Pd-catalyzed intramolecular direct arylations at high temperature

Article abstract of DOI:10.1016/j.tet.2008.01.060

Pd-catalyzed cyclodehydrohalogenation involving oxidative addition of aromatic C-Br or activated azaheteroaromatic C-Cl bonds and C(sp²)-H activation have been investigated at high reaction temperatures (180-200 °C). This allowed the fast (10-3

Full text of DOI:10.1016/j.tet.2008.01.060

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 6030e6037
www.elsevier.com/locate/tet
Pd-catalyzed intramolecular direct arylations at high temperature
a
Philippe Franck , Steven Hostyn , Beata Dajka-Halasz , Agnes Polonka-Balint ,
a
b
b
ꢀ
´
Katrien Monsieurs , Peter Matyus , Bert U.W. Maes
´
´
a
b
a,
*
´
a Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium
b Department of Organic Chemistry, Semmelweis University, HTgyes E. u. 7., H-1092 Budapest, Hungary
Received 3 September 2007; received in revised form 29 November 2007; accepted 30 November 2007
Available online 17 January 2008
Abstract
Pd-catalyzed cyclodehydrohalogenation involving oxidative addition of aromatic CeBr or activated azaheteroaromatic CeCl bonds and
C(sp2)eH activation have been investigated at high reaction temperatures (180e200 ꢀC). This allowed the fast (10e30 min) synthesis of a
variety of azaheteroaromatic ring systems (dibenzo[f,h]phthalazine, dibenzo[f,h]cinnoline, benzofuro[2,3-d]pyridazine, 5H-pyridazino[4,5-b]-
indole, 7H-indolo[2,3-c]quinoline and 5H-d-carboline) in moderate to good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Palladium; C(sp2)eH activation; Microwave; Pyridazinone; Quinolinone; 5H-d-Carboline
1. Introduction
the experiment with a 23 mol % catalyst loading an almost
complete conversion occurred within one hour. This observa-
tion inspired us to study Pd-catalyzed intramolecular direct ar-
ylations at even higher temperatures. Microwave irradiation in
a single-mode microwave unit (Discover, CEM) was selected
to easily reach and monitor the high temperatures. In the
meantime also the team of Bedford reported on the beneficial
effect of high temperature in Pd-catalyzed intramolecular ary-
lation reactions.2 The reactions in the microwave were exe-
cuted on the same scale as the oil bath experiments, only the
concentration was increased by a factor of ten since the stan-
dard disposable microwave vials have only a volume of
10 mL. At 180 ꢀC, using a loading of 23 mol %, a complete
conversion of starting material could be achieved within
only 10 min irradiation (ramp time included). When we deter-
mined the minimum amount of catalyst required to achieve
full conversion of N-(2-bromophenyl)quinolin-3-amine in
a 10 min reaction at 180 ꢀC we found that 0.2 mol % is still
sufficient. This is a reduction in reaction time by a factor
288 and a 115-fold decrease of the catalyst loading for the syn-
thesis of 7H-indolo[2,3-c]quinoline. It seems that higher reac-
tion temperatures increase conversion rate to a much larger
extend than the catalyst decomposition rate. Working up the
reaction mixture revealed that also the isolated yield was
Recently, we reported on the construction of D-ring
substituted 7H-indolo[2,3-c]quinolines via regioselective
Pd-catalyzed intramolecular direct arylation of N-(2-bromophe-
nyl)quinolin-3-amines.1 The cyclizations were achieved using
a Pd-catalyst and involve C(sp2)eH bond activation of a quino-
linyl group. In our test system N-(2-bromophenyl)quinolin-3-
amine, we observed that a very high loading of catalyst
(23 mol %) and a long reaction time (48 h) were required to
achieve a good conversion (and yield) at 130 ꢀC [standard re-
action conditions: 23 mol % PdCl2(PPh3)2 and NaOAc$3H2O
in DMA at 130 ꢀC (oil bath temperature)]. A detailed study
of the cyclization of N-(2-bromophenyl)quinolin-3-amine
with an HPLCeUV system revealed that most of the conver-
sion of starting material occurs in the first hour and subse-
quently a very slow further transformation to reaction
product follows. Also when a lower catalyst loading was
used a similar behaviour could be observed. Interestingly,
when the reaction temperature was increased to 160 ꢀC for
* Corresponding author. Tel.: þ32 3 265 32 05; fax: þ32 3 265 32 33.
E-mail address: bert.maes@ua.ac.be (B.U.W. Maes).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.01.060

P. Franck et al. / Tetrahedron 64 (2008) 6030e6037
6031
Table 1
better than achieved under our standard (lower temperature)
reaction conditions. This is most probably a combination of
two factors: (a) in an oil bath at 130 ꢀC using 23 mol % of cata-
lyst the reaction can never be brought to complete conversion
(even after 48 h of heating) and (b) the very high loading of
catalyst generates a large amount of triphenylphosphine and
triphenylphosphine oxide, which makes the work-up more dif-
ficult with reaction product loss as an obvious consequence.
An exact comparison of oil bath and microwave heating re-
vealed that no microwave effects have to be taken into account
to explain the observed rate enhancements. The microwave-as-
sisted ring closure of N-(2-bromophenyl)quinolin-3-amine is
only governed by thermal effects (Arrhenius) and no micro-
wave is therefore required to perform the reaction. Neverthe-
less, from a practical point of view, the microwave unit is
still more convenient than classical heating since it is easier
to reach, maintain and monitor the required high temperatures.
The developed high temperature protocol proved to be general
for the synthesis of substituted (Me, Cl, CF3) 7H-indolo[2,3-c]-
quinolines from the corresponding N-(2-bromophenyl)qui-
nolin-3-amines. For these reactions the minimum amount of
catalyst required was not determined and we always used
a 1 mol % catalyst loading. In order to see whether the devel-
oped reaction conditions at high temperature can also be used
to prepare other ring systems we decided to restudy some
Pd-catalyzed ring closure reactions involving C(sp2)eH acti-
vation we previously performed, in the frame of a collaboration
with Hungarian scientists centered around the synthesis of
pyridazino-fused ring systems,3 under standard oil bath condi-
tions using a high catalyst loading. In addition, two new sub-
strate types were tested. In this way the general applicability
of the high temperature protocol could be tested.
O
O
Bn
Bn
N
N
N
N
PdCl2(PPh3)2
NaOAc.3H2O
DMA
Br
Ar atm.
1
2
Standard protocol (D)
High temperature
protocol (mW)
Catalyst load (mol %)
Temperature (ꢀC)
Time (hh:mm)
Yield (%)
20
130
64:00
56
1
180
00:10
69
Pd-catalyzed intramolecular direct arylation of 5-(2-bromo-
phenyl)-2-methyl-6-phenylpyridazin-3(2H)-one (3) using 20
mol % catalyst at 130 ꢀC (oil bath temperature) for 8 h gave
46% 2-methyldibenzo[f,h]cinnolin-3(2H)-one (4) (Table 2).5
When the high temperature protocol was applied complete
conversion of 3 was achieved in 10 min. The isolated yield al-
most doubled, which is a direct consequence of the more easy
purification due to the reduced catalyst loading (Table 2).
2.2. Five-membered ring formation
2.2.1. Synthesis of pyridazino-fused benzo[b]furane and
indole
In 2004 we reported the first examples on catalytic C(4)eH
activation of pyridazin-3(2H)-ones.6 Pyridazin-3(2H)-ones
‘tethered’ via C-5 to a 2-bromophenyl ring via an oxygen
and nitrogen atom could be cyclized via a Pd-catalyzed direct
arylation. In this way benzofuro[2,3-d]pyridazine and 5H-pyri-
dazino[4,5-b]indole ring systems were constructed.
2. Results and discussion
Cyclization of 5-(2-bromophenoxy)-2-methylpyridazin-
3(2H)-one (5a) using 20 mol % PdCl2(PPh3)2 at 130 ꢀC (oil
bath temperature) for 6 h yielded 99% 2-methylbenzo[b]-
furo[2,3-d]pyridazin-1(2H)-one (6a) (Table 3).6 Under high
temperature conditions with 1 mol % catalyst a slightly re-
duced yield of 85% was obtained but only a 10 min reaction
time was required (Table 3). For the phenyl substituted
2.1. Six-membered ring formation
2.1.1. Synthesis of pyridazino-fused phenanthrenes
The synthesis of polycyclic aromatic carbons via metal-cata-
lyzed direct arylation reactions is well documented in the lit-
erature.4 In 2003 we explored if a similar approach could be
used to prepare polycyclic aromatic carbons containing a pyr-
idazine unit such as pyridazino-fused phenanthrenes.5 For this
purpose molecules with a phenyl and 2-bromophenyl group
‘linked’ via a pyridazine unit were synthesized.
Table 2
O
O
Pd-catalyzed intramolecular arylation of 2-benzyl-5-(2-bro-
mophenyl)-4-phenylpyridazin-3(2H)-one (1) using 20 mol %
PdCl2(PPh3)2 and NaOAc$3H2O in DMA at 130 ꢀC (oil bath
temperature) was very slow since after 16 h only 30% of
2-benzyldibenzo[f,h]phthalazin-1(2H)-one (2) as well as 39%
of starting material could be isolated.5 A complete conversion
of substrate could even not be achieved after 64 h since we still
recovered 10% 1 (Table 1). When we subjected 1 to our micro-
wave protocol [1 mol % PdCl2(PPh3)2, NaOAc$3H2O, DMA,
180 ꢀC (mW), 10 min] a full conversion of starting material
was observed within 10 min. The isolated yield was slightly
higher than under classical reaction conditions (Table 1).
Me
Me
N
N
Br
N
N
PdCl2(PPh3)2
NaOAc.3H2O
DMA
Ar atm.
3
4
Standard protocol (D)
High temperature
protocol (mW)
Catalyst load (mol %)
Temperature (ꢀC)
Time (hh:mm)
Yield (%)
20
130
08:00
46
1
180
00:10
90

6032
P. Franck et al. / Tetrahedron 64 (2008) 6030e6037
protocol.7 Therefore substituted 5-[(2-bromophenyl)amino]-
Table 3
pyridazin-3(2H)-ones were required, which we prepared via
chemoselective Pd-catalyzed amination of 2-benzyl-5-iodopyri-
dazin-3(2H)-one (9) with 2-bromoanilines (10a,b). 2-Benzyl-
instead of 2-methyl-5-iodopyridazin-3(2H)-one was selected
as substrate as this would allow a further derivatization of the
cyclic hydrazide after ring system construction via debenzyl-
ation with AlCl3. For 5-[(2-bromo-4-methylphenyl)amino]-
pyridazin-3(2H)-one (11b) a good yield was obtained using
Pd(OAc)2/rac. BINAP in combination with 3 equiv K2CO3 in
toluene (Table 5). However, BuchwaldeHartwig reaction of
2-benzyl-5-iodopyridazin-3(2H)-one with 2-bromo-4-trifluoro-
methoxyaniline did not yield a full conversion in the same reac-
tion time. Switching to Cs2CO3, which is a stronger base in
toluene, did afford 100% conversion and an isolated yield of
66% of 5-{[2-bromo-4-(trifluoromethoxy)phenyl]amino}pyri-
dazin-3(2H)-one (11a) (Table 5).
While ring closure of 5-[(2-bromophenyl)amino]-2-methyl-
pyridazin-3(2H)-one (7) at 180 ꢀC required 30 min reaction
time, cyclizations of 2-benzyl-5-{[2-bromo-4-(trifluorome-
thoxy)phenyl]amino}pyridazin-3(2H)-one (11a) and 2-benz-
yl-5-[(2-bromo-4-methylphenyl)amino]pyridazin-3(2H)-one
(11b) could be achieved in 10 min (Table 6). The isolated
yields were good in both cases.
O
R
O
R
Br
Me
Me
N
N
N
N
PdCl2(PPh3)2
NaOAc.3H2O
DMA
O
O
Ar atm.
6a R = H
6b R = Ph
5a R = H
5b R = Ph
Standard protocol (D)
High temperature
protocol (mW)
R¼H
Catalyst load (mol %)
Temperature (ꢀC)
Time (hh:mm)
Yield (%)
20
130
06:00
99
1
180
00:10
85
R¼Ph
Catalyst load (mol %)
Temperature (ꢀC)
Time (hh:mm)
Yield (%)
20
130
11:00
49
1
180
00:30
94
derivative, oil bath conditions with 20 mol % catalyst gave
complete conversion in 11 h (Table 3).6 Interestingly, ring
closure of 5-(2-bromophenoxy)-2-methyl-6-phenylpyridazin-
3(2H)-one (5b) under microwave irradiation with a 1 mol %
catalyst loading could not be achieved in 10 min. A longer re-
action time (30 min) at 180 ꢀC was required for this substrate
in order to convert all starting material. The obtained yield is
substantially higher for the experiment performed under high
reaction temperature conditions (Table 3). Also in this case
this can be attributed to the work-up.
The aza-b-carboline derivative 2-methyl-2,5-dihydro-1H-
pyridazino[4,5-b]indole-1-one (8) has been previously syn-
thesized by us in 73% yield via Pd-catalyzed intramolecular
direct arylation of 5-[(2-bromophenyl)amino]-2-methylpyri-
dazin-3(2H)-one (7) using 20 mol % catalyst (Table 4).6
When our microwave protocol was applied, 85% of 8 could
be obtained, albeit also in this case a 30 min reaction time
was required (Table 4).
2.2.2. Synthesis of indolo-fused quinoline
In the last five years Maes and co-workers have been in-
volved in the validation of cryptolepines as potential new anti-
plasmodial drugs.1,8 In the frame of this project, substituted
derivatives of isoneocryptolepine (5-methyl-5H-indolo[2,3-c]-
quinoline), the benzo-b-carboline isomer of the isomeric natu-
ral products cryptolepine, neocryptolepine and isocryptolepine,
were required. 5-Methyl-5,7-dihydro-6H-indolo[2,3-c]quinolin-
6-one (16) (formally a 5-methyl-5H-indolo[2,3-c]quinolin-6-ol)
could be synthesized via our high temperature protocol. Com-
plete conversion of 3-[(2-bromophenyl)amino]-1-methylqui-
nolin-2(1H)-one (15) was smoothly achieved with 1 mol %
of PdCl2(PPh3)2 when 200 ꢀC and a reaction time of 15 min
were selected (Scheme 1). The observed CeH activation is
rather interesting as it, to the best of our knowledge, represents
the first example in which a C(4)eH of a quinolin-2(1H)-one
unit is involved. One example dealing with a related C(4)eH
activation in a pyridin-2(1H)-one has been reported by Padwa.9
Due to the interest in the 5H-pyridazino[4,5-b]indole skel-
eton from a pharmaceutical point of view we decided to pre-
pare some substituted derivatives using our high temperature
Table 4
Table 5
O
O
Me
Br
Me
N
N
N
N
R
Br
PdCl2(PPh3)2
NaOAc.3H2O
DMA
N
H
N
O
O
H2N
H
Br
Bn
Bn
R
7
8
10a-b
N
N
N
N
Ar atm.
Pd(OAc)2 / BINAP
Base
I
N
H
11a-b
Standard protocol (D)
High temperature
protocol (mW)
Toluene
reflux
9
Catalyst load (mol %)
Temperature (ꢀC)
Time (hh:mm)
Yield (%)
20
130
03:00
73
1
180
00:30
85
Compound
R
Base
Yield (%)
11a
11b
OCF3
Me
Cs2CO3
K2CO3
66
61

P. Franck et al. / Tetrahedron 64 (2008) 6030e6037
6033
Table 6
of a C(2)eCl bond in the pyridine ring certainly poses a chal-
lenge due to the well known decreased reactivity of CeCl in
comparison with CeBr bonds in oxidative addition reactions.
2-Chloro-N-(4-methylphenyl)pyridin-3-amine (17a) was se-
lected as test system. When our high temperature protocol
was applied we observed transformation into 8-methyl-5H-
pyrido[3,2-b]indole (18a). A catalyst loading of 1 mol % and
10 min reaction time at 180 ꢀC were clearly not sufficient to
achieve full conversion. Based on the commercial availability
of 2-chloro-3-iodopyridine and a wide variety of anilines, we
reasoned that an optimized protocol could be very useful for
rapid 5H-d-carboline library design. Therefore we searched
for the minimum loading of catalyst required to get 100% con-
version in 10 min, rather than performing attempts to increase
the reaction time to achieve this goal. A systematic increase
revealed that 8 mol % is required (Table 7). With these opti-
mized reaction conditions, an isolated yield of 80% of 18a
was obtained. Unsubstituted 5H-d-carboline (18b) could be
made in 69% using this procedure. In comparison with the
procedure of Sakamoto the obtained yield is almost 20%
higher (Table 7) using a catalyst loading, which is still
1.75 mol % lower. Interestingly, the required reaction time to
synthesize 18b could be reduced by a factor 402 in compari-
son with the literature protocol. Next, we tried to introduce
other substituents with different electronic properties on the
phenyl ring involved in the aromatic CeH activation. Electron
donating (OMe) as well as electron withdrawing groups
(COOEt) in the 4-position of the phenylamino ring were
well tolerated yielding the corresponding 5H-d-carbolines
(18c and 18d) in moderate to high yields (Table 7).
R
O
O
Bn
Br
R
Bn
N
N
N
N
N
H
1 mol% PdCl2(PPh3)2
NaOAc.3H2O
DMA
N
H
11a-b
12a-b
µW, 180 °C
Ar atm.
Compound
R
Time (hh:mm)
Yield (%)
12a
12b
OCF3
Me
00:10
00:10
67
77
C(6)eH metal-catalyzed activation of pyridin-2(1H)-ones have
been well studied.10
The substrate for the Pd-catalyzed intramolecular direct
arylation was synthesized via site-selective Pd-catalyzed ami-
nation involving a chemoselective oxidative addition (Scheme
1).11 Clearly, the CeBr bond of 3-bromo-1-methylquinolin-
2(1H)-one (14) is more reactive than the CeBr bond of 2-
bromoaniline due to the amino substituent of the latter, which
sterically and electronically deactivates this bond for oxidative
addition. 3-Bromo-1-methylquinolin-1(2H)-one (14) was eas-
ily obtained via methylation of 3-bromoquinolin-1(2H)-one
(13) (Scheme 1). The synthesis of 3-bromoquinolin-1(2H)-
one (13) has been previously reported by Erickson and
co-workers.12
2.2.3. Synthesis of 5H-d-carbolines (5H-pyrido[3,2-b]-
indoles)
3. Conclusion
In 1999 Sakamoto and co-workers reported the synthesis
of 5H-d-carboline via Pd-catalyzed intramolecular arylation
of 2-bromo-N-phenylpyridin-3-amine.13 Although 5H-pyrido-
[3,2-b]indole could be isolated in a moderate yield (51%),
the published protocol is rather harsh since it required a reac-
tion time of 67 h at 153 ꢀC using a catalyst loading of almost
10 mol %. It is unclear if substituted derivatives can be pre-
pared since no examples were shown in the paper. In 2002
Maes and co-workers reported on the chemoselective Pd-cata-
lyzed amination of 2-chloro-3-iodopyridine with anilines.14
N-Aryl-2-chloropyridin-3-amines could be selectively ob-
tained in high yields. We wondered whether these pyridines
could be used as substrates in a Pd-catalyzed cyclization
involving catalytic aromatic CeH activation. The presence
Pd-catalyzed cyclizations involving oxidative addition of
an aromatic CeBr bond and C(sp2)eH activation have been
executed using PdCl2(PPh3)2 as precatalyst with NaOAc$
3H2O as base in DMA at 180 ꢀC (mW). PdCl2(PPh3)2 is a
relatively cheap commercially available precursor for the in
situ generation of Pd(0) species and could be used in a low
loading only (1 mol %). Another attractive feature of the pre-
sented protocol is that the majority of the reactions can be per-
formed in a reaction time of only 10 min. Only in a few cases
the standard high temperature procedure was not sufficient.
Via the selection of an even higher reaction temperature
(200 ꢀC) and/or longer reaction time (max. 30 min) full con-
version could easily be achieved in these cases. Another
Br
Br
NH
O
Br
O
N
O
Br
O
H2N
Pd(OAc)2
H
MeI
KOH
MeOH
RT
1 mol% PdCl2(PPh3)2
NaOAc.3H2O
DMA
N
Me
N
Me
N
Me
N
H
XANTPHOS
Cs2CO3
dioxane
reflux
13
14
15
16
µW, 200 °C
15 min
96%
85%
93%
N2 atm.
Ar atm.
Scheme 1.

6034
P. Franck et al. / Tetrahedron 64 (2008) 6030e6037
Table 7
(0.200 g, 1.47 mmol). Subsequently, the vial was flushed with
argon for 1 min. Then, 1 mL of a stock solution of the catalyst
in DMA (1 mol %) was added via a syringe and the resulting
mixture was stirred and flushed with argon for an additional
2 min. Next, the vial was sealed with an Al crimp cap with
a septum and heated at 180 ꢀC in a CEM Discover microwave
apparatus. The set power was 100 W and the total heating time
was 10 min (ramp time included). The reaction vial was
cooled down to room temperature using a propelled air flow.
It was evaporated to dryness under reduced pressure.
H
N
H
N
8 mol% PdCl2(PPh3)2
NaOAc.3H2O
DMA
N
Cl
R
N
17a-d
18a-d
R
µW, 180 °C
Ar atm.
Compound
R
Time (hh:mm)
Yield (%)
18a
18b
18c
18d
Me
H
00:10
00:10
00:10
00:10
80
69
63
92
OMe
COOEt
4.2.1. 2-Benzyldibenzo[f,h]phtalazin-1(2H)-one (2)
2-Benzyl-5-(2-bromophenyl)-4-phenylpyridazin-3(2H)-one
(1)5 (0.250 g, 0.60 mmol) was used as starting compound. The
crude product was taken up in a mixture of water (30 mL) and
dichloromethane (30 mL), the two layers were separated and
the water phase was extracted with dichloromethane
(30 mL). The combined organic layer was dried over
MgSO4, then evaporated yielding yellow crystals. It was puri-
fied with flash column chromatography on silica gel using tol-
uene as the eluent yielding the title compound in 69%. The
characterization data are identical as those reported in the
literature.5
very attractive feature of the procedure is that Pd-catalyzed cy-
clizations involving oxidative addition of an activated azahe-
teroaromatic CeCl bond and C(sp2)eH activation could also
be performed under similar reaction conditions albeit a higher
loading of precatalyst was required to achieve full conversion
in 10 min reaction time. The high temperature protocol pre-
sented seems to be generally applicable when aromatic CeBr
or activated azaheteroaromatic CeCl bonds are involved in
the cyclizations and will be useful for the construction of other
heteroaromatic ring systems. The short reaction times re-
quired, the high conversions and good yields make the proce-
dure especially interesting for fast library design in medicinal
and agrochemical research programmes.
4.2.2. 2-Methyldibenzo[f,h]cinnolin-3(2H)-one (4)
5-(2-Bromophenyl)-2-methyl-6-phenylpyridazin-3(2H)-one
(3)5 (0.204 g, 0.60 mmol) was used as starting compound. The
crude product was taken up in a mixture of water (30 mL) and
dichloromethane (30 mL), the two layers were separated and
the water phase was extracted with dichloromethane
(2ꢁ30 mL). The combined organic layer was dried over
MgSO4 and then evaporated. The residue was purified with
flash column chromatography on silica gel using dichlorome-
thane/ethyl acetate (7:3) as the eluent yielding the title com-
pound in 90%. The characterization data are identical as
those reported in the literature.5
4. Experimental
4.1. General
All melting points were determined on a Buchi apparatus
¨
1
and are uncorrected. The H and 13C NMR spectra were re-
corded on a Bruker spectrometer Avance 400 in the solvent in-
1
dicated with TMS as the internal standard. The H and 13C
NMR spectra of compound 11a, 11b, 12a, 12b were recorded
on a Varian Mercury Plus spectrometer at 400 MHz (13C NMR
at 100 MHz) in the solvent indicated with TMS as the internal
standard. All coupling constants are given in hertz and chemi-
cal shifts are given in parts per million. Flash column chroma-
tography was performed on Kieselgel 60 (ROCC or Merck,
0.040e0.063 mm), for compounds 11a and 11b a Flash Mas-
ter II Argonaut type apparatus was used (Kieselgel 60, Merck,
0.040e0.063 mm). The elemental analyses have been carried
out with an Elementar Vario EL III apparatus.
4.2.3. 2-Methylbenzo[b]furo[2,3-d]pyridazin-1(2H)-one(6a)
5-(2-Bromophenoxy)-2-methylpyridazin-3(2H)-one (5a)6
(0.169 g, 0.60 mmol) was used as starting compound. The
crude product was taken up in a mixture of water (30 mL)
and dichloromethane (30 mL), the two layers were separated
and the water phase was extracted with dichloromethane
(2ꢁ30 mL). The combined organic layer was dried over
MgSO4 and evaporated. The crude product was purified with
flash column chromatography on silica gel using a 8:2 mixture
of toluene/ethyl acetate as the eluent, yielding the title com-
pound in 85%. The characterization data are identical as those
reported in the literature.6
4.2. General procedure for the high temperature
Pd-catalyzed intramolecular direct arylations
4.2.4. 2-Methyl-4-phenylbenzo[b]furo[2,3-d]pyridazin-
1(2H)-one (6b)
Preparation of the stock solution of catalyst: PdCl2(PPh3)2
(0.211 g, 0.03 mmol) was dissolved in 5 mL of DMA. Next,
the mixture was flushed with Ar for 5 min and subsequently
stirred until the catalyst was completely dissolved.
Procedure: A microwave vial of 10 mL was charged with
pyridazin-3(2H)-one derivative (0.6 mmol) and NaOAc$3H2O
5-(2-Bromophenoxy)-2-methyl-6-phenylpyridazin-3(2H)-
one (5b)6 (0.214 g, 0.60 mmol) was used as starting com-
pound. In this case, the total heating time was 30 min. The
crude product was taken up in a mixture of water (30 mL)
and dichloromethane (30 mL), the two layers were separated

P. Franck et al. / Tetrahedron 64 (2008) 6030e6037
6035
and the water phase was extracted with dichloromethane
(2ꢁ30 mL). The combined organic layer was dried over
MgSO4 and evaporated. The crude product was purified with
flash column chromatography on silica gel using a 3:2 mixture
of heptane/ethyl acetate as the eluent, yielding the title com-
pound in 94%. The characterization data are identical as those
reported in the literature.6
131.4, 129.1, 128.7, 128.5, 127.9, 123.2, 121.9, 113.1,
111.8, 53.7, 21.9. Anal. Calcd for C18H15N3O$0.2H2O:
C, 73.80; H, 5.30; N, 14.34. Found: C, 73.86; H, 5.12; N,
13.87.
4.2.8. 5-Methyl-7H-indolo[2,3-c]quinolin-6(5H)-one (16)
The general procedure was followed using 3-(2-bromo-
phenylamino)-1-methylquinolin-2(1H)-one (15) (0.197 g,
0.6 mmol) at 200 ꢀC for 15 min; eluent: dichloromethane/
methanol (96:4); yield: 93%; beige solid; mp >300 ꢀC (de-
comp.); dH (DMSO-d6): 12.34 (br s, 1H, NH), 8.53 (dd,
J¼7.8, 1.5 Hz, 1H, H-11), 8.49 (d, J¼8.2 Hz, 1H, H-1), 7.69
(dd, J¼8.5, 1.0 Hz, 1H, H-8), 7.65 (ddd, J¼8.3, 0.9, 0.9 Hz,
1H, H-4), 7.54 (ddd, J¼8.5, 7.1, 1.5 Hz, 1H, H-9), 7.48
(ddd, J¼8.2, 7.1, 1.1 Hz, 1H, H-3), 7.44 (ddd, J¼7.9, 7.1,
1.0 Hz, 1H, H-10), 7.32 (ddd, J¼8.1, 7.0, 1.1 Hz, 1H, H-2),
3.84 (s, 3H, CH3); dC (DMSO-d6): 155.8, 139.5, 136.4,
127.6, 126.8, 126.2, 124.0, 123.1, 122.9, 122.6, 121.2, 119.4,
117.5, 116.1, 113.6, 29.7. Anal. Calcd for C16H12N2O:
C, 77.40; H, 4.87; N, 11.28. Found: C, 76.83; H, 4.68; N,
11.21.
4.2.5. 2-Methyl-2,5-dihydro-1H-pyridazino[4,5-b]indole-1-
one (8)
5-[(2-Bromophenyl)amino]-2-methylpyridazin-3(2H)-one
(7)6 (0.168 g, 0.60 mmol) was used as starting compound. In
this case, the total heating time was 30 min. The crude product
was taken up in a mixture of water (30 mL) and dichlorome-
thane (30 mL), the two layers were separated and the water
phase was extracted with dichloromethane (2ꢁ30 mL). The
combined organic layer was dried over MgSO4 and evapo-
rated. The crude product was purified with flash column chro-
matography on silica gel using a 9:1 mixture of ethyl acetate/
chloroform as the eluent, yielding the title compound in 85%.
The characterization data are identical as those reported in the
literature.6
4.2.6. 2-Benzyl-8-(trifluoromethoxy)-2,5-dihydro-1H-
pyridazino[4,5-b]indol-1-one (12a)
4.3. General procedure for the Pd-catalyzed amination
reaction of 2-benzyl-5-iodopyridazin-3(2H)-one with
2-bromoaniline derivatives
The general procedure was followed using 2-benzyl-5-{[2-
bromo-4-(trifluoromethoxy)phenyl]amino}pyridazin-3(2H)-one
(11a) (0.2640 mg, 0.6 mmol). The crude product was crystal-
lized from a mixture of ethanol and water (9:1, 10 mL), then it
was purified via flash column chromatography using hexane/
ethylacetate (1:1) as the eluent yielding the title compound in
67%. White crystals; mp 267.1e269.7 ꢀC; dH (DMSO-d6):
12.55 (br s, 1H, NH), 8.50 (s, 1H, H-4), 8.10 (s, 1H, H-9), 7.34
(d, J¼8.8 Hz, 1H, H-7), 7.50e7.45 (m, 1H, H-6), 7.35e7.20
(m, 5H, H-200, 600), 5.40 (s, 2H, 2-CH2); dC (DMSO-d6): 157.8,
143.2, 137.8, 137.7, 136.8, 128.4, 127.8, 127.7, 122.4, 121.1
A round-bottomed flask was purged with Ar and charged
with Pd(OAc)2 (0.03 mmol), racemic BINAP (0.03 mmol)
and toluene (5 mL). While stirring, the mixture was flushed
with Ar for approximately 10 min. Then, 2-benzyl-5-iodopyr-
idazin-3(2H)-one (9) (1.5 mmol), 2-bromoaniline derivative
(1.2 equiv), K2CO3 (3 equiv) (Cs2CO3 for the trifluorome-
thoxy derivative) and 5 mL toluene were added to the mixture.
The resulting mixture was flushed with Ar for a few minutes
under magnetic stirring and subsequently heated in an oil
bath (oil bath temperature 120 ꢀC, Ar atmosphere) for 24 h.
The reaction mixture was filtered over Celite and rinsed well
with dichloromethane (200 mL). The solvent was evaporated
in vacuo and the residue was purified via flash column chroma-
tography (Flash Master) using ethylacetate/hexane (1:1) mix-
ture as the eluent.
1
(q, JCeF¼254 Hz), 120.1, 119.0, 114.3, 113.2, 111.4, 53.0;
dF (DMSO-d6): ꢂ57.49. Anal. Calcd for C18H12F3N3O2: C,
60.17; H, 3.37; N, 11.69. Found: C, 60.28; H, 3.08; N, 11.51.
4.2.7. 2-Benzyl-8-methyl-2,5-dihydro-1H-pyridazino[4,5-b]-
indol-1-one (12b)
The general procedure was followed using 2-benzyl-5-
[(2-bromo-4-methylphenyl)amino]pyridazin-3(2H)-one (11b)
(0.2220 mg, 0.6 mmol). The crude product was taken up in
a mixture of water (40 mL) and dichloromethane (50 mL),
the two layers were separated and the water phase was ex-
tracted with dichloromethane (30 mL). The combined organic
layer was dried over MgSO4, then evaporated yielding beige
crystals. The residue was purified via flash column chromatog-
raphy on silica gel (it was brought on column mixed with sil-
ica gel) using hexane/ethylacetate (1:1) as the eluent yielding
the title compound in 77%. White crystals; mp 263.0e
265.1 ꢀC; dH (DMSO-d6): 12.18 (br s, 1H, NH), 8.42 (s, 1H,
H-4), 7.99 (s, 1H, H-9), 7.55 (d, J¼8.4 Hz, 1H, H-7), 7.40e
7.20 (m, 6H, H-200-600 and H-6), 5.41 (s, 2H, 2-CH2), 2.51
(s, 3H, CH3); dC (DMSO-d6): 158.8, 138.7, 137.4, 137.2,
4.3.1. 2-Benzyl-5-{[2-bromo-4-(trifluoromethoxy)phenyl]-
amino}pyridazin-3(2H)-one (11a)
The general procedure was followed using 2-bromo-4-(tri-
fluoromethoxy)aniline (0.4690 g, 1.8 mmol). Yield: 66%;
beige crystals; mp 175.2e175.9 ꢀC; dH (CDCl3): 7.57 (d,
J¼2.7 Hz, 1H, H-6), 7.53e7.52 (m, 1H, H-30), 7.42e7.38
(m, 3H, H-300, 400, 500), 7.35e7.23 (m, 3H, H-200, 600 and
H-60), 7.20e7.15 (m, 1H, H-50), 6.20 (d, J¼2.7 Hz, 1H,
H-4), 6.19 (br s, 1H, NH), 5.27 (s, 2H, 2-CH2); dC (CDCl3):
161.8, 146.5, 145.3, 137.3, 136.0, 131.7, 129.3, 128.5,
1
126.9, 124.4, 121.9, 120.6 (q, JCeF¼258 Hz), 118.3, 103.3,
54.9; dF (CDCl3): ꢂ58.63. Anal. Calcd for C18H13BrF3N3O2:
C, 49.11; H, 2.98; N, 9.55. Found: C, 49.52; H, 2.75; N, 9.48.

6036
P. Franck et al. / Tetrahedron 64 (2008) 6030e6037
4.3.2. 2-Benzyl-5-[(2-bromo-4-methylphenyl)amino]-
pyridazin-3(2H)-one (11b)
1.4 Hz, 1H, H-5), 7.39 (ddd, J¼8.4, 6.7, 1.5 Hz, 1H, H-7),
7.34 (ddd, J¼8.5, 7.0, 1.2 Hz, 1H, H-40), 7.34 (dd, J¼8.5,
1.4 Hz, 1H, H-60), 7.30 (s, 1H, H-4), 7.22 (ddd, J¼8.0, 6.6,
1.2 Hz, 1H, H-6), 6.91 (ddd, J¼8.4, 7.0, 1.1 Hz, 1H, H-50),
3.86 (s, 3H, CH3); dC (CDCl3): 158.7, 138.9, 134.3, 133.5,
132.0, 128.1, 126.6, 126.4, 123.2, 122.9, 121.7, 119.5,
115.7, 113.9, 108.4, 30.4. Anal. Calcd for C16H13BrN2O: C,
58.38; H, 3.98; N, 8.51. Found: C, 58.34; H, 3.80; N, 8.53.
The general procedure was followed using 2-bromo-4-meth-
ylaniline (0.3420 g, 1.8 mmol). Yield: 61%; beige crystals; mp
176.8e178.2 ꢀC; dH (CDCl3): 7.53 (d, J¼2.7 Hz, 1H, H-6),
7.50e7.10 (m, 8H, aromatic protons), 6.15 (d, J¼2.7 Hz, 1H,
H-4), 6.05 (br s, 1H, NH), 5.26 (s, 2H, 2-CH2), 2.33 (s, 3H,
CH3); dC (CDCl3): 162.1, 145.9, 137.7, 137.5, 134.5, 134.1,
131.8, 129.9, 129.2, 128.4, 124.3, 118.4, 102.2, 54.8, 21.3.
Anal. Calcd for C18H16BrN3O: C, 58.39; H, 4.36; N, 11.35.
Found: C, 58.33; H, 4.13; N, 11.19.
4.6. General procedure for the synthesis of 5H-d-carbolines
(18) via high temperature Pd-catalyzed intramolecular direct
arylations
4.4. 3-Bromo-1-methylquinolin-2(1H)-one (14)
A microwave vial of 10 mL was charged with the appro-
priate N-aryl-2-chloropyridin-3-amine (17) (0.6 mmol),
PdCl2(PPh3)2 (0.0337 g, 0.048 mmol, 8 mol %) and
NaOAc$3H2O (0.200 g, 1.47 mmol). Subsequently, the vial
was flushed with Ar for 1 min. Then, 1 mL of DMA was added
via a syringe and the resulting mixture was stirred and flushed
with Ar for an additional 2 min. Next, the vial was sealed with
an Al crimp cap with a septum and heated at 180 ꢀC in a CEM
Discover microwave apparatus. The set power was 100 W and
the total heating time was 10 min. After the reaction vial was
cooled down to room temperature using a propelled air flow, it
was opened and poured in a round-bottomed flask. The vial
was rinsed with methanol (50 mL) and the combined organic
phase was evaporated to dryness. Finally, the crude product
was purified via column chromatography on silica gel (the resi-
due was brought on column mixed with silica) yielding the
title compound.
The synthesis of this compound has been reported previ-
ously.15 We followed an alternative methylation procedure.
A round-bottomed flask was charged with 3-bromoquinolin-
2(1H)-one (13) (1.120 g, 5 mmol), KOH (0.421 g, 7.5 mmol)
and methanol (10 mL). The mixture was flushed with N2 under
magnetic stirring. Subsequently, MeI (3.1 mL, 49.8 mmol)
was added and the resulting mixture was stirred for 3 h at
room temperature. Then the solvent was removed under re-
duced pressure. To the residue, H2O (50 mL) and CH2Cl2
(50 mL) were added. The organic layer was separated, the
aqueous phase was extracted with CH2Cl2 (2ꢁ25 mL) and
the combined organic phase was evaporated to dryness under
reduced pressure yielding the target compound in 96%. White
solid; mp 144 ꢀC; dH (CDCl3): 8.13 (s, 1H, H-4), 7.60 (ddd,
J¼8.8, 7.4, 1.6 Hz, 1H, H-6), 7.52 (dd, J¼7.8, 1.4 Hz, 1H,
H-8), 7.36 (d, J¼8.6 Hz, 1H, H-5), 7.26 (ddd, J¼7.9, 7.1,
0.8 Hz, 1H, H-7), 3.80 (s, 1H, CH3); dC (CDCl3): 158.5,
140.6, 139.4, 130.9, 128.1, 122.7, 120.6, 117.7, 114.4, 31.1.
4.6.1. 8-Methyl-5H-pyrido[3,2-b]indole (18a)
The general procedure was followed using 2-chloro-N-
(4-methylphenyl)pyridin-3-amine (17a)14 (0.1312 g, 0.6 mmol);
eluent: dichloromethane/ethyl acetate (95:5); yield: 80%;
white solid; mp 212 ꢀC; dH (DMSO-d6): 11.27 (br s, 1H,
NeH), 8.43 (dd, J¼4.6, 1.4 Hz, 1H, H-2), 8.00 (d,
J¼1.7 Hz, 1H, H-9), 7.85 (dd, J¼8.2, 1.4 Hz, 1H, H-4),
7.47 (d, J¼8.3 Hz, 1H, H-6), 7.35 (dd, J¼8.2, 4.6 Hz, 1H,
H-3), 7.33 (dd, J¼8.3, 1.7 Hz, 1H, H-7), 2.49 (s, 3H,
CH3); dC (DMSO-d6): 141.0, 140.8, 138.8, 133.1, 128.7,
128.0, 121.7, 119.9, 119.6, 117.7, 111.3, 21.0. Anal. Calcd
for C12H10N2$0.8H2O: C, 73.30; H, 5.95; N, 14.25. Found:
C, 74.27; H, 5.11; N, 14.22.
4.5. 3-(2-Bromophenylamino)-1-methylquinolin-2(1H)-one
(15)
A round-bottomed flask was charged with Pd(OAc)2
(0.034 g, 0.150 mmol, 2.5 mol %) and XANTPHOS (9,9-
dimethyl-4,5-bis(diphenylphosphino)-9H-xanthene) (0.096 g,
0.165 mmol, 5.5 mol %) followed by dry dioxane (12 mL)
(freshly distilled). The mixture was flushed with N2 for
10 min. Meanwhile, in another round-bottomed flask 3-
bromo-1-methylquinolin-2(1H)-one (14) (0.708 g, 3 mmol),
2-bromoaniline (0.619 g, 3.6 mmol) and caesium carbonate
(2.932 g, 9 mmol) (Aldrich, 99%) were weighed. To this mix-
ture, the Pd-catalyst was added and the flask was flushed with
N2 for 5 min. The resulting mixture was stirred and heated at
reflux (oil bath temperature: 110 ꢀC) for 1 h under N2 atmo-
sphere. After cooling down to room temperature, dichlorome-
thane (25 mL) was added and the suspension filtered over
a path of Celite and rinsed well with dichloromethane
(125 mL). The solvent was removed under reduced pressure
and the residue purified by column chromatography on silica
gel using dichloromethane/heptane (6:4) as the eluent yielding
the title compound in 87%. White solid; mp 108 ꢀC; dH
(CDCl3): 7.63 (br s, 1H, NH), 7.63 (dd, J¼8.0, 1.5 Hz, 1H,
H-8), 7.56 (dd, J¼8.1, 1.5 Hz, 1H, H-30), 7.44 (dd, J¼7.8,
4.6.2. 5H-Pyrido[3,2-b]indole (18b)
The general procedure was followed using 2-chloro-N-
phenylpyridin-3-amine (17b)14 (0.1228 g, 0.6 mmol); eluent:
dichloromethane/ethyl acetate (9:1); yield: 69%. The charac-
terization data are identical as those reported in the
literature.13,16
4.6.3. 8-Methoxy-5H-pyrido[3,2-b]indole (18c)
The general procedure was followed using 2-chloro-N-(4-
methoxyphenyl)pyridin-3-amine (17c)14 (0.1408 g, 0.6 mmol);
eluent: dichloromethane/ethyl acetate (8:2); yield: 63%; pale
yellow solid; mp 155 ꢀC; dH (DMSO-d6): 11.22 (br s, 1H,

P. Franck et al. / Tetrahedron 64 (2008) 6030e6037
6037
´
`
5. Tapolcsanyi, P.; Maes, B. U. W.; Monsieurs, K.; Lemiere, G. L. F.; Riedl,
Z.; Hajos, G.; Van den Driessche, B.; Dommisse, R. A.; Matyus, P.
NeH), 8.43 (dd, J¼4.6, 1.4 Hz, 1H, H-2), 7.85 (dd, J¼8.2,
1.4 Hz, 1H, H-4), 7.69 (d, J¼2.6 Hz, 1H, H-9), 7.49 (d, J¼
8.8 Hz, 1H, H-6), 7.36 (dd, J¼8.2, 4.6 Hz, 1H, H-3), 7.16
(dd, J¼8.8, 2.6 Hz, 1H, H-7), 3.88 (s, 3H, OeCH3); dC
(DMSO-d6): 153.4, 141.0, 140.7, 135.3, 133.5, 121.8, 119.9,
117.9, 117.1, 112.5, 101.8, 55.5. Anal. Calcd for C12H10N2O:
C, 72.71; H, 5.08; N, 14.13. Found: C, 72.45; H, 4.88; N, 14.07.
´
´
Tetrahedron 2003, 59, 5919.
´
6. Dajka-Halasz, B.; Monsieurs, K.; Elias, O.; Karolyhazy, L.; Tapolcsanyi,
´
P.; Maes, B. U. W.; Riedl, Z.; Hajos, G.; Dommisse, R. A.; Lemiere,
G. L. F.; Kosmrlj, J.; Matyus, P. Tetrahedron 2004, 60, 2283.
´
´
´
´
´
`
ˇ
´
´
7. (a) Monge Vega, A.; Aldana, I.; Fernandez-Alvarez, E. Eur. J. Med. Chem.
1978, 13, 573; (b) Monge Vega, A.; Aldana, I.; Parrado, P.; Font, M.;
Alvarez, E. F. J. Pharm. Sci. 1982, 71, 1406; (c) Monge, A.; Parrado,
´
P.; Font, M.; Fernandez-Alvarez, E. J. Med. Chem. 1987, 30, 1029; (d)
Monge, A.; Font, M.; Parrado, P.; Fernandez-Alvarez, E. Eur. J. Med.
Chem. 1988, 23, 547; (e) Monge, A.; Aldana, I.; Alvarez, T.; Font, M.;
Santiago, E.; Latre, J. A.; Bermejillo, M. J.; Lopez-Unzu, M. J.; Fernan-
dez-Alvarez, E. J. Med. Chem. 1991, 34, 3023; (f) Monge, A.; Aldana, I.;
Alvarez, T.; Losa, M. J.; Font, M.; Cenarruzabeitia, E.; Lasheras, B.;
Frechilla, D.; Castiella, E.; Fernandez-Alvarez, E. Eur. J. Med. Chem.
1991, 26, 655; (g) Frechilla, D.; Bernedo, E.; Castiella, E.; Lasheras,
B.; Cenarruzabeitia, E.; Monge, A.; Aldana, I.; Alvarez, T.; Losa, M. J.;
Font, M. Eur. J. Pharmacol. 1992, 219, 409; (h) Monge, A.; Aldana, I.;
Losa, M. J.; Font, M.; Cenarruzabeitia, E.; Castiella, E.; Frechilla, D.;
Santiago, E.; Martinez de Irujo, J. J.; Alberdi, E.; Lopez-Unzu, M. J.
Arzneim.-Forsch. 1993, 43, 1175; (i) Frechilla, D.; Castiella, E.; Lasheras,
B.; Cenarruzabeitia, E.; Monge, A.; Aldana, I.; Alvarez, T.; Losa, M. J.;
Font, M. J. Cardiovasc. Pharmacol. 1993, 21, 89; (j) Monge, A.; Navarro,
4.6.4. Ethyl 5H-pyrido[3,2-b]indole-8-carboxylate (18d)
The general procedure was followed using ethyl 4-[(2-chloro-
pyridin-3-yl)amino]benzoate (17d)14 (0.1660 g, 0.6 mmol);
eluent: dichloromethane/ethyl acetate (8:2); yield: 92%; white
solid; mp 220e221 ꢀC; dH (DMSO-d6): 11.89 (br s, 1H, NeH),
8.85 (d, J¼1.7 Hz, 1H, H-9), 8.56 (dd, J¼4.6, 1.4 Hz, 1H, H-2),
8.13 (dd, J¼8.6, 1.7 Hz, 1H, H-7), 7.99 (dd, J¼8.2, 1.4 Hz, 1H,
H-4), 7.67 (d, J¼8.6 Hz, 1H, H-6), 7.48 (dd, J¼8.2, 4.6 Hz, 1H,
H-3), 4.38 (q, 2H, OeCH2), 1.39 (t, 3H, CH3); dC (DMSO-d6):
166.2, 143.0, 142.1, 140.9, 133.7, 128.2, 121.9, 121.2, 121.0,
120.9, 118.8, 111.7, 60.4, 14.2. Anal. Calcd for
C14H12N2O2$1.1H2O: C, 64.65; H, 5.50; N, 10.77. Found: C,
64.90; H, 5.23; N, 10.74.
´
M.-E.; Font, M.; Santiago, E.; Alberdi, E.; Martınez-Irujo, J.-J. Arch.
Pharm. 1995, 328, 689; (k) Matsuo, I.; Takakuwa, T.; Kishii, K.; Harada,
M.; Mitani, M. JP Patent 08113574 A2, 1996.
`
8. (a) Jonckers, T. H. M.; Maes, B. U. W.; Lemiere, G. L. F.; Rombouts, G.;
Pieters, L.; Haemers, A.; Dommisse, R. A. Synlett 2003, 615; (b) Van
Acknowledgements
`
Miert, S.; Jonckers, T.; Cimanga, K.; Maes, L.; Maes, B.; Lemiere, G.;
Dommisse, R.; Vlietinck, A.; Pieters, L. Exp. Parasitol. 2004, 108, 163;
The authors acknowledge the financial support of the FWO-
Flanders (Fund for Scientific Research-Flanders) (project
1.5.088.04), the University of Antwerp (NOI), the Flemish
Government (Impulsfinanciering van de Vlaamse Overheid
voor Strategisch Basisonderzoek PFEU 2003) and the Hungar-
ian Ministry of Health (ETT-508/2006). S.H. thanks the IWT-
Flanders (The Institute for the promotion of Innovation by
Science and Technology in Flanders) and P.F. the BOF UA
(Special Research Fund of the University of Antwerp) for a
scholarship. We would like to thank Koen Smits for his con-
tribution to the preparation of 5-methyl-7H-indolo[2,3-c]qui-
nolin-6(5H)-one.
`
´
(c) Hostyn, S.; Maes, B. U. W.; Pieters, L.; Lemiere, G. L. F.; Matyus,
´
P.; Hajos, G.; Dommisse, R. A. Tetrahedron 2005, 61, 1571; (d) Van
Miert, S.; Hostyn, S.; Maes, B. U. W.; Cimanga, K.; Brun, R.; Kaiser,
´
`
M.; Matyus, P.; Dommisse, R.; Lemiere, G.; Vlietinck, A.; Pieters, L.
J. Nat. Prod. 2005, 68, 674.
9. Harris, J. M.; Padwa, A. Org. Lett. 2003, 5, 4195.
10. See for instance: (a) Grigg, R.; Sridharan, V.; Stevenson, P.; Sukirthalin-
gam, S.; Worakun, T. Tetrahedron 1990, 46, 4003; (b) Comins, D. L.;
Baevsky, M. F.; Hong, H. J. Am. Chem. Soc. 1992, 114, 10971; (c)
Comins, D. L.; Hong, H.; Saha, J. K.; Jianhua, G. J. Org. Chem. 1994,
59, 5120e5121; (d) Comins, D. L.; Nolan, J. M. Org. Lett. 2001, 3, 4255.
11. For examples on site-selective Pd-catalyzed aminations based on chemo-
selective oxidative addition: (a) Jonckers, T. H. M.; Maes, B. U. W.;
`
Lemiere, G. L. F.; Dommisse, R. Tetrahedron 2001, 57, 7027; (b) Loones,
K. T. J.; Maes, B. U. W.; Meyers, C.; Deruytter, J. J. Org. Chem. 2006, 71,
260; (c) Loones, K. T. J.; Maes, B. U. W.; Dommisse, R. A. Tetrahedron
2007, 63, 8954; (d) See Refs. 8a and 8c.
References and notes
12. Sabol, M. R.; Owen, J. M.; Erickson, W. R. Synth. Commun. 2000, 30,
427.
1. Hostyn, S.; Maes, B. U. W.; Van Baelen, G.; Gulevskaya, A.; Meyers, C.;
Smits, K. Tetrahedron 2006, 62, 4676.
13. Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999,
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2. Bedford, R. B.; Betham, M. J. Org. Chem. 2006, 71, 9403.
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´
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