Iron powder promoted regio-selective friedel-crafts acylation of indole under solvent-free conditions

Article abstract of DOI:10.14233/ajchem.2013.14277

A facile, efficient and environment-friendly protocol for the regioselective synthesis of 3-acyl indoles has been developed by one-pot catalytic Friedel-Crafts acylation of indole in presence of the iron powder as catalyst under solvent-free conditions at room temperature.

Full text of DOI:10.14233/ajchem.2013.14277

Asian Journal of Chemistry; Vol. 25, No. 11 (2013), 6117-6120
http://dx.doi.org/10.14233/ajchem.2013.14277
Iron Powder Promoted Regio-Selective Friedel-Crafts
Acylation of Indole Under Solvent-Free Conditions
*
LIRONG ZHANG, FENGPING YI , JIANZHONG ZOU and SHAOYAN QU
School of Perfume and Aroma Technology, Shanghai Institute of Technology, Shanghai 201418, P.R. China
*Corresponding author: Tel: +86 21 60873280; E-mail: yifengping@sit.edu.cn; zlir2008@163.com
(Received: 7 July 2012;
Accepted: 30 April 2013)
AJC-13415
A facile, efficient and environment-friendly protocol for the regioselective synthesis of 3-acyl indoles has been developed by one-pot
catalytic Friedel-Crafts acylation of indole in presence of the iron powder as catalyst under solvent-free conditions at room temperature.
Key Words: Friedel-Crafts acylation, Indole, Iron powder, Solvent free.
acylation of indole with acyl chlorides in good to high yields
under solvent free conditions in short reaction time. There-
fore, in this paper we described a successful protocol for the
synthesis of 3-acyl indoles catalyzed by iron powder.
INTRODUCTION
The indole moiety is present in a range of pharmaceutical
materials and the synthesis of 3-acyl indoles has gained consi-
derable attention. 3-Substituted indoles are not only significant
therapeutic agents but also used as synthetic intermediates in
alkaloid synthesis1,2. Various synthetic methods are reported
in the literature for 3-substituted indoles3-13. The common
method to prepare 3-acyl indoles is Friedel-Crafts reaction
under acidic conditions, which resulting in the side reactions
caused from high nucleophilic nature of indole6-13. Hence,
several efforts have also been made to reduce the competing
side reactions10-12. On the other hand, the development of suit-
able catalysts for the facile synthesis of 3-acyl indoles without
NH-protection has attracted much attention. Lewis acids such
as alkyl aluminium chloride8,9 imidazolium chloroaluminate6,
SnCl47 as well as ZrCl413 have been reported as the promoters.
Iron(III) oxide promoting aromatic Friedel-Crafts acylation
have been known14. We speculated that iron containing comp-
ound could play a required role and be beneficial in selective
acylaltion of indole.
EXPERIMENTAL
Chemicals were obtained from commercial suppliers and
used without further purification. The NMR spectra were
recorded on a BRUKER Avance III (500 MHz for 1H) in
deuterochloroform (CDCl3) at room temperature. The chemical
shift values are given in ppm and tetramethylsilane was used
as an internal standard. Representative experimental proce-
dure for the synthesis of 3-benzolylindole. To the iron powder
(1.4 mmol, 85 mg) was dropped in benzoyl chloride (364 mg,
3 mmol) by a syring at rt under nitrogen, then indole (2 mmol,
234 mg) was added under a flow of nitrogen.After completion
of the reaction as indicated by TLC (1 h), 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 concen-
trated under vacuum. The column chromatographic purification
of crude mass on silica gel eluting with EtOAc-petroleum ether
provided the desired product.
Although numerous methods to achieve Friedel-Crafts
acylation of indole are known, newer methods continue to
attract attention for their experimental simplicity and effec-
tiveness. A surface reaction may be more desirable than a
solution counterpart, because the reaction is more convenient
to run or a high yield of product is attained. For these reasons,
surface synthetic organic chemistry is a rapidly growing field
of study. It was also shown that zinc powder promotes the
acylation of activated and unactivated aromatics under micro-
wave irradiation15. We have now discovered that iron powder
alone promotes an efficient regioselective Friedel-Crafts
All acylation reactions were carried out following repre-
sentative procedure.
1H-indol-3-yl-phenylmethanone (3)13. White solid; m.p.
243-245 ºC; 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)13. White
solid; m.p. 116-118 ºC; 1H NMR (CDCl3, 500 MHz): δ 8.46-

6118 Zhang et al.
Asian J. Chem.
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. 234-237 ºC; 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 =
8.0Hz, 1H).
found to be the better choice for this reaction. Since the addition
order played significant effect tothe synthesis of 3-acylated
indoles7, we also investigated the effect of reactant addition
order. The results demonstrated that in the protocol present
here, the addition order of indole, acyl chloride and catalyst
did not show important effect to the acylation (Table-1, entries
1, 15 and16).
(2-Methyl-1H-indol-3-yl)-phenyl-methanone (6)13. White
solid; m.p. 138-140 ºC; 1H NMR (CDCl3, 500 MHz): δ 7.93
(d, J = 7.2 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.55 (t, J = 7.6
Hz, 3H), 7.33-7.38 (m, 2H), 7.29-7.24 (m, 2H), 3.88 (s, 3H).
(5-Methoxy-1H-indol-3-yl)-phenyl-methanone (7)6.
White solid; m.p. 223-225 ºC; 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).
TABLE-1
FRIEDEL-CRAFTS ACYLATION OF INDOL WITH BENZOYL
CHLORIDE UNDER VARIOUS REACTION CONDITIONSa
OMe
O
O
catalyst
Cl
+
rt
N
H
N
H
1a
3
2a
(5-Bromo-1H-indol-3-yl)-phenyl-methanone (8)13. White
solid; m.p. 265-267 ºC; 1H NMR (CDCl3, 500 MHz): δ 8.38
(d, J = 2.0Hz, 1H), 8.01 (s, 1H), 7.80-7.76 (m, 2H), 7.63-7.61
(m, 1H), 7.52-7.46 (m, 3H), 7.41 (d, J = 8.4Hz, 1H).
1-(1H-Indol-3-yl)ethanone (9)13. White solid; m.p. 189-
190 ºC; 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),
2.53 (s, 3H).
Entry
Catalyst
Iron powderc
Solvent
Neat
Time (h)
Yield (%)
65
1
2
0.3
8
Fe2O3
Neat
20
3
FeCl3
Neat
6
36
4
FeSO4
Neat
2
52
5
Fe2(SO4)3
ZnO
Neat
8
31
6
Neat
4
39
7
ZrO2
Neat
7
18
8
SnO2
Neat
7
15
4-Chlorophenyl (1H-indol-3-yl)methanone (10)13.Yellow-
ish white solid; m.p. 241-242 ºC; 1H NMR (CDCl3, 500 MHz):
δ 8.24 (d, J = 7.5Hz, 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).
1H-Indol-3-yl (4-methoxyphenyl)methanone (11)13. Light
yellow solid; m.p. 88-89 ºC; 1H NMR (CDCl3, 500 MHz): δ
8.23 (d, J = 7.0 Hz, 1H), 7.94 (s, 1H), 7.80 (d, J = 7.5 Hz, 2H),
7.52 (d, J = 7.0 Hz, 1H), 7.23-7.21 (m, 2H), 7.05 (d, J = 7.5
Hz, 2H), 3.83 (s, 3H).
1-(1H-Indol-3-yl)-2,2-dimethylpropan-1-one (12)13.
White solid; m.p. 160-162 ºC; 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),
7.32-7.28 (m, 2H), 1.41 (s, 9H).
9
In2O3
Neat
12
1
12
10
11
12
13
14
15d
16e
Iron powder
Iron powder
Iron powder
Iron powder
Iron powder
Iron powder
Iron powder
DCM
DMF
DCE
CH3CN
CHCl3
Neat
45
3
41
1
49
1
47
1
49
0.3
53
Neat
0.3
40
aReaction condition: Indole (2 mmol), benzoyl chloride (1.5 mmol),
catalyst (2mmol), solvent (3 mL). Addition order: indole was added to
the reaction mixture containing benzoyl chloride and catalyst.
bIsolated yield; cMesh number: 80.
dAddition order: benzoyl chloride was added to the reaction mixture
containing indole and iron powder.
eAddition order: iron powder was added to the reaction mixture
containing indole and benzoyl chloride.
RESULTS AND DISCUSSION
The effect of the catalyst amount and reaction temperature
on the yield of the corresponding acylated product was carried
out. Thus far, 100 mol % iron powder had been used to catalyze
the acylation of indole. Indeed, the catalyst concentrations had
major influence to the observed yield as shown in Table-2,
entries 1-4. In our optimized protocol, 70 mol % iron powder
was found to be necessary. Increasing the amount of catalyst
did not improve the yields, while further reducing the amount
of added catalyst to 50 mol % decreased the yield obviously.
Furthermore, the results (Table-2, entries 2, 5 and 7) revealed
that the acylation of indole catalyzed by iron powder depended
strongly on the reaction temperature. The reaction proceeded
at room temperature favoured the desired acylation. The variation
in equivalent of reactants (Table-2, entries 2 and 6) revealed
that the 1 equiv of indole and 1.5 equiv of acyl chloride were
optimal.
The screening of the catalysts was conducted using indole
(1a) and benzoyl chloride (2a) as a model reaction. The results
are summarized in Table-1, entries 1-9. Among the catalysts
examined including conventional Lewis acid, metal oxides and
iron containing compound, iron power demonstrated the greatest
activity of the catalysts tested in the Friedel-Crafts acylation
of indole, in terms of reaction rate and isolated yield. In a
typical experiment, indole (1a) was added to a mixture of iron
powder and benzoyl chloride (2a). The mixture was stirred at
room temperature until the reaction was completed. The
product was isolated by simple extraction of the solid mass by
ethyl acetate followed by the usual workup. The indole with
benzoyl chloride reacted very rapidly within 20 min. We also
examined the effect of the solvents toward this reaction (Table-
1, entries 10-14). Although the reaction proceeded smoothly
in dichloromethane or dichloroethane, only 45 % and 49 %
yields of the product were detected. Thus iron powder was
To demonstrate the generality of this method, we set out
to explore the scope of the optimized Friedel-Crafts acylation

Vol. 25, No. 11 (2013)
Iron Powder Promoted Regio-Selective Friedel-Crafts Acylation of Indole 6119
TABLE-2
protocol. We observed that, a wide range of aroyl and alkanoyl
chlorides underwent smooth acylation with various indoles
without NH protection and produced diverse 3-acyl indoles
(3-12) in good to high yields and reacted very rapidly (Table-3,
entries 1-11). As it can be seen, the electron-deficient indoles
such as 5-cyano indole and 5-bromo indole provided the high
yield under the reaction conditions presented (Table-3, entries
SCREENING OF CATALYST AMOUNT, TEMPERATURE
AND REACTANT MOLE RATIO FOR FRIEDEL
-CRAFTS ACYLATION OF INDOLEa
O
O
iron powder
Temp.
Cl
+
N
N
H
H
1a
2 a
3
3 and 6). Particularly, the methoxy substituted indole, which
is known for its susceptibility toward oligomerizations, was
found to afford the product in good yield within 3 h for complete
conversion with no polymerized or dimerized side products
(Table-3, entry 5).Additionally, it should be noted that acylation
of indole with acid anhydride as acylating agent does not occur
(Table-3, entry 8). The result is consistent with the proposed
mechanism provided by Sarvari and Sharghi16. Pivoloyl chloride,
which is feasible to decarbonylative alkylation, underwent
acylation with indole smoothly in the protocol to afford the
desired product in satisfactory yield (Table-3, entry 11).
Entry
Iron powder (mol %)
Temp. (oC)
Yield (%)b
1
2
50
70
rt
rt
33
66
65
63
32
72
43
3
100
120
70
rt
4
rt
5
6c
0
70
rt
7
70
40
aReaction condition: Indole (2 mmol), benzoyl chloride (1.5 mmol),
reaction time 1 h; bIsolated yield; cMesh number: 80; dMole ratio of
indole and acyl chloride =1:1.5
TABLE-3
FRIEDEL-CRAFTS 3-ACYLATION OF VARIOUS INDOLES WITH VERSATILE ACYL CHLORIDEa
O
R
3
O
iron powder (0.7 equiv.)
+
R
2
R
Cl
R
3
2
rt, N
N
2
N
R
1
R
1
1a- 1f
3- 12
2a- 2f
Entry
1
R1
H
R2
H
R3
C6H5
Product
Time (h)
0.3
Yield (%)b
69
O
N
H
3
2
3
CH3
H
H
C6H5
0.5
0.3
75
70
O
N
4
H
4-NO2C6H5
NO
O
2
N
H
5
4
5
H
H
2-CH3
C6H5
0.3
65
60
O
N
H
6
5-OCH3
C6H5
3
O
MeO
N
H
7
6
7
H
H
5-Br
C6H5
0.5
0.3
63
70
O
Br
N
H
O
8
H
CH3
N
H
9

6120 Zhang et al.
Asian J. Chem.
Entry
8
R1
H
R2
H
R3
Product
O
Time (h)
24
Yield (%)b
0
CH3
N
H
9
9
H
H
H
H
H
H
4-ClC6H5
4-OCH3C6H5
(CH3)3C
1
2
61
66
73
Cl
O
N
H
10
10
11
OMe
O
N
H
11
0.5
O
N
H
12
aRectioncondition: Indole (2 mmol), acyl chloride (3mmol), iron powder (mesh number: 80) (0.7 equiv.); bIsolated yield
2. Y.S. Wu, M.S. Coumar, J.Y. Chang, H.Y. Sun, F.M. Kuo, C.C. Kuo,
Y.J. Chen, C.Y. Chang, C.L. Hsiao and J.P. Liou, J. Med. Chem., 52,
4941 (2009).
Conclusion
In summary, we have described a novel and highly
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efficient solvent-free protocol for regioselective Friedel-Crafts
acylation of the C3 position of indolesusing nontoxic and
inexpensive iron powder.This synthetic method can be employed
to the synthesis of a wide range of 3-acyl indoles without NH
protection.The present approach offers the advantages of clean
reaction, simple methodology, short reaction time, high yield,
easy purification and economic availability of the catalyst.
7. O. Ottoni, A.D.F. Neder, A.K.B. Dias, R.P.A. Cruz and L.B. Aquino, Org.
Lett., 3, 1005 (2001).
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2277 (2004).
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Org. Lett., 2, 1485 (2000).
ACKNOWLEDGEMENTS
10. K.S. Yeung, Z. Qiu, M.E. Farkas, Q. Xue, A. Regueiro-Ren, Z. Yang, J.A.
Bender, A.C. Good and J.F. Kadow, Tetrahedron Lett., 49, 6250 (2008).
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The authors thank the financial support from Innovation
Program of Shanghai Municipal Education Commission
No.11ZZ180, Science Foundation of Shanghai Institute of
Technology No. YJ2012-29, Program of Local Colleges Ability
Building of Science and Technology Commission of Shanghai
Municipality No. 11520502600 and Affiliation Program No.
LM201247 from Shanghai science and technology achieve-
ment transformation Promotion Association.
13. S.K. Guchhait, M. Kashyap and H. Kamble, J. Org. Chem., 76, 4753 (2011).
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