 146.3, 143.6, 129.9, 129.8, 129.4, 127.3,
3
+
126.7, 89.8; HRMS (ESI) for C H IN [M+H] calcd
9
7
+
ion [M+H] , a solution of polyethylene glycol 300 in
CH OH/H O with 1 mmol ammonium acetate was added
255.9623, found 255.9627.
3
2
just before the mass spectrometer (at a rate of 1 mL/min)
to the mobile phase. The calculated masses of PEG
4.1.2. Synthesis of 2-chloro-3-iodoquinoline (1). In
a 100 mL flask m-chloroperoxybenzoic acid (4.8 mmol,
1.4 g) was added in portions to a stirred solution of 3-iodo-
quinoline (4.3 mmol, 1.1 g) in dichloromethane (10 mL) at
room temperature. The mixture was stirred overnight
+
+
[
M+H] and [M+NH ] ions were used as internal calibrant
4
(lock mass). XANTPHOS (9,9-dimethyl-4,5-bis(diphenyl-
phosphanyl)-9H-xanthene) and Cs CO (99%) were
2
3

8958
K. T. J. Loones et al. / Tetrahedron 63 (2007) 8954–8961
(
17 h). Subsequently, saturated NaHCO solution (10 mL)
3
2-chloro-3-iodoquinoline (1) (1.5 mmol, 0.359 g), amidine
(2) (1.8 mmol), and Cs CO (6.0 mmol, 1.955 g). To this
was added. After CO2 evolvement ceases, 3 N NaOH
2 mL) was added. Next the mixture is extracted with di-
2
3
(
mixture, the preformed Pd-catalyst was added under an N2
flow. The 50 mL flask was subsequently rinsed with
2ꢂ5 mL toluene. Then the resulting mixture was flushed
with N for 5 min and heated for 17 h at reflux (N atmo-
chloromethane (3ꢂ30 mL). The combined organic fractions
were washed with water (100 mL) and brine (100 mL) and
dried over MgSO . The solvent was removed under reduced
pressure.
4
2
2
sphere). After cooling down to room temperature, toluene
was removed by evaporation. Silica gel (1.5 g) was mixed
with the crude product. This solid mixture was brought on
top of a silica gel column and eluted with dichloro-
methane/methanol (99:1).
Benzoyl chloride (8.5 mmol, 1 mL) was added over 10 min
to a vigorously stirred mixture of the crude 3-iodoquinoline
N-oxide (10) and sodium hydroxide (11.0 mmol, 0.44 g) in
water (12 mL) and dichloromethane (6 mL). When the addi-
tion was nearly complete, a vigorous reflux was observed.
The flask was cooled in an ice-bath, and addition was re-
sumed. After 1 h stirring the precipitate was filtered off,
rinsed well with water (50 mL) and dichloromethane
0
0
4.2.1. Pyrido[2 ,1 :2,3]imidazo[4,5-b]quinoline (4a). The
general procedure was followed using Pd(OAc)2
(0.06 mmol, 0.013 g, 4 mol %), XANTPHOS (0.06 mmol,
0.035 g, 4 mol %), and 2-aminopyridine (2a) (1.5 mmol,
ꢀ
(
50 mL) and dried in vacuo.
0.141 g). The oil bath temperature was 160 C. Yield 0.316 g
ꢀ
1
(
96%); yellow solid; mp: 189 C; H NMR (400 MHz,
A mixture of the crude 3-iodoquinolin-2(1H)-one (11) and
POCl (3 mmol, 0.28 mL) in toluene (1.2 mL) was stirred
for 10 min under a N atmosphere. Subsequently the stirred
2
CDCl ): d 8.95 (1H, d, J¼6.8 Hz, H ), 8.65 (1H, s, H ),
3
11
6
8.25 (1H, d, J¼8.6 Hz, H ), 8.10 (1H, d, J¼8.3 Hz, H ),
3
2
5
7.77ꢁ7.72 (2H, m, H , H ), 7.63 (1H, dd, J¼9.2, 6.6 Hz,
3 8
suspension was heated at reflux for 2 h. Next the reaction
mixture was poured onto ice and aq NH OH (70 mL) was
added. The water phase was extracted with diethyl ether
H ), 7.59 (1H, dd, J¼8.3, 6.9 Hz, H ), 6.95 (1H, dd, J¼6.8,
10 3
9
4
1
3
6.6 Hz, H ); C NMR (100 MHz, CDCl ): d 151.3, 144.3
4
143.9, 135.0, 134.0, 128.4 (2Cs), 128.3, 128.2, 125.8,
125.2, 124.5, 117.8, 110.6; HRMS (ESI) for C H N
4 10 3
(3ꢂ50 mL) and the combined organic layers were washed
with water (150 mL) and brine (150 mL). The organic phase
1
+
[M+H] calcd 220.0875, found 220.0871.
was dried over MgSO . The solvent was evaporated and the
4
0
0
crude product was purified by flash column chromatography
on silica gel using dichloromethane/heptane (7:3) as the
eluant.
4.2.2. Diquino[1,2-a:3 ,2 -d]imidazole (4b). The general
procedure was followed using Pd(OAc)2 (0.06 mmol,
0.013 g, 4 mol %), rac-BINAP (0.06 mmol, 0.037 g,
4
Yield 0.391 g (97%); yellow solid; mp: 188 C; H NMR
mol %), and 2-aminoquinoline (2b) (1.8 mmol, 0.259 g).
ꢀ
1
1
To confirm that we prepared 10 and 11, H NMR spectra of
the crude reaction products were recorded.
(400 MHz, CDCl ): d 10.23 (1H, d, J¼8.1 Hz, H ), 8.65
3
13
(
1H, s, H ), 8.37 (1H, d, J¼8.6 Hz, H ), 8.10 (1H, d,
6
2
1
4
.1.3. 3-Iodoquinoline N-oxide (10). H NMR (400 MHz,
J¼8.3 Hz, H ), 7.87 (1H, ddd, J¼8.1, 7.1, 1.4 Hz, H ),
10 9 8
5
1
2
CDCl ): d 8.75 (1H, s, H ), 8.66 (1H, d, J¼9.0 Hz, H ),
7.82 (2H, br d, J¼9.2 Hz, not resolved, H , H or H ),
3
2
8
8
.09 (1H, s, H ), 7.77ꢁ7.73 (2H, m, H , H ), 7.64 (1H, dd,
7.78 (1H, dd, J¼8.6, 6.8 Hz, H ), 7.60 (1H, dd, J¼8.3,
4
5
7
3
J¼7.9, 7.1 Hz, H ).
6.8 Hz, H ), 7.56 (1H, br d, J¼9.6 Hz, H or H ), 7.52
6
4
8
9
13
(
1H, br t, J¼7.5 Hz, not resolved, H ); C NMR
1
1
1
4.1.4. 3-Iodoquinolin-2(1H)-one (11). H NMR (400 MHz,
CDCl ): d 12.06 (1H, s, NH), 8.50 (1H, s, H ), 7.62 (3H, m,
(100 MHz, CDCl ): d 151.7, 147.7, 144.6, 136.3, 135.6,
3
134.8, 130.7, 128.9, 128.6, 128.3, 128.0, 126.9, 124.8,
124.7 (2Cs), 122.6, 117.8, 117.4; HRMS (ESI) for
C H N [M+H] calcd 270.1031, found 270.1037.
3
4
H , H , H ), 7.26ꢁ7.22 (1H, m, H ).
5
6
8
7
+
1
8 12 3
4
white solid; mp: 111 C; H NMR (400 MHz, CDCl ):
.1.5. 2-Chloro-3-iodoquinoline (1). Yield 0.734 g (59%);
ꢀ
1
0
0
4.2.3. Isoquino[1 ,2 :2,3]imidazo[4,5-b]quinoline (4c).
The general procedure was followed using Pd(OAc)2
(0.06 mmol, 0.013 g, 4 mol %), rac-BINAP (0.06 mmol,
0.037 g, 4 mol %), and 1-aminoisoquinoline (2c)
(1.8 mmol, 0.259 g). Yield 0.395 g (98%); brown solid;
3
d 8.67 (1H, s, H ), 7.99 (1H, br d, J¼8.5 Hz, H ), 7.75
4
8
(
1H, br dd, J¼8.5, 6.9 Hz, H ), 7.72 (1H, br d, J¼7.6 Hz,
7
1
3
H ), 7.58 (1H, br dd, J¼7.6, 6.9 Hz, H ); C NMR
5 6
(
100 MHz, CDCl ): d 152.3, 148.6, 146.8, 131.0, 128.5,
3
ꢀ
1
1
28.1, 127.7, 126.4, 90.9; HRMS (ESI) for C H Cl I N
1 1
mp: 277 C; H NMR (400 MHz, CDCl ): d 8.85 (1H, d,
3
9
6
1
+
[
M+H] calcd 289.9233, found 289.9228.
J¼7.9 Hz, H or H ), 8.67 (1H, s, H ), 8.64 (1H, d, J¼
1
4
13
7
.3 Hz, H ), 8.26 (1H, d, J¼8.5 Hz, H ), 8.11 (1H, br d,
6
9
4
.2. General procedure for the preparation of
J¼8.2 Hz, H ), 7.80ꢁ7.70 (4H, m, H or H , H , H ,
12 4 1 2 3
0
0
pyrido[2 ,1 :2,3]imidazo[4,5-b]quinoline and its benzo
and aza analogs (4) via an auto-tandem inter- and
intramolecular Pd-catalyzed amination
H ), 7.58 (1H, ddd, J¼8.2, 6.8, 1.1 Hz, H ), 7.11 (1H, d,
5 3
10 11
1
3
J¼7.3 Hz, H ); C NMR (100 MHz, CDCl ): d 151.4,
145.4, 144.5, 135.8, 133.5, 131.6, 128.6, 128.4, 128.2,
28.1, 127.7, 127.4, 125.5, 124.8, 124.7, 123.3, 121.1,
1
+
A round bottom flask of 50 mL was charged with Pd(OAc)2
0.06 mmol, 0.013 g, 4 mol %), rac-BINAP (0.06 mmol,
111.3; HRMS (ESI) for C H N [M+H] calcd
18 12 3
270.1031, found 270.1038.
(
0
4
.037 g, 4 mol %) or XANTPHOS (0.06 mmol, 0.035 g,
mol %) and toluene (5 mL). The obtained mixture was
0
0
4.2.4. Pyrazino[2 ,1 :2,3]imidazo[4,5-b]quinoline (4d).
The general procedure was followed using Pd(OAc)2
(0.06 mmol, 0.013 g, 4 mol %), rac-BINAP (0.06 mmol,
flushed with N for 10 min under magnetic stirring. Mean-
2
while a round-bottomed flask of 100 mL was charged with

K. T. J. Loones et al. / Tetrahedron 63 (2007) 8954–8961
8959
0
0
0
0
.037 g, 4 mol %), and aminopyrazine (2d) (1.8 mmol,
ꢀ
4.3.2. Diquino[1,2-a;2 ,3 -d]imidazole (7b). The general
procedure was followed using 2-aminoquinoline (2b)
(1.8 mmol, 0.259 g). Yield 0.343 g (85%); brown solid;
.171 g). Yield 0.267 g (81%); yellow solid; mp: 246 C;
1
H NMR (400 MHz, CDCl ): d 9.33 (1H, d, J¼1.6 Hz,
3
ꢀ
1
H ), 8.84 (1H, s, H ), 8.77 (1H, dd, J¼4.6, 1.6 Hz, H ),
mp: 237 C, H NMR (400 MHz, CDCl ): d 8.95 (1H, s,
3
1
11
3
8
.28 (1H, br d, J¼8.6 Hz, H ), 8.14 (1H, dd, J¼8.4,
H ), 8.51 (1H, d, J¼8.3 Hz, H ), 8.30 (1H, d, J¼8.5 Hz,
7
6
8
1
.2 Hz, H ), 8.04 (1H, d, J¼4.6 Hz, H ), 7.82 (1H, ddd,
H ), 8.05 (1H, d, J¼8.2 Hz, H ), 7.83 (2H, m, H , H ),
1
0
4
2
5
9
11
J¼8.6, 6.7, 1.2 Hz, H ), 7.63 (1H, br dd, J¼8.4, 6.7 Hz,
7.82 (1H, d, J¼9.5 Hz, H ), 7.73 (1H, dd, J¼8.5, 6.7 Hz,
8
12
1
3
H ); C NMR (100 MHz, CDCl ): d 146.6, 145.4, 144.7,
9
H ), 7.68 (1H, d, J¼9.5 Hz, H ), 7.54 (1H, dd, J¼8.2,
3
3
13
1
3
1
1
2
42.8, 135.5, 129.3, 128.7, 128.6, 128.5, 127.7, 126.9,
25.6, 117.6; HRMS (ESI) for C H N [M+H] calcd
21.0827, found 221.0832.
6.7 Hz, H ), 7.51 (1H, dd, J¼7.8, 7.5 Hz, H ); C NMR
4
10
+
(100 MHz, CDCl ): 157.2, 153.8, 146.8, 135.8, 134.6,
3
1
3
9
4
130.8, 130.1, 129.1, 128.7, 128.0, 124.7, 124.6 (2Cs),
123.8, 123.0, 119.7, 117.7, 114.8; HRMS (ESI) for
C H N [M+H] calcd 270.1031, found 270.1038.
18 12 3
0
0
+
4
.2.5. Pyridazino[6 ,1 :2,3]imidazo[4,5-b]quinoline (4e).
The general procedure was followed using Pd(OAc)2
0.06 mmol, 0.013 g, 4 mol %), XANTPHOS (0.06 mmol,
0
0
(
4.3.3. Isoquino[2 ,1 :1,2]imidazo[4,5-b]quinoline (7c).
The general procedure was followed using 1-aminoisoqui-
noline (2c) (1.8 mmol, 0.259 g). Yield 0.363 g (90%); brown
0
0
.035 g, 4 mol %), and 3-aminopyridazine (2e) (1.8 mmol,
ꢀ
1
.171 g). Yield 0.307 g (93%); brown solid; mp: 199 C; H
ꢀ
1
NMR (400 MHz, CDCl ): d 8.76 (1H, s, H ), 8.52 (1H, dd,
3
solid; mp: 304 C (decomp.); H NMR (400 MHz, CDCl ):
3
11
J¼4.0, 1.4 Hz, H ), 8.42 (1H, d, J¼8.6 Hz, H ), 8.12 (1H,
d 8.97 (1H, d, J¼6.9 Hz, H or H ), 8.51 (1H, s, H ), 8.34
3
7
1
4
8
d, J¼8.3 Hz, H ), 8.06 (1H, dd, J¼9.6, 1.4 Hz, H ), 7.80
(1H, d, J¼8.6 Hz, H ), 8.22 (1H, d, J¼7.3 Hz, H ), 8.03
1
0
1
12
6
(
1H, dd, J¼8.6, 6.8 Hz, H ), 7.61 (1H, dd, J¼8.3, 6.8 Hz,
(1H, d, J¼8.3 Hz, H ), 7.78ꢁ7.72 (4H, m, H or H , H ,
8
9 4 1 2
1
3
H ), 7.40 (1H, dd, J¼9.6, 4.0 Hz, H ); C NMR (100 MHz,
H , H ), 7.54 (1H, br dd, J¼8.3, 6.7 Hz, H ), 7.12 (1H,
5 3
9
2
3 11 10
1
3
CDCl ): d 146.7, 145.5, 144.2, 141.7, 134.6, 129.1, 128.9,
3
d, J¼7.3 Hz, H ); C NMR (100 MHz, CDCl ): d 157.1,
128.4, 128.2, 127.0, 126.6, 125.3, 124.6; HRMS (ESI) for
C H N [M+H] calcd 221.0827, found 221.0832.
153.4, 147.6, 132.7, 131.8, 129.5, 128.7, 128.4, 127.7,
127.1, 126.8, 124.5, 124.4, 123.3, 123.0, 121.6, 115.4,
+
1
3 9 4
+
111.5; HRMS (ESI) for C H N [M+H] calcd
270.01031, found 270.1029.
1
8 12 3
4
.3. General procedure for the synthesis of pyrido-
0 0
[
1 ,2 :1,2]imidazo[4,5-b]quinoline and its benzo and
0
The general procedure was followed using aminopyrazine
0
aza analogs via an orthogonal tandem intermolecular
Pd- and intramolecular Cu-catalyzed amination
4.3.4. Pyrazino[1 ,2 :1,2]imidazo[4,5-b]quinoline (7d).
(
mp: 338 C (decomp.); H NMR (400 MHz, CDCl ): d 9.46
2d) (1.8 mmol, 0.171 g). Yield 0.046 g (14%); yellow solid;
ꢀ
1
A round-bottomed flask of 50 mL was charged with
Pd (dba) (0.030 mmol, 0.028 g, 2.0 mol %), XANTPHOS
3
(1H, d, J¼1.5 Hz, H ), 8.81 (1H, s, H ), 8.46 (1H, dd,
2
3
4
11
(
obtained mixture was flushed with N for 10 min under mag-
0.066 mmol, 0.038 g, 4.4 mol %), and DME (5 mL). The
J¼4.6, 1.5 Hz, H ), 8.39 (1H, d, J¼8.8 Hz, H ), 8.11 (1H,
2
7
d, J¼8.2 Hz, H ), 8.10 (1H, d, J¼4.6 Hz, H ), 7.85 (1H,
2
10 1
netic stirring. Meanwhile a pressure tube of 80 mL was
charged with CuI (0.15 mmol, 0.028 g, 10 mol %), 2,3-di-
bromoquinoline (5) (1.5 mmol, 0.355 g), amidine (2)
(1.8 mmol), and cesium carbonate (6.0 mmol, 1.955 g). To
this mixture, the preformed Pd-catalyst was added under
br dd, J¼8.8, 6.7 Hz, H ), 7.62 (1H, br dd, J¼8.2, 6.7,
9 3
8
1
3
H ); C NMR (100 MHz, CDCl ): d 155.9, 149.6, 146.4,
146.1, 129.8, 129.7, 128.0, 127.4, 125.4, 124.6, 120.9,
+
118.8, 118.2; HRMS (ESI) for C H N [M+H] calcd
1
3 9 4
221.0827, found 221.0832.
an N flow. The 50 mL flask was subsequently rinsed with
2
0
0
2
with N for 5 min, sealed, and heated (oil bath temperature:
ꢂ5 mL DME. Then the resulting mixture was flushed
4.3.5. Pyridazino[1 ,6 :1,2]imidazo[4,5-b]quinoline (7e).
The general procedure was followed using 3-aminopyrid-
azine (2e) (1.8 mmol, 0.171 g). Yield 0.231 g (70%); brown
2
ꢀ
1
60 C) under vigorous magnetic stirring for 24 h. After
ꢀ
1
cooling down to room temperature, DME was removed
by evaporation. Silica gel (1.5 g) was mixed with the
crude product. This solid mixture was brought on top of a sil-
ica gel column and eluted with dichloromethane/methanol
solid; mp: 217 C (decomp.); H NMR (400 MHz, CDCl ):
3
d 8.94 (1H, s, H ), 8.45 (1H, dd, J¼4.1, 1.3 Hz, H ), 8.36
1
1
2
(1H, d, J¼8.7 Hz, H ), 8.16 (1H, dd, J¼9.5, 1.3 Hz, H ),
7
4
8.11 (1H, br d, J¼8.2 Hz, H ), 7.81 (1H, dd, J¼8.7,
1
0
(97:3).
6.7 Hz, H ), 7.58 (1H, dd, J¼8.2, 6.7 Hz, H ), 7.43 (1H,
8
9
1
3 3
3
dd, J¼9.5, 4.1 Hz, H ); C NMR (100 MHz, CDCl ):
0
0
4
.3.1. Pyrido[1 ,2 :1,2]imidazo[4,5-b]quinoline (7a). The
general procedure was followed using 2-aminopyridine
2a) (1.8 mmol, 0.169 g). Yield 0.263 g (80%); yellow solid;
d 154.9, 148.9, 148.3, 141.1, 129.5, 129.2, 128.3, 126.5,
124.9, 124.8, 124.4, 123.3, 118.4; HRMS (ESI) for
+
(
C H N [M+H] calcd 221.0827, found 221.0817.
13 9 4
ꢀ
1
mp: 294 C (decomp.), H NMR (400 MHz, CDCl ): d 8.62
3
(
1H, s, H ), 8.56 (1H, d, J¼6.8 Hz, H ), 8.33 (1H, d,
4.4. General procedure for the synthesis of pyrido-
6
8
0
0
J¼8.7 Hz, H ), 8.03 (1H, d, J¼8.2 Hz, H ), 7.79 (1H, d,
[1 ,2 :1,2]imidazo[4,5-b]quinoline and its benzo and
aza analogs via an auto-tandem inter- and intramole-
cular Pd-catalyzed amination
2
5
J¼9.3 Hz, H ), 7.77 (1H, dd, J¼8.7, 6.8 Hz, H ), 7.60
1
1
3
(
1H, dd, J¼9.3, 6.8 Hz, H ), 7.53 (1H, dd, J¼8.2, 6.8 Hz,
1
0
1
3
H ), 6.92 (1H, t, J¼6.8 Hz, H ); C NMR (100 MHz,
4 9
CDCl ): d 157.2, 153.7, 148.5, 133.1, 129.4, 128.9, 127.9,
3
A round-bottomed flask of 50 mL was charged with
Pd (dba) (0.030 mmol, 0.028 g, 2.0 mol %), XANTPHOS
(9,9-dimethyl-4,5-bis(diphenylphosphanyl)-9H-xanthene)
1
(
26.7, 124.3, 123.7, 122.2, 118.4, 116.5, 110.6; HRMS
ESI) for C H N [M+H] calcd 220.0875, found
2
3
+
1
4 10 3
2
20.0864.
(0.066 mmol, 0.038 g, 4.4 mol %), and DME (5 mL). The

8960
K. T. J. Loones et al. / Tetrahedron 63 (2007) 8954–8961
obtained mixture was flushed with N for 10 min under
2
magnetic stirring. Meanwhile a pressure tube of 80 mL
was charged with 2,3-dibromoquinoline (5) (1.5 mmol,
J¼8.3 Hz, H
0
), 8.32 (1H, dd, J¼4.9, 1.9 Hz, H
0
), 8.26
6
3
(1H, s, H ), 8.19 (1H, s, NH), 7.87 (1H, d, J¼8.5 Hz, H ),
4
8
7.78 (1H, ddd, J¼8.3, 7.3, 1.9 Hz, H
0
), 7.65 (1H, dd,
4
0
.355 g), amidine (2) (1.8 mmol), and cesium carbonate
6.0 mmol, 1.955 g). To this mixture, the preformed Pd-
J¼8.5, 6.9 Hz, H ), 7.62 (1H, d, J¼7.9 Hz, H ), 7.36 (1H,
0
6 5
7
5
(
catalyst was added under an N flow. The 50 mL flask was
dd, J¼7.9, 6.9 Hz, H ), 6.99 (1H, dd, J¼7.3, 4.9 Hz, H
);
1
3
C NMR (100 MHz, CDCl ): 152.8, 148.2, 147.8, 145.7,
3
2
subsequently rinsed with 2ꢂ5 mL DME. Then the resulting
139.6, 138.0, 130.1, 127.0, 126.5, 125.2, 124.4, 118.1,
112.9, 108.2; HRMS (ESI) for C H N Br [M+H] calcd
300.0136, found 300.0144.
+
mixture was flushed with N for 5 min, sealed, and heated
2
14 11 3
ꢀ
(
oil bath temperature: 160 C) under vigorous magnetic
stirring for 24 h. After cooling down to room temperature,
DME was removed by evaporation. Silica gel (1.5 g) was
mixed with the crude product. This solid mixture was
brought on top of a silica gel column and eluted with
dichloromethane/methanol (97:3).
4.5.2. 3-Bromo-N-(quinolin-2-yl)quinolin-2-amine (6b).
The general procedure was followed using 2-aminoquino-
line (2b) (1.8 mmol, 0.259 g). Yield: 0.458 g (87%); yellow
ꢀ
1
solid; mp: 146 C; H NMR (400 MHz, CDCl ): 9.06 (1H, d,
3
J¼8.7 Hz, H
0
), 8.43 (1H, s, NH), 8.32 (1H, s, H ), 8.24 (1H,
0
4
4
0
general procedure was followed using 2-aminopyridine
0
4
.4.1. Pyrido[1 ,2 :1,2]imidazo[4,5-b]quinoline (7a). The
d, J¼8.7 Hz, H
), 7.93ꢁ7.88 (2H, m, H , H
0
), 7.81 (1H, d,
8
3
8
J¼7.9 Hz, H
0
), 7.71ꢁ7.60 (3H, m, H , H , H ), 7.45ꢁ7.39
0
5
7
7
5
1
3
(
2a) (1.8 mmol, 0.169 g). Yield 0.051 g (15%).
(2H, m, H , H ); C NMR (100 MHz, CDCl ): 152.4,
0
6 6
3
1
127.2, 126.6 (2Cs), 125.8, 125.4, 124.6, 124.3, 114.1,
48.4, 147.2, 145.7, 139.9, 137.9, 130.2, 129.8, 127.5,
0
0
procedure was followed using 2-aminoquinoline (2b)
4
.4.2. Diquino[1,2:a;2 ,3 :d]imidazole (7b). The general
+
108.3; HRMS (ESI) for C H N Br [M+H] calcd
1
8 13 3
(
1.8 mmol, 0.259 g). Yield 0.266 g (66%).
350.0293, found 350.0280.
0
0
4.4.3. Isoquino[2 ,1 :1,2]imidazo[4,5-b]quinoline (7c).
The general procedure was followed using 1-aminoisoqui-
noline (2c) (1.8 mmol, 0.259 g). Yield 0.291 g (72%).
4.5.3. 3-Bromo-N-(isoquinolin-1-yl)quinolin-2-amine
(6c). The general procedure was followed using 1-aminoiso-
quinoline (2c) (1.8 mmol, 0.259 g). Yield 0.453 g (86%); or-
ꢀ
1
ange solid; mp: 139 C; H NMR (400 MHz, CDCl ): 15.93
3
0
The general procedure was followed using aminopyrazine
0
4
.4.4. Pyrazino[1 ,2 :1,2]imidazo[4,5-b]quinoline (7d).
(1H, s, NH), 9.01 (1H, m, H ), 8.32 (1H, s, H ), 7.76 (1H, d,
4
8
J¼8.7 Hz, H
0
or H8
0
), 7.67 (1H, dd, J¼7.2, 6.8 Hz, H ),
0 0 0 0
5 5 8 6 7
5
7
(
2d) (1.8 mmol, 0.171 g). Yield 0.0 g (0%).
7.61ꢁ7.57 (4H, m, H , H
or H , H , H ), 7.45 (1H, m,
H
0
or H
0
), 7.33 (1H, dd, J¼7.8, 7.2 Hz, H ), 6.82 (1H, br
3
4
6
0
The general procedure was followed using 3-aminopyrid-
0
13
4 3 3
4
.4.5. Pyridazino[1 ,6 :1,2]imidazo[4,5-b]quinoline (7e).
d, J¼6.7 Hz, H
of H ); C NMR (100 MHz, CDCl ):
0 0
156.9, 154.3, 144.0, 139.2, 137.3, 137.0, 136.4, 131.7,
129.4, 127.7, 127.5, 127.3, 126.5, 125.9, 125.0, 124.1,
azine (2e) (1.8 mmol, 0.171 g). Yield 0.116 g (35%).
+
119.2, 110.1; HRMS (ESI) for C H N Br [M+H] calcd
1
350.0293, found 350.0299.
8 13 3
4
(
.5. General procedure for the synthesis of 3-bromo-N-
azaheteroaryl)quinolin-2-amines
4.5.4. 3-Bromo-N-(pyrazin-2-yl)quinolin-2-amine (6d).
The general procedure was followed using aminopyrazine
A round-bottomed flask of 50 mL was charged with
Pd (dba) (0.030 mmol, 0.028 g, 2.0 mol %), XANTPHOS
(2d) (1.8 mmol, 0.171 g). Yield: 0.357 g (79%); yellow
2
3
ꢀ
solid; mp: 134 C; H NMR (400 MHz, CDCl ): 10.24
3
1
(
(
9,9-dimethyl-4,5-bis(diphenylphosphanyl)-9H-xanthene)
0.066 mmol, 0.038 g, 4.4 mol %), and DME (5 mL). The
(1H, d, J¼1.3 Hz, H
), 8.30 (3H, m, H , H , H6 ),
0 0 0
3 4 5
obtained mixture was flushed with N for 10 min under mag-
2
netic stirring. Meanwhile a round-bottomed flask of 100 mL
was charged with 2,3-dibromoquinoline (5) (1.5 mmol,
8.11 (1H, br s, NH), 7.91 (1H, d, J¼8.4 Hz, H ), 7.68
8
(1H, dd, J¼8.4, 7.1 Hz, H ), 7.65 (1H, d, J¼7.9 Hz,
7
1
3
H ), 7.40 (1H, dd, J¼7.9, 7.1 Hz, H );
C NMR
(100 MHz, CDCl ): 149.5, 147.4, 145.6, 142.0, 140.0,
5
6
0
.355 g), amidine (2) (1.8 mmol), and cesium carbonate
6.0 mmol, 1.955 g). To this mixture, the preformed Pd-cat-
3
(
alyst was added under an N flow. The 50 mL flask was sub-
138.5, 136.3, 130.5, 127.3, 126.5, 125.5, 124.9, 107.5;
HRMS (ESI) for C H N Br [M+H] calcd 301.0089,
found 301.0089.
+
2
13 10 4
sequently rinsed with 2ꢂ5 mL DME. Then the resulting
mixture was flushed with N for 5 min and heated at reflux
2
ꢀ
(
oil bath temperature: 95 C) (N atmosphere) under vigor-
2
4.5.5. 3-Bromo-N-(pyridazin-3-yl)quinolin-2-amine (6e).
The general procedure was followed using aminopyrid-
azine (2e) (1.8 mmol, 0.171 g). Yield: 0.379 g (84%); yel-
ous magnetic stirring for 7 h. After cooling down to room
temperature, DME was removed by evaporation. Silica gel
ꢀ
low solid; mp: 158 C; H NMR (400 MHz, CDCl ): 9.10
3
1
(
1.5 g) was mixed with the crude product. This solid mixture
was brought on top of a silica gel column and eluted with di-
chloromethane/methanol (99:1).
(1H, br d, J¼9.1 Hz, H
0
), 8.88 (1H, br d, J¼4.6 Hz, H
0
),
8.65 (1H, br s, NH), 8.29 (1H, s, H ), 7.84 (1H, d,
4
6
4
J¼8.4 Hz, H ), 7.65 (1H, br dd, J¼8.4, 6.9 Hz, H ),
8
7
4.5.1. 3-Bromo-N-(pyridin-2-yl)quinolin-2-amine (6a).
The general procedure was followed using Pd (dba)
7.63 (1H, d, J¼8.2 Hz, H ), 7.51 (1H, dd, J¼9.1,
0
5 6
5
1
3
4.6 Hz, H
), 7.39 (1H, br dd, J¼8.2, 6.9 Hz, H );
C
2
3
(
(
(
0.060 mmol,
0.056 g,
4.0 mol %),
XANTPHOS
0.132 mmol, 0.076 g, 8.8 mol %), and 2-aminopyridine
NMR (100 MHz, CDCl ): 156.5, 148.0, 147.1, 145.4,
3
140.1, 120.4, 127.7, 127.0, 126.6, 125.5, 124.9, 117.5,
108.0; HRMS (ESI) for C H N Br [M+H] calcd
301.0089, found 301.0089.
+
2a) (1.8 mmol, 0.169 g). Yield 0.384 g (85%); yellow solid;
ꢀ
1
3 10 4
1
mp: 119 C; H NMR (400 MHz, CDCl ): 8.89 (1H, d,
3

K. T. J. Loones et al. / Tetrahedron 63 (2007) 8954–8961
8961
Acknowledgements
12. (a) Kitawaki, T.; Hayashi, Y.; Chida, N. Heterocycles 2005, 65,
561; (b) Kitawaki, T.; Hayashi, Y.; Ueno, A.; Chida, N.
Tetrahedron 2006, 62, 6792.
13. Koeckelberghs, G.; De Cremer, L.; Vanormelingen, W.;
Dehaen, W.; Verbiest, T.; Persoons, A.; Samyn, C.
Tetrahedron 2005, 61, 687.
1
The authors acknowledge financial support from the Univer-
sity of Antwerp (NOI BOF UA 2005) and the Flemish
Government enabling the purchase of NMR equipment
(
Impulsfinanciering van de Vlaamse Overheid voor Strate-
gisch Basisonderzoek PFEU 2003). We would like to thank
Dr. G. Mignani of Rhodia for the donation of rac-BINAP as
well as P. Franck for technical assistance.
14. (a) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int.
Ed. 2005, 44, 403; (b) Willis, M. C.; Brace, G. N.; Findlay,
T. J. K.; Holmes, I. P. Adv. Synth. Catal. 2006, 348, 851.
1
5. Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A.; Lemi ꢀe re,
G. L. F. Chem. Commun. 2004, 2466.
References and notes
16. Loones, K. T. J.; Maes, B. U. W.; Meyers, C.; Deruytter, J.
J. Org. Chem. 2006, 71, 260.
1
2
. Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131.
. Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346,
17. Abramovitch, R. A.; Hey, D. H. J. Chem. Soc. C 1966, 12, 1095.
18. Desbois, N.; Chezal, J. M.; Fauvelle, F.; Debouzy, J. C.;
Lartigue, C.; Gueiffier, A.; Blache, Y.; Moreau, E.;
Madelmont, J. C.; Chavignon, O.; Teulade, J. C.
Heterocycles 2005, 65, 1121.
1
599.
3
. Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1348.
. Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609.
4
5
6
7
19. Sabol, M. R.; Owen, J. M.; Erickson, W. R. Synth. Commun.
2000, 30, 427.
. Hartwig, J. F. Synlett 2006, 1283.
. Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
. Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv.
Synth. Catal. 2006, 348, 23.
20. (a) For other methods published to prepare 1 see: Marsais, F.;
Godard, A.; Qu ꢁe guiner, G. J. Heterocycl. Chem. 1989, 26,
1589; (b) Hong, C. S.; Seo, J. Y.; Yum, E. K.; Sung, N.
Heterocycles 2004, 63, 631; (c) Arrington, K.; Fraley, M.;
Hartman, G. Patent no: WO2003037252, 2003.
8
9
. Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev. 2004,
2
48, 2337.
. Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
400.
21. Temperature measured inside the vessel (fiber optic probe). Oil
ꢀ
5
bath temperature: 160 C. For more information see: Ref. 16.
22. A test reaction was carried out in which intermediate 6d was
1
1
0. For taxonomy of tandem catalysis see: Fogg, D. E.; dos Santos,
E. N. Coord. Chem. Rev. 2004, 248, 2365.
ꢀ
heated for 24 h at 140 C in the presence of CuI and cesium car-
1. (a) Nozaki, K.; Takahashi, K.; Nakano, K.; Hiyama, T.; Tang,
H. Z.; Fujiki, M.; Yamaguchi, S.; Tamao, K. Angew. Chem.,
Int. Ed. 2003, 42, 2051; (b) Nakano, K.; Hidehira, Y.;
Takahashi, K.; Hiyama, T.; Nozaki, K. Angew. Chem., Int.
Ed. 2005, 44, 7136; (c) Kuwahara, A.; Nakano, K.; Nozaki, K.
J. Org. Chem. 2005, 70, 413.
bonate. After analysis of the reaction mixture only traces of 6d
and 7d could be detected. The reaction mixture had a black
color so we assume that 6d decomposed at this high tempera-
ture.
23. Turck, A.; Pl ꢁe , N.; Ndzi, B.; Qu ꢁe guiner, G.; Haider, N.;
Schuller, H.; Heinisch, G. Tetrahedron Lett. 1993, 34, 161.