Carboxylation of indoles and pyrroles with CO2 in the presence of dialkylaluminum halides

Article abstract of DOI:10.1016/j.tetlet.2009.05.076

The Lewis acid-mediated carboxylation of arenes with CO₂ has been successfully applied to 1-substituted indoles and pyrroles by using dialkylaluminum chlorides instead of aluminum trihalides. Thus, the carboxylation of 1-methylindoles, 1-benzyl-, and 1-phenylpyrroles proceeds regioselectively with the aid of an equimolar amount of Me₂AlCl under CO₂ pressure (3.0 MPa) at room temperature to afford the corresponding indole-3-carboxylic acids and pyrrole-2-carboxylic acids in 61-85% yields, while the same treatment of 1,2,5-trimethylpyrrole affords the 3-carboxylic acid in 52% yield.

Full text of DOI:10.1016/j.tetlet.2009.05.076

Tetrahedron Letters 50 (2009) 4512–4514
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carboxylation of indoles and pyrroles with CO in the presence
2
of dialkylaluminum halides
Koji Nemoto, Satoru Onozawa, Naoki Egusa, Naoya Morohashi, Tetsutaro Hattori *
Department of Environmental Studies, Graduate School of Environmental Studies, Tohoku University, 6-6-11 Aramaki-Aoba, Aoba-ku, Sendai 980-8579, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The Lewis acid-mediated carboxylation of arenes with CO has been successfully applied to 1-substituted
indoles and pyrroles by using dialkylaluminum chlorides instead of aluminum trihalides. Thus, the car-
boxylation of 1-methylindoles, 1-benzyl-, and 1-phenylpyrroles proceeds regioselectively with the aid of
2 2
an equimolar amount of Me AlCl under CO pressure (3.0 MPa) at room temperature to afford the corre-
2
Received 11 May 2009
Accepted 21 May 2009
Available online 25 May 2009
sponding indole-3-carboxylic acids and pyrrole-2-carboxylic acids in 61–85% yields, while the same
treatment of 1,2,5-trimethylpyrrole affords the 3-carboxylic acid in 52% yield.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Carboxylation
Alumination
Indolecarboxylic acid
Pyrrolecarboxylic acid
Indole-3-carboxylic acid and pyrrole-2-carboxylic acid are
important structural motifs found in various artificial drugs, as
well as biologically active natural products, such as a drug for
the prophylaxis and treatment of acute respiratory infections, Arb-
First, the carboxylation of 1-methylindole (1a) was tested with
varying aluminum-based Lewis acids (1.0 mol equiv) under CO
2
pressure (3 MPa) at room temperature (Table 1, entries 1–10).13
The reaction was carried out in benzene or toluene, depending
on the acidity of the Lewis acid employed, so as not to contaminate
desired carboxylic acid(s) with undesired one(s) formed by the car-
boxylation of the solvent; under the reaction conditions, toluene
was slightly carboxylated with the aid of aluminum trihalides
while benzene was not, and both the solvents were not carboxyl-
ated with weaker Lewis acids. Alkylaluminums were employed
as hexane solutions and, therefore, an amount of incidental hexane
was included into the reaction mixture in runs carried out by using
alkylaluminums. The reaction proceeded regioselectively to give
1
idol, a serotonin 5-hydroxytryptamine type-3 receptor antagonist
2
used as an antiemetic, Tropisetron, and a potent calcium channel
3
modulator, Ryanodine. Although a number of synthetic ap-
proaches have been reported for the construction of these struc-
4
5
8
tures via cyclization reactions, such as the Fischer, Saegusa–Ito,
Hantzsch, and Knorr syntheses,7 the Friedel–Crafts acylation,
6
9
10
the carbonation of arylmetal species, and so on, they require a
multi-step reaction sequence and/or prefunctionalization of start-
ing materials and, therefore, a more straightforward method is de-
sired. It has been known that arenes are directly carboxylated with
2
CO with the aid of Lewis acids to give arylcarboxylic acids, though
1
1
generally in poor yields. The reaction is believed to be an electro-
philic aromatic substitution; an aromatic nucleus is attacked by Le-
CO (3.0 MPa)
Lewis acid
2
R' 3
N
R'
2- and/or 3-CO H
2
wis acid-activated CO
2
to give an arenium intermediate, which
2
eliminates a proton to give a carboxylic acid after aqueous workup
solvent
room temp., 3 h
N
R
1
1b
(
the S
E
Ar mechanism).
In our continuing efforts to extend the
R
12
scope and utility of this reaction, we have found that 1-substi-
tuted indoles and pyrroles can be efficiently carboxylated under
1–4
CO
the S
2
pressure in the presence of dialkylaluminum halides, although
Ar mechanism may not or not always operate in the carbox-
R
N
E
N
N
N
R
ylation of these heteroaromatic compounds. Herein, we report pre-
liminary results of the carboxylation of indoles and pyrroles 1–4
under the Friedel–Crafts conditions (Scheme 1).
R
1
1
a: R = Me
b: R = H
2a: R = Me
2b: R = Ph
3a: R = Me
3b: R = Bn
4
3
3
c: R = Ph
d: R = H
*
Corresponding author. Tel.: +81 22 795 7262; fax: +81 22 795 7293.
E-mail address: hattori@orgsynth.che.tohoku.ac.jp (T. Hattori).
Scheme 1.
0
040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.05.076

K. Nemoto et al. / Tetrahedron Letters 50 (2009) 4512–4514
4513
Table 1
and 2b, and 1-substituted pyrroles 3a–c were remained almost in-
tact after the treatment. On the other hand, 1-unsubstituted com-
pounds 1b and 3d were completely deuterated at the 1-position.
Therefore, the carboxylation of 1a is suggested to proceed rather
a
Carboxylation of indoles and pyrroles
Entry
Substrate
Lewis acid
AlCl
Solvent
Yield (%) (2-:3- ratio)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
2a
2b
3a
3a
3a
3a
3b
3c
3d
3d
4
3
Benzene
Benzene
Benzene
Benzene
36 (–:1)
32 (–:1)
32 (–:1)
32 (–:1)
5 (–:1)
21 (–:1)
62 (–:1)
85 (–:1)
69 (–:1)
6 (–:1)
48 (–:1)
65 (–:1)
59 (–:1)
0 (–:1)
28 (–:1)
21 (–:1)
73 (–:1)
61 (–:1)
2 (–:1)
AlBr
AlBr
AlBr
3
3
3
via the metallation of 1a with Me
ation of the resulting indole-3-ylaluminum species than via the
Ar mechanism. This is supported by the fact that an organoalu-
minum species, which was prepared beforehand by the treatment
of 1a with an equimolar amount of Me AlCl in toluene–hexane un-
der nitrogen, was exposed to 3.0 MPa CO for 3 h to give the 3-car-
2
AlCl, followed by the carbon-
c
d
S
E
AlI
MeAlCl
3
Benzene
2
Toluene–hexane
Benzene–hexane
Toluene–hexane
Toluene–hexane
Toluene–hexane
Hexane
Me
Me
2
AlCl
AlCl
2
2
2
2
Et AlCl
boxylic acid in 65% yield. The organoaluminum species is expected
to be methyl(1-methylindole-3-yl)aluminum chloride because
methane was detected from the gas phase by GC analysis when
the metallation was carried out in a sealed vessel. The relatively
low yields of 1-unsubstituted carboxylic acids as compared to
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Me
Me
Me
Me
Me
Me
Me
Me
Me
3
2
2
2
2
2
2
2
2
Al
AlCl
AlCl
AlCl
AlCl
AlCl
AlCl
AlCl
AlCl
CS
CH
2
–hexane
Cl –hexane
2
2
THF–hexane
Toluene–hexane
Toluene–hexane
Toluene–hexane
Toluene–hexane
Benzene
Toluene–hexane
Toluene–hexane
Toluene–hexane
Toluene–hexane
Toluene–hexane
Toluene–hexane
Toluene–hexane
Toluene–hexane
those of 1-substituted ones are attributed to the N-metallation of
e
15
1
b and 3d; the resulting aluminum amide will be in situ carbon-
ated to an aluminum carbamate, which resists further carboxyla-
tion and is decomposed to recover the substrate by aqueous
workup. Close scrutiny of the literature revealed that in 2000,
Okauchi et al. reported the acylation of indoles with the aid of dial-
AlCl
3
MeAlCl
2
7 (–:1)
Me
Me
Me
Me
Me
Me
Me
2
3
2
2
2
2
2
AlCl
Al
25 (7:1)
3 (50:1)
80 (1:–)
79 (1:–)
6 (10:1)
6 (8:1)
1
6
kylaluminum chlorides. They found that 1-substituted and 1-
unsubstituted indoles were efficiently acylated at the 3-position
AlCl
AlCl
AlCl
AlCl
AlCl
with various acyl chlorides in the presence of Me
while the use of a conventional Friedel–Crafts catalyst, AlCl
2
AlCl or Et
2
AlCl,
, for
e
3
52 (–:1)
the reaction of indole (1b) resulted in the decomposition and olig-
omerization of 1b. The successful use of dialkylaluminum chlorides
was attributed to their mild Lewis acidities and abilities to scav-
enge HCl liberated by the acylation. Later on, Huffman et al.
pointed out the intermediary of an indole-3-ylaluminum species
in the acylation, based on the observation that the treatment of
a
Reaction conditions: substrate (1.00 mmol), Lewis acid (1.0 mol equiv), solvent
3
(
1.0–2.2 cm ), CO
2
(3.0 MPa), room temp., 3 h.
b
Determined by 1H NMR analysis.
c
d
e
Me
Ph
Lewis acid (2.0 mol equiv) was employed.
3
SiCl (1.0 mol equiv) was added.
3
SiCl (1.0 mol equiv) was added.
1
D
-pentylindole with Me
2
AlCl, after quenching the mixture with
1
7
2
O, afforded 3-deuterio-1-pentylindole. Therefore, the present
1
-methylindole-3-carboxylic acid but the yield varied depending
observation is not the first example of the alumination of 1-substi-
tuted indoles with dialkylaluminum chlorides. However, it is
important to have shown the possibility that 1a is metallated un-
der CO2 atmosphere and in situ carbonated to give a carboxylic
acid. One may suspect that Me AlCl is carbonated with CO under
on the Lewis acid employed; Me
2
AlCl and Et
2
AlCl exhibited better
and AlBr , which are
Although the
carboxylation of arenes is promoted by the addition of trialkyl-
performances than stronger Lewis acids, AlCl
3
3
12a,b
indispensable for the carboxylation of arenes.
2
2
1
2c
or triarylhalosilanes,
such a beneficial effect could not be ob-
the reaction conditions. However, the treatment of Me AlCl with
2
served for 1a (entries 3 and 4, as compared with entry 2). The
employment of solvents other than benzene and toluene did not
improve the yield of the carboxylic acid (entries 11–14). We then
3.0 MPa CO2 in hexane at room temperature for 3 h gave, after
acidic workup, no acetic acid. In addition, by using the CO -pre-
2
treated Me AlCl, 1a could be carboxylated in 61% yield under the
2
prescribed Me
vent, respectively. The reaction of 2-substituted 1-methylindoles
a and 2b afforded the corresponding 3-carboxylic acids in good
yields, while the reaction of indole (1b) was sluggish even by using
.0 mol equiv of Me AlCl (entries 15–18). A similar exploration of
reaction conditions for 1-methylpyrrole (3a) again revealed that
the combination use of Me AlCl and toluene was most suitable
2
AlCl and toluene as a standard Lewis acid and sol-
conditions employed in entry 8 (Table 1). Therefore, the carbon-
ation of Me AlCl is negligible. Quite recently, Huffman et al. exam-
2
2
ined the acylation of 1-(p-toluenesulfonyl)pyrrole with acyl halides
1
8
in the presence of aluminum-based Lewis acids. They concluded
2
2
that when AlCl is used as a Lewis acid, the acylation proceeds via a
3
pyrrolylaluminum intermediate, while the reaction using weaker
2
Lewis acids, such as EtAlCl2 and Et AlCl, proceeds via the S Ar
2
E
for the carboxylation to take place, giving 1-methylpyrrole-2-car-
boxylic acid with good regioselectivity over the 3-carboxy isomer
mechanism. However, in order to fully elucidate the reaction
mechanisms of the present carboxylation of heteroaromatic com-
pounds, further experiments have to be done to know how much
(
entries 19–22). Under the conditions, 1-benzyl and 1-phenyl
derivatives 3b and 3c were exclusively converted into the corre-
sponding 2-carboxylic acids in high yields, while pyrrole (3d)
hardly gave the expected 2-carboxylic acid (entries 23–26). On
the other hand, the reaction of 1,2,5-trisubstituted pyrrole 4 took
place at the 3-position (entry 27).
acidity is required for a Lewis acid to activate CO to the extent that
2
the Lewis acid-CO complex can react with aromatic nuclei by the
2
SEAr mechanism.
Until recently, there have been only a few reports on the direct
1
9
9
metallation of indoles and pyrroles, other than lithiation. It has
been a hot and fascinating topic that the alkali metal-mediated
In order to shed light on the reaction mechanisms, the suscep-
tibility of compounds 1–3 toward metallation was tested. Each
2
0
20,21
22
23
magnesiation,
zincation,
alumination,
cupration,
and
2
4
compound was treated with an equimolar amount of Me
2
AlCl
cadmation of aromatic compounds, including indoles and pyr-
roles, have been achieved by using ate bases
2
0–24
(
1.0 M solution in hexane) under nitrogen at room temperature
or a neutral
2
1b
for 3 h. After quenched with D
2
O, the reaction mixture was ex-
and
base.
It should be noted that Me AlCl metalated 1-methylindole
2
tracted with CDCl
3
and the extract was dried over MgSO
4
(1a) at the 3-position (vide supra), while an ate base, i-Bu Al(TM-
3
1
22
was analyzed by H NMR spectroscopy. It was revealed that 1a
P)Li, metalates 1-(Boc)indole at the 2-position. Iwao and co-
was deuterated at the 3-position; the percentage of deuterated
workers reported that 1-(2,2-diethylbutanoyl)indole was lithiated
at the most acidic 2-position with a sterically undemanding super
1
a in the recovered one was 81%. Other 1-substituted indoles 2a

4
514
K. Nemoto et al. / Tetrahedron Letters 50 (2009) 4512–4514
base, sec-BuLi–tert-BuOK, while it was lithiated at the 3-position
10. Jones, G.; Stanforth, S. P. Org. React. 1997, 49, 1.
0
00
00
11. (a) Friedel, C.; Crafts, J. M. Compt. Rend. 1878, 86, 1368; (b) Olah, G. A.; Török,
B.; Joschek, J. P.; Bucsi, I.; Esteves, P. M.; Rasul, G.; Prakash, G. K. S. J. Am. Chem.
Soc. 2002, 124, 11379, and references cited therein; (c) Munshi, P.; Beckman, E.
J. Ind. Eng. Chem. Res. 2009, 48, 1059.
with bulky sec-BuLi–N,N,N ,N ,N -pentamethyldiethylenetriamide
9
a
(
PMDTA). It should also be noted that 1-phenylpyrrole (3c) was
selectively carboxylated at the 2-position, as regiocontrol in the
metallation of 1-arylpyrroles with organolithiums or ate bases
has been a troublesome problem.9
1
2. (a) Suzuki, Y.; Hattori, T.; Okuzawa, T.; Miyano, S. Chem. Lett. 2002, 102; (b)
Hattori, T.; Suzuki, Y.; Miyano, S. Chem. Lett. 2003, 32, 454; (c) Nemoto, K.;
Yoshida, H.; Suzuki, Y.; Morohashi, N.; Hattori, T. Chem. Lett. 2006, 35, 820.
b,21a
13. Typical procedure for the carboxylation (Table 1, entry 8): In a 50 cm3 autoclave
In conclusion, we have shown here that 1-substituted indoles
equipped with a glass inner tube and a magnetic stirring bar were charged
and pyrroles are directly carboxylated with CO
of dialkylaluminum chlorides, which provides an easy access to
-substituted indole-3-carboxylic acids and pyrrole-2-carboxylic
2
in the presence
3
compound 1a (131 mg, 1.00 mmol), toluene (1.0 cm ), and Me
2
AlCl (1.0 M
3
solution in hexane; 1.0 cm ) under nitrogen and the apparatus was purged
with CO by repeated pressurization and subsequent expansion, the final
1
2
pressure being adjusted to 3.0 MPa. After stirring the mixture at room
temperature for 3 h, the reactor was depressurized and the mixture was
quenched with 2 M HCl and extracted with chloroform. The organic layer was
acids. Further studies on the reaction mechanisms are underway.
Acknowledgments
extracted with 0.5 M Na CO3 and the extract was acidified with conc. HCl to
2
liberate the free acid, which was extracted with chloroform. The extract was
dried over MgSO
4
and evaporated to leave a residue, which was purified by TLC
developer to give 1-
This study was supported in part by a Grant-in-Aid for Scientific
Research on a Priority Area ‘Advanced Molecular Transformations
of Carbon Resources’ from the Ministry of Education, Culture,
Sports, Science and Technology, Japan.
(
silica gel) with diethyl ether–hexane (1:1) as
a
14
methylindole-3-carboxylic acid (149 mg, 85%). The exclusive formation of
the 3-carboxylic acid was confirmed by the 1H NMR analysis of the residue left
by the evaporation of the chloroform extract.
1
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5. Konishi, K.; Aida, T.; Inoue, S. J. Org. Chem. 1990, 55, 816.
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