Palladium-Catalyzed Carbonylation of Haloindoles: No Need for Protecting Groups

Article abstract of DOI:10.1021/ol035988r

(Equation presented) For the first time, palladium-catalyzed carbonylations of unprotected bromoindoles have been performed successfully with different N- and 0-nucleophiles. Various indole carboxylic acid derivatives are accessible in excellent yield. For example, aminocarbonylation of 4-, 5-, 6-, or 7-bromoindole with arylethylpiperazines provides a direct one-step synthesis for CNS active amphetamine derivatives.

Full text of DOI:10.1021/ol035988r

ORGANIC
LETTERS
2
004
Vol. 6, No. 1
-10
Palladium-Catalyzed Carbonylation of
Haloindoles: No Need for Protecting
Groups
7
†
†
†
†
‡
Kamal Kumar, Alexander Zapf, Dirk Michalik, Annegret Tillack, Timo Heinrich,
‡
‡
,†
Henning B o1 ttcher, Michael Arlt, and Matthias Beller*
Leibniz-Institut f u¨ r Organische Katalyse an der UniVersit a¨ t Rostock e.V. (IfOK),
Buchbinderstrasse 5-6, D-18055 Rostock, Germany, and Merck KGaA,
Frankfurter Str. 250, D-64293 Darmstadt, Germany
matthias.beller@ifok.uni-rostock.de
Received October 13, 2003
ABSTRACT
For the first time, palladium-catalyzed carbonylations of unprotected bromoindoles have been performed successfully with different N- and
O-nucleophiles. Various indole carboxylic acid derivatives are accessible in excellent yield. For example, aminocarbonylation of 4-, 5-, 6-, or
7-bromoindole with arylethylpiperazines provides a direct one-step synthesis for CNS active amphetamine derivatives.
4
The introduction of carboxylic acid groups into arenes using
carbonylation reactions is an interesting method among the
array of catalytic conversions of aryl halides performed by
aryl bromides and chlorides. Due to their importance as
building blocks for pharmaceuticals and agrochemicals, we
became especially interested in the carbonylation of het-
eroaryl chlorides. For example, we have performed alkoxy-
1
palladium complexes. “Classic” syntheses of aromatic esters
or amides generally require a carboxylic acid precursor.
Alternatively, arene carboxylic acid derivatives can be
prepared through palladium-catalyzed carbonylation of the
corresponding aryl halides in the presence of a suitable
(
1) (a) Tsuji, J. Palladium Reagents and Catalysts: InnoVations in
Organic Synthesis; Wiley: Chichester, 1995. (b) Diederich, F.; Stang, P. J.
Metal-Catalyzed Cross-Coupling Reactions; Wiley-VCH: Weinheim,
1998.
2
(2) (a) Colquhoun, H. M.; Thompson, D. J.; Twigg, M. V. Carbonylation,
Direct Synthesis of Carbonyl Compounds; Plenum Press: New York, 1991.
(b) Gulevich, Y. V.; Bumagin, N. A.; Beletskaya, I. P. Russ. Chem. ReV.
nucleophile. Advantages of this method include the broad
availability of substrates and the high tolerance of palladium
catalysts against a variety of functional groups. Therefore,
this route has become a useful tool for the preparation of
substituted benzoic acid derivatives.3
For some time, we have been involved in the development
of more efficient palladium catalysts for carbonylation of
1
988, 57, 299. (c) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner,
C. W. J. Mol. Catal. 1995, 104, 17. (d) Stromnova, T. A.; Moiseev, I. I.
Russ. Chem. ReV. 1998, 67, 485. (e) Skoda-Foldes, R.; Kollar, L. Curr.
Org. Chem. 2002, 6, 1097.
(3) Recent examples: (a) Wannberg, J.; Larhed, M. J. Org. Chem. 2003,
6
8, 5750. (b) Blaser, H.-U.; Diggelmann, M.; Meier, H.; Naud, F.;
Scheppach, E.; Schnyder, A.; Studer, M. J. Org. Chem. 2003, 68, 3725. (c)
Holzapfel, C. W.; Ferreira, A. C.; Marais, W. J. Chem. Res. 2002, 218. (d)
Calo, V.; Giannoccaro, P.; Nacci, A.; Monopoli, A. J. Organomet. Chem.
2002, 645, 152. (e) Schnyder, A.; Indolese, A. J. Org. Chem. 2002, 67,
594.
†
Leibniz-Institut f u¨ r Organische Katalyse an der Universit a¨ t Rostock
e.V. (IfOK).
‡
Merck KGaA.
1
0.1021/ol035988r CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/06/2003

Table 1. Aminocarbonylation of 5-Bromoindole with Piperidine: A Model Reaction
entry
Pd
ligand
Pd/L [mol %]
solvent
temp [°C]
time [h]
pCO [bar]
conversiona [%]
yielda [%]
1
2
3
4
5
6
7
8
9
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
P d (P h CN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PhCN)2Cl2
Pd(PPh3)2Cl2
dppb
PPh3
d p p f
dppf
dppf
dppf
dppf
dppf
dppf
1:3
1:6
1:3
1:3
1:3
0.1:0.3
1:3
1:3
toluene
toluene
tolu en e
NMP
dioxane
toluene
toluene
toluene
toluene
130
130
130
130
130
130
110
130
130
20
12
20
12
12
12
12
12
20
25
25
25
25
25
25
25
10
25
29
24
92
11
53
9
20
17
31
23
10
81
0
38
0
3
2
28
1:3
a
Based on 5-bromoindole; determined by GC (hexadecane as internal standard). Reaction conditions: 5-bromoindole (1.0 mmol), piperidine (1.5 mmol),
NEt3 (1.5 mmol), solvent (10 mL) in a 25 mL autoclave.
carbonylations of pyridines, pyrazines, quinolines, and
pyrimidines in the past.5
More recently, we turned our attention to carbonylations
of haloindoles. In particular, we were attracted by the
possibility of synthesizing indole carboxylic amides as shown
in Figure 1, in a straightforward manner. The resulting
carboxylated indoles, there was no such reaction of easily
available bromoindoles reported. Also, other types of pal-
ladium-catalyzed coupling reactions of unprotected haloin-
7
doles are rare. One of the possible reasons for the lack of
these reactions is the presence of the acidic NH proton and
the possibility of the haloindole to oligomerize or polymerize
in the presence of a palladium catalyst. In addition, it seems
difficult to introduce other amines, alcohols, or water as
nucleophiles in the presence of the free indole nitrogen.
Nevertheless, we started our investigation using the re-
action of 5-bromoindole with piperidine as a model sys-
tem. Selected results are shown in Table 1. From our pre-
vious work in palladium-catalyzed carbonylations of aryl
halides, it is known that bidentate ligands lead to good
selectivities and improved activities compared to monoden-
4,5
tate ligands. Therefore, we performed initial reactions using
,4-bis(diphenylphosphino)butane (dppb) as a ligand in the
1
presence of bis(benzonitrile)palladium(II) dichloride (Pd/
ligand 1:3).
Figure 1. Bioactive Indole Derivatives.
As shown in Table 1 (entry 1), even at 130 °C (20 h, 25
bar of CO pressure), only 23% yield of 5-(N-piperidylcar-
bonyl)indole (4) was obtained. Despite the disappointingly
low yield, this result was somewhat encouraging because a
high chemoselectivity (79%) was observed. Hence, attack
of 5-bromoindole on the acylpalladium complex is sig-
nificantly slower compared to the reaction of piperidine.
Under similar reaction conditions, the use of triphenylphos-
phine as a ligand, expectedly, yielded an even smaller
amount of the desired product (entry 2). Fortunately, using
products are known to be potent ligands for the serotonin
(
5-HT) subtype 2A receptor and therefore constitute potential
6
CNS active compounds.
However, a literature survey regarding carbonylation
reactions of indoles revealed that, despite the usefulness of
(
4) (a) M a¨ gerlein, W.; Indolese, A. F.; Beller, M. J. Organomet. Chem.
2
2
002, 641, 30. (b) M a¨ gerlein, W.; Indolese, A. F.; Beller, M. Angew. Chem.
001, 113, 2940. M a¨ gerlein, W.; Indolese, A. F.; Beller, M. Angew. Chem.,
1,1′-bis(diphenylphosphino)ferrocene (dppf) as a ligand with
Int. Ed. 2001, 40, 2856. (c) Beller, M.; Indolese, A. F. Chimia 2001, 55,
84. (d) Schnyder, A.; Beller, M.; Mehltretter, G.; Indolese, A. F.; Nsenda,
6
Pd(PhCN) Cl (Pd/L 1:3) (entry 3) afforded a significant
2
2
T.; Studer, M. J. Org. Chem. 2001, 66, 4311. (e) M a¨ gerlein, W.; Indolese,
A. F.; Beller, M. J. Mol. Cat. 2000, 156, 213.
(
5) Beller, M.; M a¨ gerlein, W.; Indolese, A. F.; Fischer, C. Synthesis 2001,
098.
6) B o¨ ttcher, H.; Marz, J.; Greiner, H.; Harting, J.; Bartoszyk, G.;
Seyfried, C.; Amsterdam, C. V. (Merck Patent GmbH, Germany), WO
(7) (a) Molander, G. A.; Biolatto, B. J. Org. Chem. 2003, 68, 4302. (b)
Molander, G. A.; Bernardi, C. R. J. Org. Chem. 2002, 67, 8424. (c)
Molander, G. A.; Katona, B. W.; Machrouhi, F. J. Org. Chem. 2002, 67,
8416. (d) Carrera, G. M.; Sheppard, G. S. Synlett 1994, 93. (e) Huth, A.;
Beetz, I.; Schuhmann, I.; Thielert, K. Tetrahedron 1987, 43, 1071.
1
(
2
001007434, 2001.
8
Org. Lett., Vol. 6, No. 1, 2004

(1H-indol-7-yl)methanone (6b) in very good isolated yields
(91 and 94% yields, respectively) (entries 1 and 2).
Table 2. Pd-Catalyzed Carbonylation of Bromoindoles with
Nucleophiles
Similarly, the aminocarbonylation of 5-bromoindole with
N-methylpiperazine gave the corresponding indole amide (6c)
in excellent yield (99%) (entry 3). Next, we explored the
potential of this method for the synthesis of other interesting
indole derivatives. In Table 2 (entries 4-7), a few examples
are shown demonstrating the generality of this reaction in
indole chemistry. Thiomorpholine was coupled smoothly to
give 6d in 93% yield at somewhat higher catalyst concentra-
tion (5 mol %). 6-Bromoindole also underwent selective
aminocarbonylation with primary amines. Here, n-butylamine
gave 6e in 95% yield. Using ethanol as a solvent and
nucleophile, ethoxycarbonylation was realized, forming an
8
indole carboxylic ester in 98% yield. This ester is an
important synthetic intermediate for the synthesis of many
9
bioactive molecules. Interestingly, the free indole carboxylic
1
0
acid (6g) was also directly accessible. However, product
purification was more difficult; thus, the yield was somewhat
lower (67%) in this case.
Finally, we applied our successful method to synthesize
11
the new CNS active amphetamine deriviatives. Here, three
different arylethylpiperazines were used as nucleophiles in
the aminocarbonylation of bromoindoles. The utilized 2-aryl-
ethylpiperazines are easily accessible by base-catalyzed
hydroamination of the corresponding styrenes with N-ben-
1
2,13
zylpiperazine
and subsequent palladium-catalyzed de-
benzylation. In general, aminocarbonylation of bromoindoles
with arylethylpiperazines produced the amphetamine deriva-
tives 8a-e in excellent isolated yields (92-99%).
For example, 2-(4-fluorophenyl)ethylpiperazine reacted
well with 7- and 6-bromoindole (Table 3, entries 1 and 2)
Table 3. Pd-Catalyzed Carbonylation of Bromoindoles with
2-Arylethylpiperazines
a
Based on bromoindole, determined by GC. Isolated yield. c Pd/L 5/15
b
d
mol %. EtOH (10 mL) was used as a solvent. Reaction conditions:
bromoindole (1.2 mmol), nucleophile (1.0 mmol), Pd(PhCN)2Cl2 (1 mol
%), dppf (3 mol %), NEt3 (1.2 mmol), toluene (10 mL).
b
increase in the catalyst activity. Testing different solvents
revealed that toluene gives the best yield for this model
reaction. However, at lower temperatures (110 °C) or at
lower carbon monoxide gas pressures (10 bar), only a
negligible amount of product 4 was obtained (Table 1, en-
tries 7 and 8). Interestingly, using a mixture of phosphines
entry
2
Ar
R
conversiona [%]
yield [%]
1c
2c
3
4
7-Br
6-Br
4-Br
5-Br
7-Br
4-F-Ph
4-F-Ph
Ph
H
H
Me
Me
H
100
100
100
100
100
8a (99)
8b (92)
8c (96)
8d (96)
8e (94)
Ph
Ph
5
a
Based on bromoindole, determined by GC. b Isolated yield. c Amine
used as double HCl salt, and 3.5 mmol of NEt3 was used. Reaction
conditions: bromoindole (1.2 mmol), nucleophile (1.0 mmol), Pd(PhCN)2Cl2
(1 mol %), dppf (3 mol %), NEt3 (1.2 mmol), toluene (10 mL).
(
Pd(PPh
, entry 9).
Next, the optimal reaction conditions found in the model
3 2 2
) Cl and dppf) produced 4 in only 28% yield (Table
1
reaction were employed for the carbonylation of four
different bromoindoles with six different nucleophiles (Table
2
). Due to their potential biological activity, our main interest
to yield exclusively the carbonylation products 8a and 8b.
No simple amination product without CO insertion or indole
oligomerization was observed in these reactions.
was focused on the use of different piperazine derivatives
as nucleophiles. N-Benzyl piperazine reacted well with
4-bromo and 7-bromoindole to give 4-benzylpiperazin-1-yl-
(1H-indol-4-yl)methanone (6a) and 4-benzylpiperazin-1-yl-
(8) Ponticello, G. S.; Baldwin, J. J. J. Org. Chem. 1979, 44, 4003.
Org. Lett., Vol. 6, No. 1, 2004
9

In addition, 2-phenethylpiperazine and 1-methyl-2-phen-
ylethylpiperazine also yielded the aminocarbonylation prod-
ucts of indoles in high yields (Table 3, entries 3-5).
In conclusion, we have developed an easy and general
protocol for the direct synthesis of various indole carboxylic
acid derivatives. In addition, we have shown that palladium-
catalyzed carbonylation of different bromoindoles in the
presence of dppf as a ligand and Et N as a base gave poten-
3
tially bioactive amphetamine analogues in excellent yield.
To the best of our knowledge, this is the first example for
the carbonylation of unprotected bromoindoles with various
nucleophiles involving cyclic and acyclic amines, alcohols,
and water.
(
9) (a) B o¨ ttcher, H.; Greiner, H.; Harting, J.; Bartoszyk, G.; Seyfried,
C.; Amsterdam, C. V. (Merck Patent GmbH, Germany), DE 19934433,
001. (b) B o¨ ttcher, H.; Bartoszyk, G.; Harting, J.; Amsterdam, C. V.;
2
Seyfried, C. (Merck Patent GmbH, Germany), DE 10102053, 2002. (c)
Crassier, H.; B o¨ ttcher, H.; Eckert, U.; Bathe, A.; Emmert, S. (Merck Patent
GmbH, Germany), DE 10102944, 2002.
Acknowledgment. Financial support from the BMBF, the
state of Mecklenburg-Western Pomerania, and the Fonds der
Chemischen Industrie is gratefully acknowledged. The Al-
exander von Humboldt foundation is thanked for a grant for
K.K. OMG has provided precious palladium salts. Prof. Dr.
M. Michalik, Dr. C. Fischer, H. Baudisch, S. Buchholz, A.
Lehmann, C. Mewes, and K. Reincke are thanked for their
analytical support.
(
10) Ikan, R.; Rapport, E. Tetrahedron 1967, 23, 3823.
(11) For pharmacology of a similar indole derivative, see: Bartoszyk,
G. D.; Amsterdam, C. V.; B o¨ ttcher, H.; Seyfried, C. A. Eur. J. Pharm.
003, 473, 229-230.
12) (a) Seayad, J.; Tillack, A.; Hartung, C. G.; Beller, M. AdV. Synth.
Catal. 2002, 344, 795. (b) Beller, M.; Breindl, C. Chemosphere 2001, 43,
2
(
2
2
1. (c) Hartung, C. G.; Breindl, C.; Tillack, A.; Beller, M. Tetrahedron
000, 56, 5157. (d) Beller, M.; Breindl, C. Tetrahedron 1998, 54, 6359.
(e) Beller, M.; Breindl, C.; Riermeier, T. H.; Eichberger, M.; Trauthwein,
H. Angew. Chem. 1998, 37, 3571. Beller, M.; Breindl, C.; Riermeier, T.
H.; Eichberger, M.; Trauthwein, H. Angew. Chem., Int. Ed. 1998, 37, 3389.
(
13) For other synthesis of 2-arylethylpiperazines and related molecules,
see: (a) Akgun, H.; Hollstein, U.; Hurwite, L. J. Pharm. Sci. 1988, 17,
35 and references therein. (b) Pelletier, S. W. Chemistry of Alkaloids; Van
Nostrand-Reinhold: New York, 1970. (c) Leake, C. D. The Amphet-
amines: Their Actions and Uses; Charles C. Thomas Co.: Springfield, IL,
Supporting Information Available: Complete experi-
mental details along with spectroscopic data for all new
molecules synthesized. This material is available free of
charge via the Internet at http://pubs.acs.org.
7
1
958. (d) Testa, B.; Salvesen, B. J. Pharm. Sci. 1980, 69, 497. (e) Laske,
R.; Meindl, W.; Holler, E.; Sch o¨ nenberger, H. Arch. Pharm. 1989, 322,
97, 847. (f) Glennon, R. A.; Yousif, M. Y.; Ismaiel, A. M.; El-Ashmawy,
2
M. B.; Herndon, J. L.; Fischer, J. B.; Server, A. C.; Howie, K. J. B. J.
Med. Chem. 1991, 34, 3360.
OL035988R
10
Org. Lett., Vol. 6, No. 1, 2004