Auto-tandem catalysis: Synthesis of substituted 11H-indolo [3,2-c]quinolines via palladium-catalyzed intermolecular C-N and intramolecular C-C bond formation

Article abstract of DOI:10.1002/adsc.200700328

D-Ring substituted 11H-indolo[3,2-c]quinolines (4) have been prepared via auto-tandem consecutive intermolecular Buchwald-Hartwig reaction and intramolecular palladium-catalyzed arylation on 4-chloroquinoline (1) with N-unsubstituted 2-chloroanilines (2).

Full text of DOI:10.1002/adsc.200700328

FULL PAPERS
DOI: 10.1002/adsc.200700328
Auto-Tandem Catalysis: Synthesis ofSubstituted 11 H-Indolo
À
[3,2-c]quinolines via Palladium-Catalyzed Intermolecular C N
À
and Intramolecular C C Bond Formation
Caroline Meyers,a Geert Rombouts,a Kristof T. J. Loones,a Alberto Coelho,a
and Bert U. W. Maesa,*
a
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium
Phone: (+32)-3-265-3205; fax: (+32)-3-265-3233; e-mail: bert.maes@ua.ac.be
Received: July 5, 2007; Revised: December 1, 2007; Published online: February 11, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: D-Ring substituted 11H-indolo[3,2-c]qui- lines (4) represent the first examples in which
G
nolines (4) have been prepared via auto-tandem con- tandem catalysis has been used to construct N-un-
secutive intermolecular Buchwald-Hartwig reaction substituted carbolines.
and intramolecular palladium-catalyzed arylation on
À
4-chloroquinoline (1) with N-unsubstituted 2-chloro- Keywords: amination; C H activation; malaria; pal-
anilines (2). The reported 11H-indolo[3,2-c]quino- ladium; tandem catalysis
A
Introduction
latter reaction is interesting in itself as published ex-
amples on intramolecular Pd-catalyzed arylations of
In 2003 our research group published a communica- electron-deficient heteroaromatics are scarce in com-
tion which described a new method for the synthesis parison with electron-rich heteroarenes.[3c] Selective
of 11H-indolo
A
ACHTREUNG
mercially available 4-chloroquinoline (1) and 2- c]quinoline (4a) yielded the antiplasmodial natural
chloro
U
ACHTREUNG
lecular arylation involving C H activation.
Scheme 1. Synthesis of 4a via consecutive palladium-catalyzed reactions.
Adv. Synth. Catal. 2008, 350, 465 – 470
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
465

Caroline Meyers et al.
FULL PAPERS
profile of isocryptolepine. For this purpose we decid- scribed that P(t-Bu)3 is a suitable ligand for the palla-
E
R
T
N
H
C
A
G
ed to prepare a set of D-ring substituted derivatives dium catalyst (Scheme 1).[1] Based on the fact that the
in order to be able to look at the effect of these sub- cyclodehydrochlorination is the most sensitive reac-
stituents on the selectivity index (cytotoxicity/anti- tion of the desired auto-tandem protocol, we conse-
plasmodial activity). The initial choice for the D-ring quently decided to investigate if the catalyst [Pd2
is based on the presumed mechanism of action of iso-
N
N
cryptolepine, namely inhibition of the heme detoxifi- used for the cyclodehydrochlorination reaction of 3a
cation process, which is similar to that of chloro- is also suitable to perform Buchwald–Hartwig amina-
quine.[5] D-Ring modified isocryptolepine analogues tions on 4-chloroquinoline (1). Ethyl 4-aminoben-
are rational from a medicinal chemistry point of view zoate (6a) was chosen as a test amine. Interestingly,
since the quinoline part in chloroquine and analogues when 1 mol% Pd
N
N
is known to be very important in the heme complexa- dioxane as solvent in combination with 1.2 equiva-
tion process and only limited substitutions are tolerat- lents of 6a and 5 equivalents of K3PO4, we observed a
ed.
complete conversion of 1 in 17 h at 1108C. The de-
Instead of simply using the earlier developed three- sired
N-(4-ethoxycarbonylphenyl)quinolin-4-amine
step methodology to prepare D-ring substituted iso- could be isolated in 95% yield after purification by
cryptolepines, starting from 4-chloroquinoline (1) and column chromatography (Table 1). When we used the
substituted 2-chloroanilines (2), we wondered if it conditions for the reaction of 1 with 6a for the cou-
would be possible to perform the two palladium-cata- pling of other anilines with an electron-withdrawing
lyzed reactions in an auto-tandem fashion group [ethyl 2-aminobenzoate (6b), 4-aminobenzoni-
(Scheme 1).[6] This would give access to a very power- trile (6c) and 4-fluoroaniline (6d)] excellent results
ful method to prepare 11H-indolo[3,2-c]quinolines (4) were also obtained (Table 1). For electron-releasing
U
in a single reaction step using only one catalyst start- substituents a slower reaction was observed. When 4-
ing from commercially available reagents. Conse- tert-butylaniline (6e) and 4-methoxyaniline (6f) were
quently, the target 5-methyl-5H-indolo[3,2-c]quino- used an increase of the catalyst loading to 5 mol%
G
lines (5) can be synthesized in just two reaction steps. was required to get complete conversion of 1 in an
Currently, tandem catalysis is at the forefront of sci- overnight protocol (Table 1). The slower conversion
entific research in organic synthesis since it permits observed with electron-releasing substituents on the
one to create complexity from easily accessible build- aniline was confirmed when comparing the conver-
ing blocks in only one reaction step.[7] This makes it a sion of the reaction of 1 with 6a and 6f, respectively,
preferred tool for the generation of libraries in phar- using an HPLC-UV system.[11] The amination reac-
maceutical and agrochemical companies. While the tions studied are completely Pd-catalyzed since under
synthesis of carbolines and carbazoles via a stepwise our reaction conditions no trace of amination product
approach involving an intramolecular Pd-catalyzed ar- could be observed when the catalyst was omitted in
ylation reaction is already very attractive,[8] the devel-
opment of tandem protocols starting from commer-
Table 1. Pd-Catalyzed amination of 4-chloroquinoline (1)
with substituted anilines (6).[a]
cially available building blocks certainly poses an ad-
ditional chemical challenge. Hitherto no methods
based on tandem catalysis have been reported for the
construction of N-unsubstituted carbolines. For N-
substituted carbazole synthesis two general auto-
tandem protocols (involving an intramolecular aryla-
tion step) have appeared.[9a,10] Recently, two inde-
pendent papers were published describing the use of
N-unsubstituted anilines allowing the synthesis of N-
unsubstituted carbazoles.[9b,10] Besides the usefulness
of a library of isocryptolepine derivatives, the absence
of tandem protocols for the synthesis of N-unsubsti-
tuted carbolines stimulated us to study the auto-
tandem palladium-catalyzed coupling of 4-chloroqui-
noline (1) and 2-chloroanilines (2).[10]
Product
R
Catalyst loading K3PO4
Yield
A
N
7a
7b
7c
7d
7e
7f
4-COOEt (6a)
2-COOEt (6b)
4-CN (6c)
4-F (6d)
4-t-Bu (6e)
4-MeO (6f)
2
2
2
2
5
5
5
5
5
5
5
5
95
81
86
88
97
80
Results and Discussion
[a]
General conditions: X mol % Pd2
G
N
À
For the intramolecular C C bond formation on N-(2-
Bu)3, 2 mmol 1, 2.4 mmol 6, 10 mmol K3PO4, dioxane,
1108C (oil bath temperature), pressure tube, 17 h.
chlorophenyl)quinolin-4-amine (3a) we previously de-
466
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 465 – 470

Auto-Tandem Catalysis: Synthesis of Substituted 11H-Indolo[3,2-c]quinolines
A
FULL PAPERS
Table 2. Synthesis of D-ring substituted 11H-indolo
A
quinolines via auto-tandem Pd-catalyzed intermolecular
[a]
À
À
C N and intramolecular C C bond formation.
Scheme 2. Synthesis of N-(2-chlorophenyl)quinolin-4-amine
(3a) via nucleophilic aromatic substitution.
Product
2-Chloroaniline (2)
Catalyst loading
[mol% Pd]
Yield
[%]
AHCTREUNG
4a
4b
4c
4d
4e
4f
4g
H (2a)
4-F (2b)
6-F (2c)
4-COOMe (2d)
4-CN (2e)
4-tBu (2f)
4-MeO (2g)
5
5
5
5
7
5
5
82
55
80
50
80
76
52
the coupling reactions of 1 with 6. In itself the results
obtained for the Buchwald–Hartwig amination of 1
with a wide variety of anilines (6a–f) under mild reac-
tion conditions are already of interest since there is
only one other report in the literature that describes
the arylamination of 4-chloroquinolines.[12] In this
report Wolf and Lerebours describe one example of
arylamination, namely the coupling of 4-chloro-2-phe-
nylquinoline with aniline using di-tert-butylphosphi-
nous acid as ligand for the catalyst. However, in their
protocol strong t-BuOK base in DMF at 1358C was
used. These rather harsh reaction conditions in a very
[a]
General conditions: X mol % Pd2
Bu)3, 2 mmol 1, 2.4 mmol 2, 20 mmol K3PO4, dioxane,
1258C (oil bath temperature), pressure tube, 24 h.
G
A
polar medium even allowed a direct nucleophilic aro- tions require Pd catalysis since omitting the catalyst
matic substitution of aniline on 4-chloro-2-phenylqui- under otherwise similar conditions gave no 3a and 4a.
noline. A similar yield of N,2-diphenylquinolin-4- With the same auto-tandem protocol 2-chloroanilines
amine could be obtained omitting the catalyst. When with electron-withdrawing [4-F (2b), 6-F (2c), 4-
we reacted 1 with 2a using t-BuOK in DMF at 1358C COOMe (2d), 4-CN (2e)] as well as electron-releasing
for 24 h a dirty reaction mixture was obtained out of substituents [4-t-Bu (2f), 4-MeO (2g)] yielded the cor-
which only 41% of 3a could be isolated after flash responding substituted 11H-indolo
A
column chromatography (Scheme 2). This is 40% a good yield (Table 2). Only for the auto-tandem re-
lower than the yield obtained using the Pd
XANTPHOS system (Scheme 1).[1]
ACHTREUNG
Based on the knowledge that 4-chloroquinoline (1) tion in 24 h (Table 2).
can be arylaminated using the same catalyst, base and
Next we further investigated if the large excess of
solvent as used for the cyclodehydrochlorination of base (10 equivalents) used in the auto-tandem reac-
3a, we attempted an auto-tandem reaction of 1 with tions (Table 2) is really required (Table 3). In our
2-chloroaniline (2a). For this experiment we used ex- communication dealing with the synthesis of isocryp-
actly the same reaction conditions (2.5 mol % Pd2 tolepine we noticed a beneficial effect of a large
A
N
20 mmolK3PO4, dioxane, pressure tube, oil bath tem- tively determine if such a “base effect”[13] is really
perature 1258C) as previously described in our com- present in the second catalytic cycle of our auto-
munication for the intramolecular Pd-catalyzed aryla- tandem protocol, namely the palladium-catalyzed ary-
tion reaction of N-(2-chlorophenyl)quinolin-4-amine lation of 3, we determined the conversion of 3a to 4a
(3a). We were very delighted to observe that with the using different amounts of K3PO4 (Table 3). Limited
same loading of catalyst as used for the ring closure reaction times of 15 and 30 min were selected and the
1
of 3a, a complete conversion of 1 to 4a was observed conversions were determined by recording H NMR
in a reaction time of 24 h (Table 2). 11H-Indolo[3,2- spectra of the crude reaction mixtures. When 2 equiv-
A
c]quinoline (4a) could be isolated in 82% yield which alents of K3PO4 were used 16% conversion to 4a oc-
is similar to the overall yield of the two-step approach curred in 15 min, while a similar experiment with 10
(77%). The reaction occurs via auto-tandem catalysis: equivalents base gave 39%. With 2 equivalents of
À
Pd-catalyzed C N bond formation (based on a che- K3PO4 in 30 min 35% conversion to 4a occurred and
moselective oxidative addition) followed by a Pd-cat- upon using 10 equivalents of base 55% conversion
alyzed arylation. Amine 3a is certainly an intermedi- was achieved. These observations clearly confirm
ate since TLC and MS analysis clearly revealed its that, although 2 equivalents of base do already not
presence during the course of the reaction. Both reac- completely dissolve in the reaction mixture, the use of
Adv. Synth. Catal. 2008, 350, 465 – 470
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
467

Caroline Meyers et al.
[3,2-c]quinolines.[a]
FULL PAPERS
Table 3. Effect of base and excess of base on the Pd-cata-
lyzed cyclodehydrochlorination of 3a and 3h.
Table 4. N-5 Methylation of 11H-indolo
ACHTREUNG
Product
R
Solvent
Yield [%]
5b
5c
5d
5e
5f
5g
8-F
10-F
8-COOMe
8-CN
8-t-Bu
8-MeO
BTF
90
78
89
60
82
82
Substrate Base
Equivalents Time (min) % 4a[a]
toluene
toluene
toluene
toluene
toluene
3a
3a
3a
3a
3a
3a
3a
3a
3h
3h
3h
K3PO4
K3PO4
K3PO4
K3PO4
2
2
10
10
5
15
30
15
30
30
30
16
35
39
55
46
5
[a]
General conditions: a) 0.25 mmol 4, 3 mL MeI, 3.75 mL
solvent, reflux, 20 h; b) 40 mL aqueous NH4OH, 40 mL
CH2Cl2.
K3PO4
t-BuONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
K3PO4
5
5
5
5
5
30
120
30
120
120
11
88
11
78
11
substrate 3a, also advantageous for the rate of the
ring-closure reaction involving C H activation.
5
À
[a]
Finally, selective N-5 methylation of the synthesized
Average conversion of two reactions. Conversion deter-
mined using H NMR.
1
D-ring substituted 11H-indolo[3,2-c]quinolines (4b–g)
A
could be smoothly performed under conditions re-
cently reported for the selective N-5 methylation of
7H-indolo
[2,3-c]quinoline (Table 4).[14] This yielded
G
a larger excess speeds up the reaction to some extent. the target compounds in moderate to good yields.
The effect of the strength of the base was also
checked (Table 3). When 5 equivalents of K3PO4, t-
BuONa and t-BuOK were used, respectively, 46%, Conclusions
5% and 11% conversion occurred in 30 min reaction
time. In 2 h 88% conversion was obtained for the We have developed the first auto-tandem Pd-cata-
À
À
latter base. We wondered if the increased acidity of lyzed consecutive C N and C C bond forming pro-
the NH of 3a in comparison to the NH of N-aryl-2- cess for N-unsubstituted carboline synthesis. 11H-
chloroanilines in the reported carbazole synthesis is Indolo[3,2-c]quinolines have been obtained in one
G
responsible for our observation.[9b] Therefore we pre- step from 4-chloroquinoline and 2-chloroanilines.
pared N-(2-chlorophenyl)-N-methylquinolin-4-amine Electron-releasing as well as electron-withdrawing
(3h) and subjected the molecule to the same ring-clo- substituents are tolerated on the 2-chloroaniline. The
sure conditions. With 5 equivalents of t-BuOK we ob- protocol is based on a weak base which is beneficial
served 11% conversion to 4h in a limited reaction from the point of view of functional group compatibil-
time of 30 min and 78% conversion for the same reac- ity.
tion in 2 h. When we compare the conversion value of
3a using t-BuOK with the one of the N-Me analogue
(3h), there is slightly better conversion for 3a. This is
an indication that the increased acidity of 3a (depro-
Experimental Section
tonation) is not responsible for the slower intramolec-
ular C C bond formation with stronger base on this
substrate. More experiments would be required to
fully prove this as a change in rate-limiting step or
mechanism cannot be excluded at this moment. Inter-
estingly, 5 equivalents K3PO4 gave a substantially
slower reaction on 3h than on 3a as only 11% conver-
sion was obtained in 2 h. In conclusion, the use of
milder bases (K3PO4 versus t-BuOM) is not only ben-
eficial for the general functional group compatibility
General Procedure for the Pd-Catalyzed Amination
of4-Chloroquinoline (1) with Substituted Anilines (6)
À
A 50-mL, round-bottomed flask was charged with Pd2
(0.02 mmol, 0.018 g), followed by dry freshly distilled diox-
ane (20 mL). To this solution P(t-Bu)3 (0.08 mmol, 0.2 mL of
(dba)3
AHCTREUNG
0.4M solution in toluene) was added via a syringe. The ob-
tained mixture was flushed with Ar for 10 min under mag-
netic stirring. Meanwhile an 80-mL pressure tube was
charged with 4-chloroquinoline (2.0 mmol, 0.324 g), aniline
(2.4 mmol) and finely ground K3PO4 (10.0 mmol, 2.12 g). To
of the protocol but in some cases, as exemplified by this mixture, the preformed Pd catalyst was added under an
468
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 465 – 470

Auto-Tandem Catalysis: Synthesis of Substituted 11H-Indolo[3,2-c]quinolines
A
FULL PAPERS
argon flow. The 50-mL flask was subsequently rinsed with
freshly distilled dioxane (2”10 mL). Then the resulting mix-
ture was flushed with argon for 5 min, closed and heated at
1108C (oil bath temperature) under vigorous magnetic stir-
ring for 17 h. After cooling down to room temperature the
crude reaction mixture was filtered through a pad of Celite
which was rinsed with CH2Cl2 (100 mL) and CH2Cl2/MeOH
(98/2) (50 mL). The filtrate was evaporated under reduced
pressure. The residue was purified by flash column chroma-
tography on silica gel.
Scientific Research – Flanders (Belgium) for a PhD scholar-
ship.
References
[1] T. H. M. Jonckers, B. U. W. Maes, G. L. F. Lemi›re, G.
Rombouts, L. Pieters, A. Haemers, R. A. Dommisse,
Synlett 2003, 615–618.
[2] For recent reviews and accounts on the Buchwald-
Hartwig reaction, see: a) A. R. Muci, S. L. Buchwald,
Top. Curr. Chem. 2002, 219, 131–209; b) B. Schlummer,
U. Scholz, Adv. Synth. Catal. 2004, 346, 1599–1626;
c) J. F. Hartwig, Synlett 2006, 1283–1294.
[3] For recent reviews dealing with intramolecular aryla-
tion reactions, see: a) L. C. Campeau, K. Fagnou,
Chem. Commun. 2006, 1253–1264; b) D. Alberico,
M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174–
238; c) I. V. Seregin, V. Gevorgyan, Chem. Soc. Rev.
2007, 36, 1173.
[4] For other reported methods to synthesize isocryptole-
pine, see: a) S. V. Dubovitskii, O. S. Radchenko, V. L.
Novikov, Russ. Chem. Bull. 1996, 45, 2656–2657; b) G.
Timµri, T. Soós, G. Hajós, Synlett 1997, 1067–1068;
c) P. E. Murray, K. Mills, J. A. Joule, J. Chem. Res. (S)
1998, 377–378; d) P. M. Fresneda, P. Molina, S. Delga-
do, Tetrahedron Lett. 1999, 40, 7275–7278; e) P. M.
Fresneda, P. Molina, S. Delgado, Tetrahedron 2001, 57,
6197–6202; f) R. N. Kumar, T. Suresh, P. S. Mohan, Tet-
rahedron Lett. 2002, 43, 3327–3328; g) T. Dhanabal, R.
Sangeetha, P. S. Mohan, Tetrahedron 2006, 62, 6258–
6263; h) T. Dhanabal, R. Sanggeetha, P. S. Mohan, Tet-
rahedron Lett. 2005, 46, 4509–4510; i) Y. Miki, M. Kur-
omatsu, H. Miyatake, H. Hamamoto, Tetrahedron Lett.
2007, 48, 9093–9095.
General Procedure for the Auto-Tandem Pd-
Catalyzed Coupling of4-Chloroquinoline (1) with
2-Chloroanilines (2)
A 50-mL, round-bottomed flask was charged with Pd2
(0.05 mmol, 0.046 g), followed by dry freshly distilled diox-
ane (20 mL). To this solution P(t-Bu)3 (0.2 mmol, 0.2 mL of
(dba)3
AHCTREUNG
1M solution in toluene) was added via a syringe. The ob-
tained mixture was flushed with argon for 15 min under
magnetic stirring. Meanwhile an 80-mL pressure tube was
charged with 4-chloroquinoline (2.0 mmol, 0.327 g), aniline
(2.4 mmol) and finely ground K3PO4 (20.0 mmol, 4.25 g). To
this mixture, the preformed Pd catalyst was added under an
argon flow. The 50-mL flask was subsequently rinsed with
freshly distilled dioxane (2”10 mL). Then the resulting mix-
ture was flushed with argon for 5 min, closed and heated at
1258C (oil bath temperature) under vigorous magnetic stir-
ring for 24 h. After cooling down to room temperature the
crude reaction mixture was filtered through a pad of Celite
which was rinsed with CH2Cl2/MeOH or CH2Cl2. The fil-
trate was evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel.
General Procedure for the Methylation of 7H-
Indolo[2,3-c]quinolines (4)
U
[5] T. J. Egan, Drug Design Reviews – Online 2004, 1, 93–
110.
In a round-bottomed flask 7H-indolo[2,3-c]quinoline (4)
A
(0.25 mmol), toluene (3.75 mL) and CH3I (3 mL) were
heated at reflux under an argon atmosphere for 20 h under
magnetic stirring. Then the reaction mixture was evaporated
to dryness under reduced pressure. The crude product was
purified by column chromatography on silica gel (eluent: di-
chloromethane/methanol, 9/1) giving the isocryptolepine hy-
droiodide (5·HI). To obtain the free base, 5·HI was brought
in a mixture of dichloromethane (40 mL) and 28–30% am-
monia in water (40 mL). The organic phase was separated
and the aqueous phase subsequently extracted with di-
chloromethane (2”40 mL). The combined organic phase
was dried over MgSO4, filtered and evaporated to dryness
to yield 5.
[6] Taxonomy of tandem catalysis, see: a) D. E. Fogg, E. N.
dos Santos, Coordin. Chem. Rev. 2004, 248, 2365–2379;
for alternative classifications/terms, see: b) J.-C. Wa-
silke, S. J. Obrey; R. T. Baker, G. C. Bazan, Chem. Rev.
2005, 105, 1001–1020; c) L. F. Tietze, Chem. Rev. 1996,
96, 115–136.
[7] For some recent examples on auto-tandem catalysis,
see: a) K. T. J. Loones, B. U. W. Maes, R. A. Dommisse,
G. L. F. Lemi›re, Chem. Commun. 2004, 2466–2467;
b) A. Kuwahara, K. Nakano, K. Nozaki, J. Org. Chem.
2005, 70, 413–419; c) M. V. Nandakumar, J. K. Ver-
kade, Angew. Chem. 2005, 117, 3175–3178; Angew.
Chem. Int. Ed. 2005, 44, 3115–3118; d) Y.-Q. Fang, M.
Lautens Org. Lett. 2005, 7, 3549–3552; e) J. Barluenga,
M. A. Fernµndez, F. Aznar, C. ValdØs, Chem. Eur. J.
2005, 11, 2276–2283; f) C.-G. Dong, Q.-S. Hu, Angew.
Chem. 2006, 118, 2347–2350; Angew. Chem. Int. Ed.
2006, 45, 2289–2292.
Acknowledgements
The authors acknowledge financial support from the Univer-
sity of Antwerp (GOA BOF UA, NOI BOF UA) and the
Flemish Government enabling the purchase of NMR equip-
ment (Impulsfinanciering van de Vlaamse Overheid voor
Strategisch Basisonderzoek PFEU 2003) as well as the tech-
nical assistance of P. Franck. C. Meyers thanks the Fund for
[8] For carbazole synthesis via Pd-catalyzed intramolecular
arylation of N-aryl-2-chloroanilines, see: a) L.-C. Cam-
peau, P. Thansandote, K. Fagnou, Org. Lett. 2005, 7,
1857–1860; for carboline synthesis via Pd-catalyzed in-
tramolecular arylation of N-azaheteroaryl-2-bromoani-
lines and N-(o-bromoazaheteroaryl)anilines, see: b) T.
Adv. Synth. Catal. 2008, 350, 465 – 470
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
469

Caroline Meyers et al.
FULL PAPERS
Iwaki, A. Yasuhara, T. Sakamoto, J. Chem. Soc., Perkin
Trans. 1 1999, 1505–1510.
[9] For carbazole synthesis via auto-tandem consecutive
Buchwald–Hartwig reaction and Pd-catalyzed intramo-
lecular arylation, see: a) R. B. Bedford, C. S. J. Cazin,
Chem. Commun. 2002, 2310–2311; b) R. B. Bedford,
M. Betham, J. Org. Chem. 2006, 71, 9403–9410.
[10] For carbazole synthesis via auto-tandem consecutive
Buchwald–Hartwig reaction and Pd-catalyzed intramo-
lecular arylation see: L. Ackermann, A. Althammer,
Angew. Chem. 2007, 119, 1652; Angew. Chem. Int. Ed.
2007, 46, 1627; this paper also contains one example
dealing with the synthesis of an N-substituted a-carbo-
K. T. J. Loones, T. H. M. Jonckers, G. L. F. Lemi›re,
R. A. Dommisse, A. Haemers, Synlett 2002, 1995–
1998; d) C. Meyers, B. U. W. Maes, K. T. J. Loones, G.
Bal, G. L. F. Lemi›re, R. A. Dommisse, J. Org. Chem.
2004, 69, 6010–6017; e) S. Hostyn, B. U. W. Maes, G.
Van Baelen, A. Gulevskaya, C. Meyers, K. Smits, Tetra-
hedron 2006, 62, 4676–4684; f) G. Rombouts, B. U. W.
Maes, T. H. M. Jonckers, K. T. J. Loones, Org. Synth.
2007, 84, 215–221. Important general remarks should
be made about ꢁbase effectsꢀ in Pd-catalyzed reactions
involving deprotonations in the rate-determining step
of the catalytic cycle. If one wants to compare absolute
amounts of base used for different bond forming reac-
À
line
[9-phenyl-3-(trifluoromethyl)-9H-pyrido
A
tions (e.g., C N), described in separate publications,
indole] via auto-tandem catalysis. It is not clear if the
protocols described can be used for the synthesis of N-
unsubstituted a-carbolines.
one has to be sure that the base particle size distribu-
tion/total contact surface area was the same. Even if
two teams buy the same quality of base from the same
chemical supplier, it is highly doubtful that this require-
ment is fulfilled as they most probably received base
from another lot. The stirring speed of the reaction
should also be similar and therefore controlled as an
interphase deprotonation mechanism will be seriously
influenced by this factor. When no fundamental com-
parisons of different reactions are aimed, the base can
be used as such if the total contact surface area is large.
If not, a simple grinding of base in a mortar can be per-
formed or a larger excess can be used. For an example
of a study dealing with a fundamental comparison of
Pd-catalyzed amination reactions on aryl iodides: see
ref.[13d]
[11] Compound 6a as aniline and 2 mol % catalyst: with 5
equivalents K3PO4 84% conversion in 1 hour and 90%
in 2 h was observed. Compound 6f as aniline and 2 mol
% catalyst: with 5 equivalents K3PO4 42% conversion
in 2 h and 50% in 4 h was observed. When 2 equiva-
lents of K3PO4 were used a similar conversion was ob-
served. This indicates that there is no “base effect” in
the Pd-catalyzed amination reactions on 1 with a Pd/P-
A
[12] C. Wolf, R. Lerebours, J. Org. Chem. 2003, 68, 7077–
7084.
[13] For examples of “base effects” in Pd-catalyzed amina-
ˇ
tion reactions, see: a) J. Kosmrlj, B. U. W. Maes,
G. L. F. Lemi›re, A. Haemers, Synlett 2000, 1581–1584;
b) M. Watanabe, M. Nishiyama, T. Yamamoto, Y. Koie,
Tetrahedron Lett. 2000, 41, 481–483; c) B. U. W. Maes,
[14] S. Hostyn, B. U. W. Maes, L. Pieters, G. L. F. Lemi›re,
P. Mµtyus, G. Hajós, R. Dommisse, Tetrahedron 2005,
61, 1571–1577.
470
asc.wiley-vch.de
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2008, 350, 465 – 470