Regioselective Friedel-Crafts acylation of indoles catalysed by zinc oxide in an ionic liquid

Article abstract of DOI:10.3184/174751912X13460004925054

A facile method for the regioselective Friedel-Crafts acylation of indoles with acyl chlorides catalysed by zinc oxide in an ionic liquid medium has been developed. The corresponding 3-acylindoles were obtained in good to high yields under mild reaction conditions. Zinc oxide, which is easily available and requires no special handling procedures, is an efficient catalyst for acylation of indoles.

Full text of DOI:10.3184/174751912X13460004925054

600 RESEARCH PAPER
OCTOBER, 600–602
JOURNAL OF CHEMICAL RESEARCH 2012
Regioselective Friedel–Crafts acylation of indoles catalysed by zinc oxide
in an ionic liquid
Li-Rong Zhang, Feng-Ping Yi*, Jian-Zhong Zou, Xuan Zhang and Zhen Wang
School of Perfume and AromaTechnology, Shanghai Institute ofTechnology, Shanghai 201418, P. R. China
A facile method for the regioselective Friedel–Crafts acylation of indoles with acyl chlorides catalysed by zinc oxide
in an ionic liquid medium has been developed. The corresponding 3-acylindoles were obtained in good to high yields
under mild reaction conditions. Zinc oxide, which is easily available and requires no special handling procedures, is
an efficient catalyst for acylation of indoles.
Keywords: Friedel–Crafts acylation, indole, zinc oxide, ionic liquid
The indole moiety is present in a range of pharmaceutical
materials and the synthesis of 3-acylindoles has gained consid-
erable attention. 3-Substituted indoles are not only significant
therapeutic agents but are used also as synthetic intermediates
in alkaloid synthesis.1,2 Various synthetic methods are reported
in the literature to prepare 3-substituted indoles.3–16 A common
method to prepare 3-acylindoles is Friedel–Crafts reaction
under acidic conditions, which always results in side reactions
as a result of the high nucleophilic nature of indole.7–10 Hence,
several efforts have been made to reduce this competing side
reactions.10–12 Also, the development of suitable catalysts for
the facile synthesis of 3-acylindoles without NH-protection
has attracted much attention. Lewis acids such as alkylalumin-
ium chlorides,8,9 imidazolium chloroaluminate,6 SnCl47 as well
as ZrCl413 have been reported as the promoters. In addition,
many studies have been carried out to achieve the goal of
making the Lewis acid role catalytic in the Friedel–Crafts acyl-
ation. Solid acids, such as zeolites, metal oxides, acid treated
metal oxides, clays and heteropoly acids have been utilised as
catalysts for hydrocarbon reactions.17 Metal oxides promoting
aromatic Friedel–Crafts acylation have been known.18,19
We speculated that they could play the required role and be
beneficial in the selective acylation of indole.
Additionally, some of the earliest examples of catalytic
reactions performed at room temperature in ionic liquids were
Friedel–Crafts reactions.20 Vaultier and coworkers reported
that the activity of bismuth(III) derivatives employed as
Freidel–Crafts catalysts for the acylation of aromatics was
found to increase dramatically when dissolved in an ionic
liquid.21 The acylation of indoles in ionic liquid medium was
first reported by Yeung.6 Recently, Hajra developed the direct
alkenylation of indoles at the 3-position with 1,3-dicarbonyl
compounds under Brønsted acidic conditions with ionic liquid
catalysis.22 Here, we report the regioselective Friedel–Crafts
acylation of indole without NH-protection with acyl chlorides
catalysed by ZnO, which is easily available and requires no
special treatment, in the presence of ionic liquid.
(Table 1, entries 10–14). Moreover, an ionic liquid with a
hydrophilic anion such as tetrafluoborate led to a poor acyla-
tion yield (Table 1, entry 10). As a result, [BMIM][PF6] was
found to be the best to favour the Friedel–Crafts acylation. The
presence of ZnO is needed for acylation, as the reaction did not
proceed without it (Table 1, entry 15). Therefore, the catalytic
system of ZnO in [BMIM][PF6] has been developed to be the
Table 1 Screening of catalysts, solvents and addition orders
for Friedel–Crafts acylation of indolea
Entry
Catalyst/mol%
Solvent
Time/h Yield/%b
1
2
ZrCl4 (50)
BiCl3 (50)
ZnCl2 (50)
SiO2 (50)
ZnO (50)
ZrO2 (50)
SnO2 (50)
In2O3 (50)
Fe2O3 (50)
ZnO (50)
ZnO (50)
ZnO (50)
ZnO (50)
ZnO (50)
none (50)
ZnO (50)
ZnO (50)
ZnO (30)
ZnO (70)
ZnO (100)
ZnO (50)
ZnO (50)
ZnO (50)
ZnO (50)
Neat
Neat
5
35
20
22
0
6
3
Neat
5.5
24
4
7
7
4
Neat
5
Neat
39
18
15
12
20
21
40
33
62
42
0
20
41
43
69
63
52
49
75
78
6
Neat
7
Neat
8
Neat
12
8
9
Neat
10
11
12
13
14
15
16c
17d
18
19
20
21e
22f
23g
24h
[BMIM][BF4]
DCM
4
4
DMF
[BMIM][PF6]
DCE
4
3.5
4
24
6
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
[BMIM][PF6]
4
3.5
3.5
3.5
3.5
3.5
3.5
8
Results and discussion
The screening of the catalysts was conducted using indole (1a)
and benzoyl chloride (2a) as a model reaction. The results are
summarised in Table 1, entries 1–9. Among the catalysts exam-
ined including conventional Lewis acid and metal oxides, ZnO
demonstrated the greatest activity of the catalysts tested in the
Friedel–Crafts acylation of indole, in terms of reaction rate and
isolated yield. Modification of conditions from neat to solution
phase enhanced the desired acylation. Thus, in [BMIM][PF6],
3-acylation indole was obtained in good yield within 3.5 h. In
contrast, in a conventional organic solvent such as DCM, DMF
and DCE, lower conversions and reaction rates were obtained
a Reaction conditions: indole (2 mmol), benzoyl chloride
(1.5 mmol), catalyst (1 mmol), solvent (1 mL), reaction temper-
ature: 15 °C. Addition order: indole was added to the reaction
mixture containing benzoyl chloride and catalyst.
b Isolated yield.
c Addition order: benzoyl chloride was added to the reaction
mixture containing indole and ZnO.
d Addition order: ZnO was added to the reaction mixture
containing indole and benzoyl chloride.
e Reaction temperature is 0 °C.
f Reaction temperature is 40 °C.
g Mole ratio of indole and acyl chloride =1:1.3.
h Scale up reaction: Indole (16mmol), benzoyl chloride (21 mmol),
catalyst (8 mmol), solvent (15 mL).
* Correspondent. E-mail: yifengping@sit.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2012 601
efficient choice for the 3-acylation of indole. During our
attempts to obtain 3-acylated indoles, we found that the
addition order of reactant played a significant effect under the
conditions described here. When ZnO and benzoyl chloride
(2a) were added to the solvent and stirred, a homogeneous
system was observed. As soon as the indole was added, a
strong colour change occurred. However, other orders of addi-
tion did not provide a homogeneous system which might be
responsible for the relatively low yields (Table 1, entries 16
and 17).
The effect of the amount of catalyst and the reaction
temperature on the yield of the corresponding acylated product
was analysed. Thus far, 50 mol% ZnO had been used to
catalyse the acylation of indole. Indeed, the catalyst concentra-
tions had a major influence on the observed yield. In our
optimised protocol, 50 mol% ZnO was found to be necessary.
An increasing amount of catalyst did not improve the yields,
while further reducing the amount of added catalyst to
30 mol% decreased the yield significantly (Table 1, entries
18–20). Furthermore, the results shown in Table 1 (entries 13,
21 and 22) indicated that the acylation of indole catalysed
by ZnO in an ionic liquid depended strongly on the reaction
temperature used. The reaction proceeding at 15 °C favoured
the desired acylation. A variation in the number of equivalents
of reactants (Table 1, entry 23) revealed that the optimum con-
ditions were 1 equiv. of indole and 1.3 equiv. of acyl chloride.
Moreover, the reaction was carried out on a gram scale and a
satisfactory yield was afforded (Table 1, entry 24) suggesting
that this method can be scaled up.
To demonstrate the generality of this method, we explored
the scope of the optimised Friedel–Crafts acylation protocol
and the results are summarised in Table 2. We found that a
wide range of aroyl and alkanoyl chlorides underwent smooth
acylation with various indoles without NH protection and
produced diverse 3-acylindoles in good to high yields. As it
can be seen, the electron-deficient indoles such as 5-cyano
indole provided the high yield under the reaction conditions
presented (Table 2, entry 3). Particularly, the methoxy substi-
tuted indole, which is known for its susceptibility toward
oligometisations, was found to afford the product in good yield
within 6 h for complete conversion with no polymerised or
dimerised side products (Table 2, entry 5).Additionally, it
should be noted that acylation of indole with acid anhydride
as acylating agent does not occur (Table 2, entry 7). Probably,
the true catalyst was zinc chloride which was generated in situ
from zinc oxide and the acyl chloride. Pivaloyl chloride,
which is susceptible to decarbonylative alkylation, underwent
acylation with indole smoothly in the protocol to afford the
desired product in satisfactory yield (Table 2, entry 10). The
results obtained in this work were good to satisfactory and
the reaction route was effective, clean and fast.
In summary, we have developed the first ZnO-promoted
Friedel–Crafts acylation of the C3 position of indoles in the
presence of an ionic liquid under mild reaction conditions.
Compared with other reported methods, the catalyst ZnO used
in this work was easily available, low cost and required no
special treatment. This protocol can be employed in the syn-
thesis of a wide range of 3-acylindoles without NH protection.
Further studies on applications of the system to other impor-
tant reactions are underway in our laboratory.
Experimental
Chemical and solvents were obtained from commercial suppliers and
used without further purification. The NMR spectra were recorded on
1
a BRUKER Advance III (500 MHz for H) in deuterio chloroform
(CDCl3) at room temperature. The chemical shift values are given in
ppm and tetramethylsilane was used as an internal standard.
A representative experimental procedure for the synthesis of 3-ben-
zolylindole was as follows. To the ZnO (1 mmol, 81.4 mg) was added
benzoyl chloride (364 mg, 2.6mmol) by a syringe at room temperature
under nitrogen, then indole (2 mmol, 234 mg) was added under a flow
of nitrogen. After completion of the reaction as indicated by TLC, the
resultant mixture was quenched with water (10 mL) and extracted
with ethyl acetate (3 × 10 mL). The combined organic layer was
washed with water (10 mL), dried with anhydrous Na2SO4, and con-
centrated in vacuo. The column chromatographic purification of the
crude mass on silica gel eluting with EtOAc-petroleum ether provided
the desired product.
All acylation reactions were carried out following this representa-
tive procedure and the product purity was verified by melting point
and proton NMR by comparison with the literature data.
1H-Indol-3-yl-phenylmethanone (3): White solid; m.p. 243–245 °C
(lit.13 243–245 °C);1H NMR (CDCl3, 500 MHz): δ 8.26 (d, J = 7.5 Hz,
1H), 7.93 (s, 1H), 7.79 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 6.5 Hz, 1H),
7.55 (t, J = 7.5 Hz, 3H), 7.27–7.25 (m, 2H).
1-Methyl-1H-indol-3-yl-phenylmethanone (4): White solid; m.p.
116–119 °C (lit.13 116–118 °C); 1H NMR (CDCl3, 500 MHz): δ 8.46–
8.45 (m, 1H),7.77 (d, J = 7.0 Hz, 2H), 7.52––7.48 (s, 1H), 7.45–7.41
(m, 3H),7.32–7.29 (m, 3H), 3.88 (s, 3H).
(1H-Indol-3-yl)-(4-nitro-phenyl)-methanone (5):8 White solid; m.p.
234–236 °C (lit. 235–236 °C); 1H NMR (CDCl3, 500 MHz): δ 8.50 (s,
1H), 8.21 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H),
7.52 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz,
1H), 7.21 (t, J = 6.5 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H).
Table 2 Friedel–Crafts 3-acylation of various indoles with acyl
chloridesa
(2-Methyl-1H-indol-3-yl)-phenyl-methanone (6): White solid; m.p.
138–141 °C (lit.13 139–141 °C); 1H NMR (CDCl3, 500 MHz): δ 8.48
(s, 1H), 7.78 (d, J = 7.2 Hz,2H), 7.56 (t, J = 7.6 Hz, 2H), 7.40 (d,
J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz,1H), 7.20 (t, J = 8.0 Hz, 1H), 7.09
(t, J = 8.0 Hz, 1H), 2.59 (s, 3H).
(5-Methoxy-1H-indol-3-yl)-phenyl-methanone (7): White solid;
m.p. 223–225 °C (lit.6 224–226 °C);1H NMR (CDCl3, 500 MHz): δ
8.47 (d, J = 6.0 Hz, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.58–7.63 (s, 1H),
7.46–7.51 (m, 2H), 7.28 (t, J = 6.5 Hz, 3H), 3.88 (s, 3H).
Entry
R1
R2
R3
Time /h Yield/%b
1
2
H
CH3
H
H
H
C6H5
C6H5
3.5
3
3, 75
4, 83
5, 88
6, 79
7, 67
8, 80
8, 0
9, 72
10, 87
11, 89
12, 76
1-(1H-Indol-3-yl)ethanone (8): White solid; m.p. 188–192 °C (lit.13
189–191 °C); 1H NMR (CDCl3, 500 MHz): δ 8.22 (d, J = 7.0 Hz, 1H),
8.13 (s, 1H),7.45 (d, J = 7.0 Hz, 1H), 7.23–7.20 (m, 2H), 2.58 (s,
3H).
3
5-CN
2-CH3
5-OMe
H
H
H
2-CH3
H
2-CH3
C6H5
3
4
H
C6H5
3
5
H
C6H5
6
6
H
CH3
3
4-Chlorophenyl(1H-indol-3-yl)methanone (9): Yellowish white
solid; m.p. 240–242 °C (lit.13 241–244 °C);1H NMR (CDCl3, 500 MHz):
δ 8.24 (d, J = 7.5 Hz, 1H), 7.96 (s, 1H), 7.81 (d, J = 7.5 Hz, 2H), 7.60
(d, J = 7.5 Hz, 2H),7.54 (d, J = 7.0 Hz, 1H), 7.33–7.23 (m, 2H).
(2-Methyl-1H-Indol-3-yl)-2,2-dimethylpropan-1-one (10): White
solid; m.p. 166–168 °C (lit.13 165–169 °C); 1H NMR (CDCl3, 500 MHz):
δ 8.82 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.25 (d, J = 7.5 Hz, 1H),
7.14–7.20 (m, 2H), 2.46 (s, 3H), 1.30 (s, 9H).
7
H
(CH3CO)O(COCH3)
4-ClC6H5
(CH3)3C
(CH3)3C
4-ClC6H5
24
4
8
H
9
H
3
10
11
H
3
4
H
a Reaction conditions: indole (2 mmol), acyl chloride (2.6 mmol),
ZnO (1 mmol), [BMIM][PF6] (1 mL).
b Isolated yield.

602 JOURNAL OF CHEMICAL RESEARCH 2012
3
4
5
6
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1-(1H-Indol-3-yl)-2,2-dimethylpropan-1-one (11): White solid;
m.p. 160–162 °C (lit.13 161–163 °C); 1H NMR (CDCl3, 500 MHz): δ
8.52 (d, J = 7.5 Hz, 1H), 7.99 (s, 1H), 7.42 (d, J = 7.5 Hz, 1H),
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2H), 7.34–7.36 (m, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.10 (t, J = 7.5 Hz,
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We thank the Shanghai Education Committee Foundation
11ZZ180, Science Foundation YJ2012-29 of Shanghai Insti-
tute of Technology and the Program of Local Colleges Ability
Building of Science and Technology Commission of Shanghai
Municipality No. 11520502600 for financial support.
Received 5 July 2012; accepted 14 August 2012
Paper 1201389 doi: 10.3184/174751912X13460004925054
Published online: 28 September 2012
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