Friedel-Crafts acylation of indoles in acidic imidazolium chloroaluminate ionic liquid at room temperature

Article abstract of DOI:10.1016/S0040-4039(02)01185-1

A practical and convenient protocol has been developed for the acidic 1-ethyl-3-methylimidazolium chloroaluminate ionic liquid (generated from 1-ethyl-3-methylimidazolium chloride (EmimCl) and aluminium chloride (X(AlCl₃), mole fraction X=0.67-0.75) promoted Friedel-Crafts acylation of indoles at room temperature. The simple experimental procedure provides 3-substituted indoles in good to high yields with less electron rich indole ring systems.

Full text of DOI:10.1016/S0040-4039(02)01185-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5793–5795
Friedel–Crafts acylation of indoles in acidic imidazolium
chloroaluminate ionic liquid at room temperature
Kap-Sun Yeung,* Michelle E. Farkas, Zhilei Qiu and Zhong Yang
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, PO Box 5100, Wallingford, CT 06492, USA
Received 29 May 2002; revised 15 June 2002; accepted 18 June 2002
Abstract—A practical and convenient protocol has been developed for the acidic 1-ethyl-3-methylimidazolium chloroaluminate
ionic liquid (generated from 1-ethyl-3-methylimidazolium chloride (EmimCl) and aluminium chloride (X(AlCl3), mole fraction
X=0.67–0.75) promoted Friedel–Crafts acylation of indoles at room temperature. The simple experimental procedure provides
3-substituted indoles in good to high yields with less electron rich indole ring systems. © 2002 Elsevier Science Ltd. All rights
reserved.
Substituted indoles are drug fragments commonly
found in molecules of pharmaceutical interest in a
variety of therapeutic areas.1 Interesting examples
include the analgesic, Pravodoline (1), and the
antiemetic, Ramosetron (2) (Fig. 1).
observed. Useful and diverse functional groups, e.g.
halogens, carbonyl, anisole, furan, CN and NO2, were
well tolerated under these strongly acidic conditions.
The regiochemistry was confirmed by correlation with
known products (36a and 116c).5b
In our laboratories, we were interested in the synthesis
of drug-like molecules that contained substituted
indoles and which were most accessible via an acylation
at the C3 position of N-unprotected indoles as the
pivotal step. The sporadic efficiency of standard meth-
ods we encountered in our reactions led us to become
intrigued by the possibility of applying the strongly
acidic imidazolium chloroaluminate ionic liquid2 gener-
ated from 1-ethyl-3-methylimidazolium chloride
(EmimCl) and aluminum chloride (X(AlCl3), mole frac-
tion X2a,3=0.67–0.75, Fig. 2) to promote the Friedel–
Crafts3,4 type acylation on N-unprotected indoles.4a
The use of imidazolium chloroaluminate in organic
synthesis represents an underexplored area. To date,
examples of useful and practical reactions mediated by
EmimCl-X(AlCl3) that can be conveniently carried out
on laboratory scale are still rare.2
OMe
O
O
N
N
H
N
N
N
O
Ramosetron (2)
Pravadoline (1)
Figure 1.
To the best of our knowledge, the preparation of
products 4 to 10 has not been reported in the literature
before. These conditions frequently offer advantages
over existing methods. For example, 3-acetyl-4-nitroin-
dole (3), a useful intermediate for the synthesis of
indole alkaloid natural products,6a was previously syn-
thesized only by non-regioselective nitration of 3-
acetylindole in poor yields (2%,6b 20%6a). The use of
poisonous carbon disulfide and excessive AlCl3 can also
We explored representative examples (Table 1) of the
acidic
imidazolium
chloroaluminate-promoted
acylation reaction (Scheme 1) of substituted N-unpro-
tected indoles with acid chlorides. Good to high yields
were obtained5a and no side products of over acylation
+
Cl
XAlCl3
X = 0.67-0.75
+
N
N
Keywords: indole; acylation; imidazolium chloroaluminate; ionic liq-
uid.
EmimCl
* Corresponding author. Fax: +1 203 6777072; e-mail: kapsun.yeung@
bms.com
Figure 2.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01185-1

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K.-S. Yeung et al. / Tetrahedron Letters 43 (2002) 5793–5795
Table 1. Examples of products and their yields obtained
from the EmimCl-X(AlCl3) promoted acylation of indoles
O
R
EmimCl-X(AlCl3)
O
r.t.
+
Cl
Rn
Rn
R
N
H
N
H
3 to 12
Scheme 1.
be avoided in the preparation of 3-acetyl-7-azaindole
(11).6c The products, including the very polar glyoxylic
acid derivative 12, usually precipitated in high purity
from the reaction mixture after the aqueous quench.
Compound 12 was prepared using ethyl chlorooxoac-
etate as the acylating agent and was directly isolated as
the acid from the reaction mixture. The formation of
the ester was observed by LC/MS, but this was con-
verted to the acid on extended reaction time. It has not
been determined if the ester hydrolysis is due to the
strongly acidic medium itself, or a result of adventitious
moisture present in the reaction mixture2a or a combi-
nation of both. In practice, this is useful if subsequent
ester hydrolysis is required for synthesis.7 A minimum
of 2 equiv. of EmimCl was required to provide suffi-
cient volume to take up the starting material for a
reaction conducted on a reasonable scale,8 although we
believed that equimolar amount of [EmimCl-X(AlCl3)]
sufficed to promote the reaction.
For reactions of relatively less reactive acid chlorides,
e.g. pivaloyl chloride 14 (Scheme 2), or electron rich
indoles, e.g. 15, Mannich-type indole dimerization9 was
the predominant reaction pathway that gave rise to a
mixture of the dimeric isomers 17 and 18 in different
ratios.10
A general experimental procedure is as follows:11 To
EmimCl (2 equiv.; purchased from TCI; weighed under
a stream of nitrogen) stirred in an oven-dried round
bottom flask at ambient temperature under a nitrogen
atmosphere, was added AlCl3 (4 equiv., X=0.67;
weighed under a stream of nitrogen). Anhydrous pow-
der of AlCl3 packaged under argon in ampules (pur-
chased from Aldrich) was preferred. For more electron
deficient indole ring systems, 6 equiv. of AlCl3 (X=
0.75) would be necessary. The mixture was vigorously
stirred to form a liquid. After all the heat generated
from mixing was dissipated, indole (1 equiv.) was added
O
O
MeO
or
+
Cl
+
N
H
Cl
N
H
Cl
13
14
15
16
EmimCl-X(AlCl3)
r.t.
Rn
Rn
Rn
Rn
N
H
N
H
HN
N
H
17
18
Scheme 2.

K.-S. Yeung et al. / Tetrahedron Letters 43 (2002) 5793–5795
5795
to the ionic liquid and the reaction mixture stirred until
a homogenous mixture resulted. Acid chloride (2
equiv.) was added and the reaction mixture stirred at
ambient temperature.12 The progress of the reaction
was monitored by TLC or LC/MS, and typical reaction
times were 1 to 18 h. After completion, the mixture was
cooled in an ice-water bath and the reaction mixture
quenched by carefully adding excess ice water. The
precipitates formed were filtered and washed with
water. Alternatively, after quenching, the mixture was
extracted with an organic solvent and the extracts
evaporated in vacuo. Crude product of lesser purity
was further purified by chromatography or
recrystallization.
4. (a) An example of Friedel–Crafts acylation of N,C2-
dialkyl-substituted indole using [EmimCl-XAlCl3] has
been reported: Earle, M. J.; McCormac, P. B.; Seddon,
K. R. Green Chem. 2000, 2, 261. For other Friedel–Crafts
reactions using [EmimCl-XAlCl3], see: (b) Surette, J. K.
D.; Green, L.; Singer, R. D. Chem. Commun. 1996, 27,
53; (c) Adams, C. J.; Earle, M. J.; Roberts, G.; Seddon,
K. R. Chem. Commun. 1998, 2097; (d) R. Y. Saleh, WO
0015594, 2000.
5. (a) Products were analytically pure and their yields
obtained after purification by column chromatography or
recrystallization. Further purification of products 3 and
1
11 was not required; (b) product 3 H NMR: (acetone-d6)
l 11.52 (b s, 1H), 8.43 (d, J=3.1, 1H,), 7.85 (dd, J=8.1,
0.6, 1H), 7.60 (dd, J=7.7, 0.6, 1H), 7.42 (appeared as t,
1
In summary, a practical and convenient protocol has
been developed for the Friedel–Crafts-type acylation of
the C3 position of indoles that is promoted by acidic
imidazolium chloroaluminate ionic liquid at room tem-
perature. This reaction appears to be much general for
less electron rich indole ring systems. It can be applied
to the synthesis of multiple-point pharmacophores of
indoles substituted at different positions with versatile
functionalities (e.g. Br, CN, NO2, CO2H, CꢀO, enoliz-
able a-protons, anisole and furan), which can lead to
unlimited chemical diversity.
J=7.9, 1H), 2.48 (s, 3H); product 11 H NMR: (DMSO-
d6) l 12.45 (b s, 1H), 8.459 (d overlapping with dd,
J=3.1, 1H), 8.458 (dd, J=7.9, 1.6, 1H), 8.31 (dd, J=4.7,
1.6, 1H), 7.23 (dd, J=7.9, 4.7, 1H), 2.46 (s, 3H).
6. (a) Murase, M.; Koike, T.; Moriya, Y.; Tobinaga, S.
Chem. Pharm. Bull. 1987, 35, 2656; (b) Noland, W. E.;
Rush, K. R. J. Org. Chem. 1966, 31, 70; (c) Galvez, C.;
Viladoms, P. J. Heterocyclic Chem. 1982, 19, 665.
7. The application of this one-pot acylation/ester hydrolysis
procedure in synthesis will be reported in due time.
8. Typical reaction scale was about 2–4 mmol of indole, and
the largest scale performed was about 45 mmol (ꢀ10 g)
of indole.
9. For related dimerization of 3-substituted indoles induced
by protic acids, see: (a) Smith, G. F.; Walters, A. E. J.
Chem. Soc. 1961, 940; (b) Hashizume, K.; Shimonishi, Y.
Bull. Chem. Soc. Jpn. 1981, 54, 3806; (c) it is known that
acylation of indoles using strong Lewis acids can some-
times be complicated by undesirable oligomerization:
Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh,
K.; Yoshino, H. Org. Lett. 2000, 2, 1485 and (d) Ottoni,
O.; Neder, A. de V. F.; Dias, A. K. B.; Cruz, R. P. A.;
Aquino, L. B. Org. Lett. 2001, 3, 1005.
Acknowledgements
We thank Dr. Nicholas A. Meanwell and Dr. John F.
Kadow for valuable comments on the manuscript, and
Dr. Alicia Regueiro-Ren for interesting discussions.
References
10. The dimeric structure was supported by NMR and MS
studies. The imidazolium chloroaluminate-promoted
indole dimerization will be the subject of further investi-
gations.
11. AlCl3, EmimCl and all reagents were used as received
from commercial sources. The use of a glove box was not
necessary.
1. USP Dictionary, 2001 edition.
2. For general reviews on ionic liquids, see: (a) Welton, T.
Chem. Rev. 1999, 99, 2071; (b) Wasserscheid, P.; Keim,
W. Angew. Chem., Int. Ed. 2000, 39, 3772; (c) Sheldon, R.
Chem. Commun. 2001, 2399; (d) various chloroaluminate
species (AlCl4−, Al2Cl7−, Al3Cl10−) are present in the
acidic ionic liquid, see (a) for details.
12. The reaction mixture often became very viscous after all
the reagents were well mixed.
3. Boon, J. A.; Levisky, J. A.; Pflug, J. L.; Wilkes, J. S. J.
Org. Chem. 1986, 51, 480.