A simple, effective, green method for the regioselective 3-acylation of unprotected indoles

Article abstract of DOI:10.3390/molecules201019605

A fast and green method is developed for regioselective acylation of indoles in the 3-position without the need for protection of the NH position. The method is based on Friedel-Crafts acylation using acid anhydrides. The method has been optimized, and Y(OTf)₃ in catalytic amounts is found to be the best catalyst together with the commercially available ionic liquid [BMI]BF₄ (1-butyl-3-methylimidazolium tetrafluoro-borate) as solvent. The reaction is completed in a very short time using monomode microwave irradiation. The catalyst can be reused up to four times without significant loss of activity. A range of substituted indoles are investigated as substrates, and thirteen new compounds have been synthesized.

Full text of DOI:10.3390/molecules201019605

Molecules 2015, 20, 19605-19619; doi:10.3390/molecules201019605
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
A Simple, Effective, Green Method for the Regioselective
3-Acylation of Unprotected Indoles
Phuong Hoang Tran 1, Hai Ngoc Tran 1, Poul Erik Hansen 2,*, Mai Hoang Ngoc Do 1
and Thach Ngoc Le 1
1
Department of Organic Chemistry, Faculty of Chemistry, University of Science,
Vietnam National University, Ho Chi Minh City 70000, Vietnam;
E-Mails: thphuong15@yahoo.com (P.H.T.); sidoantruong@gmail.com (H.N.T.);
dhnmai@gmail.com (M.H.N.D.); lenthach@yahoo.com (T.N.L.)
2
Department of Science, Systems and Models, Roskilde University, POB 260,
Roskilde DK-4000, Denmark
* Author to whom correspondence should be addressed; E-Mail: Poulerik@ruc.dk;
Tel.: +45-46-742-432.
Academic Editor: Jason P. Hallett
Received: 5 October 2015 / Accepted: 22 October 2015 / Published: 27 October 2015
Abstract: A fast and green method is developed for regioselective acylation of indoles in
the 3-position without the need for protection of the NH position. The method is based on
Friedel-Crafts acylation using acid anhydrides. The method has been optimized, and Y(OTf)3
in catalytic amounts is found to be the best catalyst together with the commercially available
ionic liquid [BMI]BF4 (1-butyl-3-methylimidazolium tetrafluoro-borate) as solvent. The reaction
is completed in a very short time using monomode microwave irradiation. The catalyst can
be reused up to four times without significant loss of activity. A range of substituted indoles
are investigated as substrates, and thirteen new compounds have been synthesized.
Keywords: Friedel-Crafts acylation; indole derivatives; ionic liquids; metal triflate;
microwave irradiation

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1. Introduction
3-Acylindoles are useful intermediates in the synthesis of various pharmaceuticals [1–4].
Regioselectivity in the 3-acylation of indoles has been an interesting and challenging subject in organic
synthesis. A wide range of 3-acylindoles was synthesized by several methods such as Friedel-Crafts
acylation [5–12], Vilsmeier-Haack type reaction [4,13], α-aminocarbonyl compounds with palladium [14],
carbamoyl electrophiles [2], α-oxocarboxylic acids [15–17], and nitrilium salt with palladium [18].
Among those, Friedel-Crafts acylation of free (NH) indoles is definitely the simplest way [19], however,
low yields were observed due to competing substitution at the 1-position. Therefore, N-acylated and
1,3-diacylated products were obtained, or indole polymerization may occur in the Friedel-Crafts acylation.
To reduce these side products, NH-protection was necessary [8,20]. The protection-deprotection steps are
not green and convenient methods [21]. Besides, traditional Lewis acid-catalyzed Friedel-Crafts acylation
must be carried out under strictly anhydrous conditions and requires a greater than stoichiometric amount
of Lewis acid [22]. Aluminum trichloride, a well-known Lewis acid commonly used in Friedel-Crafts
acylations requires a complicated work-up process and causes environmental problems [22]. The
development of alternative Lewis acid-catalyzed 3-acylations of indoles has been studied intensively [19].
Among these alternative Lewis acid catalysts, metal triflates were a good option in various organic
reactions [19]. In comparison to traditional Lewis acids, metal triflate-catalysed Friedel-Crafts acylation
does not require strictly anhydrous conditions due to their water-tolerant characteristics [23]. Besides,
only 1–5 mole % of metal triflate is sufficient for complete conversion [23]. Furthermore, this can easily
be recovered after workup.
Although metal triflates have been applied extensively in Friedel-Crafts acylation of aromatic
compounds [24–28], there has been only one report on the use of indium triflate for the acylation of
indoles [29]. However, in that case, excess reagent and NH-protection were required to obtain 3-acylated
indoles in good yields. Recently, metal triflates dissolved in ionic liquids were found to be a good
catalytic system in Friedel-Crafts acylations [30]. The Friedel-Crafts acylation using metal triflate in
ionic liquids has been shown to increase the yield with high regioselectivity and to simplify the recovery
of the catalyst [31–37].
Microwave-mediated organic synthesis provides a useful method due to specific interactions
and energy efficiency. Microwave irradiation has allowed the design of efficient processes with
significant improvements of yield and selectivity in a short reaction time and simplification of product
purification [38].
We report here the development of a new method for the Friedel-Crafts 3-acylation of indoles with
various acid anhydrides using metal triflates in ionic liquids under microwave activation. In this paper,
we are especially interested in rare-earth metal triflates due to their high catalytic activity and imidazolium
ionic liquids because they are commercially available.
2. Results and Discussion
The first step was to find the best catalyst from among fourteen metal triflates, including ten rare-earth
metal triflates and four well-known triflates such as bismuth triflate, indium triflate, copper triflate and
yttrium triflate. The acylation of indole with propionic anhydride was chosen as the model reaction.

Molecules 2015, 20
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Indole was treated with 1 mol % of metal triflate in the presence of 1 equiv. of propionic anhydride
under microwave irradiation at 120 °C for 5 min. The results are presented in Table 1. Among these
triflates, yttrium triflate showed the best catalytic activity for Friedel-Crafts 3-propionylation of indole.
Rare-earth metal triflates were also efficient (73%–81%), while bismuth and praseodynium triflates are
demonstrated to be less reactive than the others. Interestingly, direct Friedel-Crafts 3-propionylation of
indole gave the desired 3-propionylindole without formation of dipropionylated product and polymers,
and less than 5% of N-propionylated product was found in all cases (with the exception of bismuth triflate,
with 9% N-propionylindole). Yttrium triflate showed the highest yield and exhibited stronger catalytic
activity than the other metal triflates. This metal triflate has been studied extensively in organic synthesis
in general [39–48].
Table 1. Effect of metal triflates on Friedel-Crafts propionylation of indoles under
microwave irradiation.
0
1
Metal Triflate Isolated Yield (%) Selective Position (1-/2-/3-)
Cu(OTf)2
Y(OTf)3
74
84
80
70
81
79
70
74
73
76
76
78
75
80
5/0/95
3/0/97
4/0/96
9/0/91
4/0/96
4/0/96
4/0/96
5/0/95
4/0/96
5/0/95
4/0/96
4/0/96
4/0/96
4/0/96
2
3
In(OTf)3
Bi(OTf)3
La(OTf)3
Ce(OTf)3
Pr(OTf)3
Nd(OTf)3
Eu(OTf)3
Gd(OTf)3
Tb(OTf)3
Dy(OTf)3
Ho(OTf)3
Tm(OTf)3
4
5
6
7
8
9
10
11
12
13
14
Next, we tested the effect of solvents on Friedel-Crafts propionylation of indole. The aim of this test
was to find the solvent leading to the highest yield with maximum formation of only 3-propionylindole.
Eighteen solvents, including traditional organic solvents and commercially available ionic liquids, were
investigated. The results are listed in Table 2. The ionic liquid [BMI]BF4 was found to be the most
effective for Friedel-Crafts propionylation of indole in excellent yield with high regioselectivity, and in
this case N-propionylation was completely absent. The result indicates that the presence of [BMI]BF4
enhances the catalytic activity of yttrium triflate. Friedel-Crafts acylation using metal triflates in ionic
liquids has recently attracted attention [31–37,49]. However, this is the first time that tis catalytic
system was applied in the Friedel-Crafts acylation of indoles.

Molecules 2015, 20
Table 2. Effect of solvents under microwave irradiation (80 °C, 5 min) a.
19608
Entry
1
Solvent
n-hexane
Yield b (%) Selective Position (1-/2-/3-) c
20
50
27
63
50
63
34
22
44
68
0
5/0/95
9/0/91
0/0/100
3/0/97
4/0/96
3/0/97
10/0/90
0/0/100
37/0/63
2/0/100
-
2
cyclopentyl methyl ether
tert-butyl methyl ether
dioxane
3
4
5
tetrahydrofuran
ethyl acetate
chloroform
6
7
8
dichloromethane
acetone
9
10
11
12
13
14
15
16
17
18
acetonitrile
methanol
dimethyl carbonate
[BMI]BF4
57
92
66
70
43
68
74
3/0/97
0/0/100
5/0/95
3/0/97
22/0/78
6/0/94
4/0/96
[BMI]Cl
[BMI]PF6
[BMI]SCN
[BPy]OTf
[EMI]Cl
a Indole (1 mmol), propionic acid anhydride (1 mmol), yttrium triflate (0.01 mmol). b Isolated yield. c Isomers
were determined by GC.
With optimized conditions in hand, we next investigated the substrate and reagent scope for the
Friedel-Crafts 3-acylation of indoles with acid anhydrides using yttrium triflate in [BMI]BF4, and the
results are presented in Table 3. Indole afforded 3-acylindole in excellent yields with high regioselectivity
for the 3-position when using aliphatic acid anhydrides as acylating reagents (Table 3, entries 1–5).
Benzoylation of indole gave the desired product in only 78% yield due to competing N-benzoylation
(Table 3, entry 6). For indoles with electron-rich substituents on the phenyl ring, indoles such as
5-methylindole and 5-methoxyindole, gave 3-acylindoles in yields of 78%–83% without polymerization
or side products. The slightly lower yields of 3-acylated products are due to increased substitution at the
1- and 2-position (Table 3, entries 7–18). However, acylation of 4- or 5-haloindoles with aliphatic acid
anhydrides produced 3-acylindoles in good yields (Table 3, entries 19–34). In addition, N-acylated
byproducts were slightly decreased in comparison with electron-rich indoles, but 2-acylindoles were
obtained in small amounts (Table 3, entries 19–29). A variety of aliphatic acid anhydrides have been
tested. Good yields were obtained for both straight-chain and branched-chain acid anhydrides. Effects
due to steric hindrance do not play a role as pivalic acid anhydride is also reactive in general (Table 3).
The use of microwave irradiation is probably very important in the case of pivalic acid anhydride as
pivaloyl chloride under Friedel-Crafts conditions are known to lead to decarbonylation [50]. The reaction
has also been tested using conventional heating for 5 min. at 80 °C with catalyst and in IL. With indole
and propionic acid anhydride the yield was 16% (6/0/94) and with butyric acid anhydride 28% (5/0/95).

Molecules 2015, 20
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The regioselectivity was worse and much longer times are needed. Looking at regioselectivity in
general, it is seen from Table 1 that the catalyst has little influence. From Table 2, most solvents give
good regioselectivity. The exceptions are acetone and [BMI]SCN. It is hard to find a common factor
for those conditions. It can be added that using propionic anhydride with indole gave a ratio of 7/93 but
only in 20% yield in the absence of catalyst. From Table 3, it is seen that pivalic acid anhydride and
2-methylpropionic acid anhydride give rise to more 2-substitution than straight chain acid anhydrides
and so does benzoic acid anhydride. A comparison of entries 23 and 34 shows that the reason is not
purely steric. More important seems to be the nature of the substitutent in the 5-position. As the three
mentioned acylium ions are more stable than those of straight chain acylium ions, it appears that a
higher yield of the 2-isomer is caused by a combination of a small steric effect, electronic influence of
the 5-position and the stability of the acylium ion.
Table 3. Friedel-Crafts acylation of indoles using Y(OTf)3/[BMI]BF4 under monomode
microwave irradiation a.
Selective Position in Parenthesis b
Isolated Yield (%)
Entry
Substrate
R′
(1-/2-/3-)
0/0/100
0/0/100
3/0/97
of 3-Substituted Derivative c
1
2
CH3
C2H5
C3H7
i-C3H7
t-C4H9
C6H5
CH3
88 d
92
3
88 e
91
4
2/2/96
5
1/4/95
89
6
5/3/92
78 f
79 g
80
7
6/0/94
8
C2H5
C3H7
i-C3H7
t-C4H9
C6H5
CH3
6/1/93
9
7/2/91
79
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1/8/91
80
1/6/93
83
3/4/93
83
79 g
8/0/92
C2H5
C3H7
i-C3H7
t-C4H9
C6H5
CH3
6/2/92
78
6/2/92
80
2/7/91
78
1/4/95
79
7/4/89
78
4/2/94
83 h
85 g
78
C2H5
C3H7
i-C3H7
t-C4H9
C6H5
4/1/95
5/2/93
2/5/93
80
1/4/95
not determined i
80 g
75

Molecules 2015, 20
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Table 3. Cont.
Selective Position in Parenthesis b
Isolated Yield (%)
Entry
Substrate
R′
(1-/2-/3-)
3/1/96
2/2/96
3/2/95
2/7/91
6/15/79
1/9/90
of 3-Substituted Derivative c
25
26
27
27
29
30
CH3
C2H5
79 h
82
C3H7
80
i-C3H7
t-C4H9
C6H5
79
65 g
77
31
32
33
C2H5
t-C4H9
C2H5
3/3/94
3/39/58
10/0/90
4/4/92
80
45
72
82
34
t-C4H9
a
Reaction conditions: indoles (1 mmol), acid anhydrides (1 mmol) and Y(OTf)3 (0.01 mmol), [BMI]BF4
(1 mmol) at 80 °C for 5 min unless otherwise noted. Other conditions were tested to obtain the best yield.
b Selectivity was determined by GC. c Isolated yield of pure isomer. d 110 °C, 10 min. e 100 °C, 5 min. f 100 °C,
1 min. g 80 °C, 10 min. h 100 °C, 10 min, i the compounds is not suitable for GC analysis.
The reusability of Y(OTf)3/[BMI]BF4 was also studied. After the first use, the recovered catalytic
system was tested in four consecutive runs without significant loss of catalytic activity in propionylation
of indole and 5-bromoindole (Scheme 1). The recovery of yttrium triflate in [BMI]BF4 is simple. After
workup, the ionic liquid containing metal triflate is dried under vacuum before the next use.
O
C2H5
H
R
R
Y(OTf)3/[BMI]BF4
MW
C2H5COOH
(C2H5CO)2O
1 mmol
+
+
N
N
H
H
R = H, Br
Indole
80 °C, 5 min
5-Bromoindole
80 °C, 10 min
Scheme 1. Recycling of Y(OTf)3/[BMI]BF4 in four consecutive runs under microwave irradiation.

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3. Experimental Section
3.1. Chemicals and Supplies
Indoles, acid anhydrides and metal triflates were purchased from Sigma-Aldrich (St. Louis,
MO, USA) and immediately used without further purification. Solvents were obtained from Labscan
(Bangkok, Thailand) and Chemsol (Hochiminhcity, Vietnam) and also directly used without purification.
Silica gel was from Merck (Darmstadt, Germany).
3.2. Instruments
Microwave irradiation was performed in a CEM Discover BenchMate apparatus (Matthews, NC,
USA) which allows microwave synthesis with safe pressure regulation using a 10 mL pressurized glass
tube with Teflon-coated septum and vertically-focused IR temperature sensor controlling reaction
temperature. Flash column chromatography was performed on silica gel (Merck). GC-MS analyses were
performed on an Agilent GC System 7890 (Santa Clara, CA, USA) equipped with an Agilent 5973N
1
mass selective detector and a DB-5MS capillary column (30 m × 250 µm × 0.25 µm). The H- and
13C-NMR spectra were recorded on an Advance 500 (Bruker, Rheinstetten, Germany) and Mercury
300 (Varian, Palo Alto, CA, USA) instrument using DMSO-d6 or CDCl3 as solvent and solvent peaks
or TMS as internal standards. HRMS (ESI) data were recorded on Bruker micrOTOF-QII MS (Bruker,
Bremen, Germany) at 80 eV.
3.3. Acylation Procedure
A 10 mL glass vessel suited for the monomode microwave oven was charged with 1 mmol substrate,
1 mmol acid anhydride, 0.01 mmol metal triflate, and 1 mmol ionic liquid. Next, the vessel was sealed
with a Teflon cap and irradiated in a monomode microwave oven at many different reaction conditions
(temperature and time) to find the optimal condition. Upon completion, the vessel was cooled down to
room temperature and the mixture was extracted with Et2O (5 × 10 mL). The ether layer was decanted
and washed with water (2 × 10 mL), saturated aqueous NaHCO3 (2 × 20 mL), and brine (2 × 10 mL).
The organic layer was dried over MgSO4, filtered, and the solvent was removed by a rotary evaporator.
The isolated yield was determined after purification by flash chromatography (silica gel, n-hexane/ethyl
acetate, gradient 10:0 to 8:2).
3.4. Recovery and Reuse of the Catalytic System Y(OTf)3/[BMI]BF4
This procedure was also carried out in the monomode microwave oven using indole or 5-bromoindole.
In order to recover the catalytic Y(OTf)3/[BMI]BF4 system after completion of the reaction, diethyl
ether was applied to wash the reaction mixture as many times as necessary to completely remove both
substrates and products. Then, the mixture Y(OTf)3/[BMI]BF4 was dried in vacuum at 80 °C for 30 min.
Due to its high solubility in the ionic liquid [BMI]BF4, Y(OTf)3 could easily be recovered in a
quantitative yield. This recycled system was used for four consecutive runs and it can be noticed that
the isolated yield of product only decreased slightly after each run. The process for recycling Y(OTf)3
in [BMI]BF4 is simple and efficient so it easily can be applied on a large scale.

Molecules 2015, 20
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3.5. Compounds
New compounds have been synthesized as follows:
3-Propionyl-5-Methylindole
1
Pale yellow solid, mp. 208–209 °C. H-NMR (300 MHz, DMSO-d6): δ 11.75 (br s, 1H), 8.23 (s, 1H),
8.04–7.93 (m, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.3, 1.5 Hz, 1H), 2.84 (q, J = 7.4 Hz, 2H),
13
2.39 (s, 3H), 1.10 (t, J = 7.4 Hz, 3H). C-NMR (75 MHz, DMSO-d6): δ 195.7, 134.9, 133.4, 130.3,
125.7, 124.1, 121.0, 115.6, 111.6, 31.8, 21.3, 9.2. GC-MS (EI, 70 eV): m/z (%) = 187 (25, [M+]).
HR-ESI-MS m/z calcd. for ([M + Na]+) 210.0889, found 210.0917.
3-Butyryl-5-methylindole
Pale yellow solid, mp. 190–191 °C. 1H-NMR (300 MHz, DMSO-d6) δ 11.75 (br s, 1H), 8.26–8.22 (m,
1H), 8.00 (d, J = 2.0 Hz, 1H), 7.30 (s, 1H), 7.01 (s, 1H), 2.77 (t, J = 7.3 Hz, 2H), 2.37 (s, 3H), 1.64
(sext, J = 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13C-NMR (75 MHz, DMSO-d6) δ 195.2, 134.9, 133.6,
130.2, 125.6, 124.0, 121.1, 116.1, 111.6, 35.7, 18.3, 13.8. GC-MS (EI, 70 eV): m/z (%) = 201 (25,
[M+]). HR-ESI-MS: m/z calcd. for ([M + Na]+) 224.1046, found 224.1053.
3-Isobutyryl-5-methylindole
1
Pale yellow solid, mp. 210–211 °C. H-NMR (300 MHz, DMSO-d6): δ 11.76 (br s, 1H), 8.26 (d,
J = 3.1 Hz, 1H), 8.00 (s, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.00 (dd, J = 8.3, 1.6 Hz, 1H), 3.41 (hept,
J = 6.8 Hz, 1H), 2.37 (s, 3H), 1.09 (d, J = 6.8 Hz, 6H). 13C-NMR (75 MHz, DMSO-d6): δ 199.3, 135.0,
133.4, 130.3, 126.0, 124.1, 121.2, 114.6, 111.6, 35.7, 21.3, 19.8. GC-MS (EI, 70 eV): m/z (%) = 201
(25, [M+]). HR-ESI-MS: m/z calcd. for ([M + Na]+) 224.1046, found 224.1063.

Molecules 2015, 20
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3-Propionyl-5-methoxyindole
1
White solid, mp. 182–183 °C. H-NMR (300 MHz, DMSO-d6): δ 11.74 (br s, 1H), 8.21 (s, 1H), 7.69
(d, J = 2.5 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.6 Hz, 1H), 3.75 (s, 3H), 2.82 (q,
J = 7.4 Hz, 2H), 1.09 (t, J = 7.4 Hz, 3H). 13C-NMR (75 MHz, DMSO-d6): δ 195.7, 155.3, 133.6, 131.4,
126.1, 115.8, 112.7, 112. 103.0, 55.2, 31.7, 9.1. GC–MS (EI, 70 eV): m/z (%) = 203 (25, [M+]).
HR-ESI-MS: m/z calcd. for ([M + Na]+) 226.0839, found 226.0856.
3-Butyryl-5-methoxyindole
White solid, mp. 166–167 °C. 1H-NMR (300 MHz, DMSO-d6): δ 11.77 (s, 1H), 8.24 (s, 1H), 7.72 (d,
J = 2.5 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 8.8, 2.6 Hz, 1H), 3.77 (s, 3H), 2.79 (t, J = 7.4 Hz,
13
2H), 1.66 (sext, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). C-NMR (75 MHz, DMSO-d6): δ 195.2,
155.3, 133.8, 131.4, 126.1, 116.3, 112.7, 112.6, 103.0, 55.2, 40.5, 18.3, 13.9. GC–MS (EI, 70 eV):
m/z (%) = 217 (25, [M+]). HR-ESI-MS: m/z calcd. for ([M + Na]+) 240.0995, found 240.1026.
3-Isobutyryl-5-methoxyindole
White solid, mp. 158–159 °C. 1H-NMR (500 MHz, CDCl3): δ 8.77 (br s, 1H), 7.97 (d, J = 2.5 Hz, 1H),
7.85 (d, J = 3.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 8.8, 2.5 Hz, 1H), 3.87 (s, 3H), 3.33
(hept, J = 6.8 Hz, 1H), 1.27 (d, J = 6.8 Hz, 7H). 13C-NMR (125 MHz, CDCl3): δ 201.1, 156.4, 131.3,
131.0, 126.7, 116.6, 114.4, 112.1, 103.6, 55.7, 37.1, 19.8. GC-MS (EI, 70 eV): m/z (%) = 217 (25,
[M+]). HR-ESI-MS: m/z calcd. for ([M + Na]+) 240.0995, found 240.1035.

Molecules 2015, 20
19614
3-Pivaloyl-5-methoxyindole
1
White solid, mp. 153–154 °C. H-NMR (300 MHz, DMSO-d6): δ 11.74 (s, 1H), 8.29 (d, J = 1.9 Hz,
1H), 7.84 (d, J = 2.5 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 6.81 (dd, J = 8.8, 2.6 Hz, 1H), 3.77 (s, 3H),
1.33 (s, 9H). 13C-NMR (75 MHz, DMSO-d6): δ 201.5, 155.7, 133.1, 131.0, 128.4, 113.0, 112.8, 112.5,
104.1, 55.6, 43.8, 29.1. GC-MS (EI, 70 eV): m/z (%) = 231 (15, [M+]). HR-ESI-MS: m/z calcd. for
([M + Na]+) 254.1152, found 254.1189.
3-Isobutyryl-5-bromoindole
1
White solid, mp. 223–224 °C. H-NMR (300 MHz, DMSO-d6): δ 12.11 (br s, 1H), 8.42 (s, 1H), 8.35
(dd, J = 2.0, 0.5 Hz, 1H), 7.44 (dd, J = 8.6, 0.5 Hz, 1H), 7.33 (dd, J = 8.6, 2.0 Hz, 1H), 3.44 (hept,
J = 6.8 Hz, 1H), 1.12 (d, J = 6.8 Hz, 6H). 13C-NMR (75 MHz, DMSO-d6): δ 199.5, 135.4, 134.7,
127.5, 125.3, 123.6, 114.4, 114.4, 114.1, 35.8, 19.7. GC-MS (EI, 70 eV): m/z (%) = 265 (25, [M+]).
HR-ESI-MS: m/z calcd. for ([M + Na]+) 287.9994, found 288.0006.
3-Pivaloyl-5-bromoindole
1
White solid, mp. 234–235 °C. H-NMR (300 MHz, DMSO-d6): δ 12.04 (br s, 1H), 8.42 (dd, J = 2.0,
0.5 Hz, 1H), 8.40 (s, 1H), 7.41 (dd, J = 8.6, 0.5 Hz, 1H), 7.30 (dd, J = 8.6, 2.0 Hz, 1H), 1.31 (s, 9H).
13C-NMR (75 MHz, DMSO-d6): δ 201.1, 134.3, 133.6, 128.9, 125.0, 124.1, 114.2, 113.7, 111.6, 43.3,
28.3. GC-MS (EI, 70 eV): m/z (%) = 279 (15, [M+]). HR-ESI-MS: m/z calcd. for ([M + Na]+)
302.0151, found 302.0186.

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3-Butyryl-5-chloroindole
Pale yellow solid, mp. 214–215 °C. 1H-NMR (500 MHz, CDCl3): δ 8.60 (br s, 1H), 8.42 (d, J = 2.0 Hz,
1H), 7.87 (d, J = 2.9 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.24 (J = 8.7, 2.1 Hz, 1H), 2.83 (t, J = 7.4 Hz, 2H),
13
1.81 (sext, J = 7.4 Hz, 2H), 1.03 (t, J = 7.4 Hz, 3H). C-NMR (125 MHz, CDCl3): δ 196.1, 134.6,
131.5, 130.2, 126.6, 124.2, 122.2, 118.1, 112.2, 41.8, 18.4, 14.0. GC-MS (EI, 70 eV): m/z (%) = 221
(25, [M+]). HR-ESI-MS: m/z calcd. for ([M + Na]+) 244.0499, found 244.0472.
3-Isobutyryl-5-chloroindole
Pale yellow solid, mp. 198–199 °C. 1H-NMR (500 MHz, CDCl3): δ 8.66 (br s, 1H), 8.44 (d, J = 2.0 Hz,
1H), 7.89 (d, J = 2.7 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.24 (dd, J = 8.7, 2.4 Hz, 1H), 3.31 (hept,
J = 6.8 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H). 13C-NMR (125 MHz, CDCl3): δ 200.4, 134.7, 131.4, 128.6,
127.0, 124.2, 122.3, 116.7, 112.2, 37.3, 19.6. GC-MS (EI, 70 eV): m/z (%) = 221 (25, [M+]).
HR-ESI-MS: m/z calcd. for ([M + Na]+) 244.0499, found 244.0537.
3-Propionyl-4-bromoindole
1
Reddish brown solid, mp. 112–113 °C. H-NMR (500 MHz, CDCl3): δ 9.59 (br s, 1H), 7.40 (dt,
J = 8.3, 0.8 Hz, 1H), 7.33 (dd, J = 7.5, 0.7 Hz, 1H), 7.24 (dd, J = 2.3, 0.9 Hz, 1H), 7.19 (dd, J = 8.2,
7.6 Hz, 1H), 3.04 (q, J = 7.4 Hz, 2H), 1.30 (t, J = 7.4 Hz, 3H). 13C-NMR (125 MHz, CDCl3): δ 194.1,
137.4, 135.0, 128.5, 126.8, 123.8, 116.8, 111.5, 108.9, 31.6, 8.6. GC-MS (EI, 70 eV): m/z (%) = 251
(70, [M+]). HR-ESI-MS: m/z calcd. for ([M + Na]+) 273.9838, found 273.9814.

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3-Pivaloyl-4-bromoindole
1
Pale yellow solid, mp = 154 °C. H-NMR (500 MHz, CDCl3): δ 9.37 (br s, 1H), 7.37 (d, J = 8.3 Hz,
1H), 7.32 (dd, J = 7.5, 0.6 Hz, 1H), 7.25 (dd, J = 2.3, 0.9 Hz, 1H), 7.17 (dd, J = 8.2, 7.6 Hz, 1H), 1.48
(s, 9H). 13C-NMR (125 MHz, CDCl3): δ 199.0, 136.1, 132.4, 128.7, 126.6, 123.7, 116.8, 111.2, 108.8,
43.5, 28.4. GC-MS (EI, 70 eV): m/z (%) = 279 (40, [M+]). HR-ESI-MS: m/z calcd for ([M + Na]+)
302.0151, found 302.0189.
4. Conclusions
In summary, a new catalytic system Y(OTf)3/[BMI]BF4 has been developed for 3-acylation of indoles
using acid anhydrides under monomode microwave irradiation. This is a simple, straightforward and
environmentally benign method to prepare 3-acylindoles in high yields, high regioselectivity and in
short reaction times.
Acknowledgments
We thank Duy Khiem Nguyen Chau (University of Minnesota Duluth, Duluth, MN, USA) for
helpful discussions.
Author Contributions
P. H. Tran, H. N. Tran designed and performed the experiments; P. E. Hansen and M. H. N. Do
analyzed the spectra and data; P. H. Tran, P. E. Hansen and T. N. Le wrote the paper.
Conflicts of Interest
The authors declare no conflict of interest.
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