Efficient Lewis acid-assisted Bronsted acid (LBA) catalysis in the iron-catalyzed Friedel-Crafts alkylation reaction of indoles

Article abstract of DOI:10.2478/s11532-010-0016-0

Lewis acid-assisted Bronsted acid (LBA) catalysis was proposed for the iron-catalyzed Friedel-Crafts alkylation of indoles with chalcones. This proposal was supported by the ESI-MS and cyclic voltammetry. The addition of acac to the iron-catalyzed Friedel

Full text of DOI:10.2478/s11532-010-0016-0

Cent. Eur. J. Chem. • 8(3) • 2010 • 669–673
DOI: 10.2478/s11532-010-0016-0
Central European Journal of Chemistry
Efficient Lewis acid-assisted Brønsted acid
(LBA) catalysis in the iron-catalyzed
Friedel-Crafts alkylation reaction of indoles
Research Article
Zhen-Yu Jianga, Ji-Rong Wua, Li Lia,b, Xi-Huai Chena, Guo-Qiao Laia,*, Jian-Xiong
Jianga, Yixin Luc, Li-Wen Xua,*
aKey Laboratory of Organosilicon Chemistry and Material Technology of Ministry
of Education, Hangzhou Normal University, Hangzhou 310012, P. R. China
bCollege of Material, Chemistry and Chemical Engineering, Hangzhou Normal
University, Hangzhou 310036, P. R. China.
cDepartment of Chemistry, National University of Singapore, Singapore 117543,
Republic of Singapore
Received 04 December 2009; Accepted 16 January 2010
Abstract: Lewis acid-assisted Brønsted acid (LBA) catalysis was proposed for the iron-catalyzed Friedel-Crafts alkylation of indoles with
chalcones. This proposal was supported by the ESI-MS and cyclic voltammetry. The addition of acac to the iron-catalyzed Friedel-
Crafts alkylation of indoles with chalcones created a powerful catalytic system, which makes the alkylation reactions occur easily
under mild conditions.
Keywords: Iron catalysis • Friedel-Crafts • Lewis acid • Brønsted acid
© Versita Sp. z.o.o
the total synthesis of indole derivatives with potential
1. Introduction
biological activities [3,4].
During past years, a variety of transition metal salts
The Friedel-Crafts alkylation reaction of indoles is a very or metal-free organic molecules are catalyzed Friedel-
important process because it is involved in the total Crafts alkylation between indoles and an electrophile
synthesis of bioactive indole alkaloids such as (for example, enone). This well-established method
hapalindoles and other 3-substituted indoles, which are for the functionalization at the 3-position of the indole
important substructures and building blocks for the
synthesis of natural products and therapeutic agents [1]. previous synthetic methods, e.g., the necessity to utilize
For example, NVP-LAQ824, currently undergoing expensive stoichiometric amounts of Lewis acidic
human clinical trials, is a potent HDAI and antitumor catalysts and toxic heavy metals, which does not meet
agent against both solid and leukemia [2]. The the contemporary requirement for green chemistry.
nucleus [5-15]. However, some drawbacks still exits in
preparation of functional indoles is therefore an Among transition metal salts, iron(III) chloride is a very
important research field. The selective akylation at the cheap and efficient Lewis acid catalyst, and has
C-2 or C-3 position will be complementary to the known attracted much attention in a great deal of useful organic
N-alkylation methodology and holds significant synthetic transformations [16-18]. With our continuous research in
potential. In particular, functionalization at the C-3 iron catalysis, herein, we wish to report some findings in
position of the indole skeleton is of great importance for the iron-catalyzed Friedel-Crafts alkylation of indoles.
E-mail: licpxulw@yahoo.com
669

Efficient Lewis acid-assisted Brønsted acid (LBA)
catalysis in the iron-catalyzed Friedel-Crafts
alkylation reaction of indoles
In this reaction, Lewis acid-assisted Brønsted acid (LBA) 2.1.2. CV analysis
catalysis was established by the combinational utilities
of ESI-MS and cyclic voltammetry.
Electrochemical measurements for cyclic voltammetry
were performed using a IM-60 electrochemical work
station (CH Instruments, Austin, TX). The working
electrode is a glass carbon electrode (3-mm-diameter),
the auxiliary electrode is a platinum wire, and the
reference electrode is a saturated calomel electrode
(SCE). The reaction solution has been purged with N2
2. Experiment Procedure
2.1. General considerations
All reaction flask and solvent were dried according to for 10 min to remove O2 from the reaction mixture.
standard methodology prior to use. Flash column
Table 1.FeCl3 catalyzed Friedel-Crafts alkylation reaction of indole
chromatography was performed over silica (100-200
mesh). NMR spectra were recorded on a 400-MHz
spectrometer. 13C NMR spectra were obtained with
broadband proton decoupling. For spectra recorded in
CDCl3, unless noted, chemical shifts were recorded
relative to the internal TMS (tetramethylsilane)
reference signal. IR spectra were recorded using a FTIR
apparatus. Thin layer chromatography was performed
using Silica. To gain insight into the the mechanism of
iron catalyzed Friedel-Crafts alkylation of indoles with
chalcones, Cyclic voltammetry (cv) and ESI-MS were
performed.
with chalcone[a].
O
HN
catalyst (5 mol%)
O
N
MeOH/rt/24-48 hr
H
1a
2a
3a
no ligand or additive:
with acac (10 mol%):
trace
75% yield
Entry
Catalyst
Solvent
Time (h)
Yield(%)[b]
1
2
3
4
5
6
7
8
9
Mg(ClO4)2
Fe(ClO4)3
FeCl3
PdCl2(CH3CN)2
Cu(OTf)2
ZnCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
CH Cl2
Me2OH
48
48
48
48
48
48
48
24
24
24
24
NR[c]
Trace[d]
Trace
NR
NR
Trace
NR
Ni(ClO4)2
Fe(acac)3
FeCl3
2.1.1. Representative Procedure for Friedel-Crafts
Alkylation Reaction of indoles and Chalcones
NR
Trace
50
75
10
11
FeCl3+acac[e]
FeCl3+acac[e]
FeCl3 (0.05 mmol) and acac (0.1 mmol) was added into
a solution of chalcone (1.0 mmol) and indole (1.1 mmol)
in freshly distilled CH3OH (2 mL). After stirring at room
temperature for 12-24 h, the mixture was diluted with
H2O (10 mL) and extracted with EtOAc (3×15 mL). The
combined organic layers were dried (Na2SO4),
concentrated in vacuo, and purified by column
[a] Reactions conditions: 5 mol% of transition metal salt, indole/chalcone = 0.55
mmol/0.5 mmol, 2 mL of solvent, at room temperature; [b] Isolated yield; [c] No
reaction; [d] <10% yield; [e] 5 mol% of FeCl3 and 10 mol% of acetylacetone (acac).
chromatography on silica gel (EtOAc-petro ether, 1:5) to 3. Results and Discussion
gain the pure product. All the products are known
compounds [9-15] and confirmed by MS, NMR, and IR. In an initial attempt, we examine the Friedel-Crafts
For the 3a:1H NMR (400 MHz, CDCl3):
= 7.97 (bs, 1 alkylation of indole and chalcone in dichloromethane
H), 7.93 (d, J = 7.2 Hz, 2 H), 7.53 (t, J = 7.4 Hz, 1 H), with several cheap or important Lewis acid catalysts
7.40-7.44 (m, 3 H), 7.35 (d, J = 7.2 Hz, 2 H), 7.23-7.31 at room temperature. We screened a series of cheap
(m, 3 H), 7.14 (q, J = 7.2, 7.2 Hz, 2 H), 7.01 (t, J =
Lewis acidic metal salts as catalyst (5 mol%) such
7.4 Hz, 1 H), 6.96 (s, 1 H), 5.07 (t, J = 7.2Hz, 1 H), 3.81 as PdCl2(CH3CN)2, Mg(ClO4)2, MgCl2, FeCl3, ZnCl2,
(dd, J = 6.8, 6.8 Hz, 1 H), 3.72 (dd, J = 7.6, 7.6 Hz, 1 H); Cu(OTf)2, etc. (Entries 1-8). Unfortunately, no addition
13C NMR (100 MHz,CDCl3):
= 198.6, 144.2, 137.0, product was detected with these transition metal salts
136.6, 133.0, 128.6, 128.4, 128.1, 127.8, 126.6, 126.3, at room temperature even in different solvents; we then
122.1, 121.4, 119.5, 119.4, 119.2, 111.1, 45.2, 38.1; IR evacuated this reaction with the addition of diketones
(KBr): 3462, 3078, 3056, 3024, 1669, 1597, 1580, 1490, or others as ligands. Interestingly, with acetylacetone
758, 746, 703, 692 cm-1; MS (EI): m/z = 325.
(acac) as an additive, we obtained the C-3 alkylation
product of indole in 50% yield. In an effort to improve
the yield of the reaction, we next screened the solvent
and found methanol is the better solvent (Entry 11). It is
important to note that the by-product of Michael addition
670

Z.-Y. Jiang et al.
of acetylacetone to chalcones was not observed in this Based on our experimental results, a suggested and
reaction. We also examined other diketones as ligands more practical mechanism of Lewis acid-assisted
under the same conditions. When dibenzoylmethane Brønsted acid (LBA) catalysis [21-22], is proposed
and 2-acetylcyclohexanone were used, the alkylation in Scheme 1. The reasons for this proposal of LBA are
product was obtained in 80% and 69% yields, given as follows: a) Only FeCl3 or other iron salts
respectively. This clearly showed the combination of catalyzed Friedel-Crafts alkylation of indoles with
FeCl3 and 1,3-diketones was suitable catalytic system chalcones gave no desired product. However, the
to promote the Friedel-Crafts alkylation reaction.
addition of acac resulted in good yield, which indicates
that the alkylation proceeded with in-situ formed
Brønsted acidic HCl as synergistic promoter. b) Without
the iron catalyst, no reaction occurred. Only HCl is not
Table 2.FeCl3 catalyzed Friedel-Crafts alkylation reaction of various
chalcones and indoles [a]
.
R3
O
HN
R3
FeCl3 (5 mol%)
acac (10 mol%)
good for the
alkylation
reaction
of
indole
O
R1
and chalcone, in which acid catalyzed electrophilic
substitution of indoles requires careful control of
acidity to prevent side reactions such as dimerisation
and polymerization. Therefore, the major role of the iron
catalyst lies in the possible formation of iron-dicarbonyl
complex (1) and (2) for the improvement of selectivity.
c) With the combination of a catalytic amount of HCl or
TsOH and Fe(acac)3 as a catalytic system, the desired
products were also formed with good yields, which
supported the proposed mechanism of Lewis
acid-assisted Brønsted acid (LBA) catalysis. The
proposed process of LBA catalysis makes us easy to
understand that the catalytic activity of iron in organic
N
MeOH, RT, 12h
R2
R1
H
R1
R2
1
2
3
Entry
R2
R3
Yield (%)[b]
1
2
3
4
5
6
7
H
p-Cl
H
H
H
H
H
H
2-Me
2-Me
5-Br
5-Br
70
72
84
75
75
84
90
p-CH3
p-OMe
p-CH3
p-OMe
p-CH3
H
p-OMe
p-Cl
H
Note: [a] Reactions conditions: 5 mol% of FeCl3 and 10 mol% of acetylacetone,
indole/chalcone = 0.55 mmol/0.5 mmol, 2 mL of MeOH, at room temperature
for 12 h; [b] Isolated yield.
A variety of indoles and chalcones were next examined transformation is increased dramatically in the presence
to generate the desired C-3 Friedel-Crafts alkylation of readily available acetylacetone (acac).
coupling products under the established reaction
Direct evidence for this hypothesis of LBA catalysis
conditions. As shown in Table 2, the isolated yields of was attained by ESI-MS and cyclic voltammetry (CV)
reaction are generally good to excellent. Nearly all analysis of the FeCl3-acac catalytic system (Figs. 1 and
reactions are clean and the target compounds are 2). In the cation ESI spectra of FeCl3 and the acetyl
obtained in good yields with no formation of side acetone (acac) dissolved in MeOH, the mass spectra
products like dimmers or trimers, which are normally are dominated by [Fe(acac)2]+ signals (Fig. 1a). As
observed by the influence of strong acids [19,20].
expected, the complex [Fe(acac)2-chalcone]+ (Fig. 1b) is
also observed in a significant amount in the mixture of
FeCl3, acac, and chalcone, in MeOH. However, it
remains to be mentioned that no complexes of iron with
indole are observed. Therefore it is worthy to note that
the intermediates (1) and (2) in Scheme 1 is existed to
support the LBA catalysis mechanism
Cyclic voltammetry (cv) is a simple and direct
method for measuring the formal potential of a half
reaction when both oxidized and reduced forms are
stable during the time required to obtain the
O
O
Ph
Ph
O
FeCl3
NH
O
O
O
Cl
O
3a
Fe
HCl
LBA Catalysis
N
H
(1)
2a
voltammogram (current-potential curve)
However, there are few reports on the analysis of metal
ion intermediates in homogeneous catalysis by cv [25].
[23,24].
O
Fe(acac)2Cl
O
Fe(acac)2Cl
H+
O
Ph
Ph
1a
Ph
Ph
Ph
To
further examine the hypothesis that the
Ph
(3)
(2)
iron-dicarbonyl complex (1) is generated in MeOH,
cyclic voltammetry experiments of FeCl3 and FeCl3-acac
in MeOH have shown that a new iron complex is formed
and it is greatly different to FeCl3 and Fe(acac)3. The
voltammogram of FeCl3 in MeOH is reversible, and the
Scheme 1. Proposed LBAs Mechanism for the Iron-catalyzed
Friedel-Crafts alkylation of indoles with chalcones
671

Efficient Lewis acid-assisted Brønsted acid (LBA)
catalysis in the iron-catalyzed Friedel-Crafts
alkylation reaction of indoles
ESI-xulw091019-015118-4_01 #104 RT: 1.56 AV:
T: + c ESIFull ms [ 150.00-1200.00]
1 NL: 1.79E7
ESI-xulw091019-015118-9_01 #284 RT: 3.83 AV:
T: + c ESIFull ms [ 300.00-1000.00]
1 NL: 4.45E7
a
b
253.83
461.79
100
100
95
95
[Fe(acac)2E]+ (E = chalcone)
+
[Fe(acac)2
]
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
15
10
5
90
398.07
85
80
75
70
65
60
55
50
45
Fe(acac)2Cl
O
O
O
O
Cl
O
Ph
Fe
Ph
207.83
40
304.08
35
30
25
367.88
20
303.94
531.87
467.99
606.84
15
467.96
542.82
493.83
10
5
340.20
350
399.89
429.91
335.69
582.06
946.89
638.01
367.82
531.85
701.89
725.92
750
580.09
600
785.90
800
789.78
800
861.55
850
721.96
855.72
665.40
m/z
1064.46
944.73
950
1127.83
910.05
900
992.66
1000
0
0
200
300
400
500
700
900
1000
1100
1200
300
400
450
500
550
600
650
m/z
700
Figure 1.(a) The cation ESI spectrum of the solution of FeCl3 and acac in MeOH; (b) The cation ESI spectrum of the solution of FeCl3, acac, and
chalcone, in MeOH.
addition of acac (0.5 equiv.) to a solution of FeCl3 in described herein collectively show that the combination
MeOH generated an irreveible cyclic voltammogram of FeCl3 with acac creates a powerful catalytic system,
(Fig. 2). Further addition of acac (1 equiv. to 4 equiv.) which makes the alkylation reactions occur easily under
resulted in no obvious difference with oxidation peak
potentials. The cv experiments lead to the conclusion
that addition of acac to FeCl3 in MeOH creates a stable
iron-dicarbonyl complex. These data in combination
with the previous described ESI-MS studies show it is
reasonable that FeCl3-acac is a more powerful catalytic
system than FeCl3 alone. The mechanistic complexity
of the FeCl3-acac system is driven by the high affinity of
acac for iron(III) and these results suggest that simple
empirical models describing the Lewis acid-assisted
Brønsted acid (LBA) catalysis in more complex systems
is more likely to be the correct mechanism.
mild conditions.
Cyclic voltammetry was performed using platinum
wire auxiliary electrodes, glassy carbon working
electrodes, and the reference electrode is a saturated
calomel electrode (SCE).
4. Conclusions
We have demonstrated that FeCl3 is a superior catalyst
for the alkylation of indoles in the presence of
acetylacetone. Lewis acid-assisted Brønsted acid (LBA)
catalysis is exhibited in the iron-catalyzed Friedel-Crafts
alkylation of indoles with chalcones, which has the
advantages of mild reaction conditions, convenient
operation, and structural diversity of the desired
products. The ESI-MS and cyclic voltammogram
Figure 2. (a) Cyclic voltammogram of FeCl3 in MeOH (0.1 M); (b)
Cyclic voltammogram of FeCl3 in MeOH (0.1M) containing
0.05M acetyl acetone (acac).
672

Z.-Y. Jiang et al.
Acknowledgements
This project was partially supported by the Natural
Science Foundation of China (20973051) and
Foundation of Zhejiang Educational Committee
(Y200803721).
References
[1] W.J. Houlihan, Indoles; Vol. I (John Wiley & Sons [14] D.P. Li, Y.C. Guo, Y. Ding, J.C. Xiao, Chem.
Inc, New York, 1972) 71
[2] S.W. Remiszewski et al., J. Med. Chem. 46, 4609 [15] J.S. Yadav,
(2003) G. Satheesh, Synlett 727 (2009)
[3] M. Ishikura, K. Yamada, Nat. Prod. Rep. 26, 803 [16] C. Bolm, J. Legros, J.L. Paih, L. Zani, Chem. Rev.
(2009) 104, 6217 (2004)
[4] M.A. Metwally, S. Shaaban, B.F. Abdel-Wahab, [17] A.A.O. Sarhan, C. Bolm, Chem. Soc. Rev. 38, 2730
G.A. EI-Hiti, Curr. Org. Chem. 13, 1475 (2009) (2009)
[5] A. Zicmanis, G. Vavilina, S. Drozdova, P. Mekss, [18] M.S.Yang,
M. Klavins, Central Eur. J. Chem. 5, 156 (2007) J.X. Jiang, G.Q. Lai, Appl. Organomet. Chem. 22, 177
[6] M. Bandini, A. Eichholzer, Amgew. Chem. Int. Ed. 48, (2008)
Commun. 799 (2006)
B.V.S. Reddy, G.. Narasimhulu,
L.W. Xu,
F.B. Zhang, H.Y. Qiu,
9608 (2009)
[19] A.V. Reddy, K. Ravinder, T.V. Goud, P. Krishnaiah,
[7] R. Jiang, X.P. Xu, T. Chen, H.Y. Li, G. Chen, S.J. Ji, T.V. Raju, Y. Venkateswarlu, Tetrahedron Lett. 44, 6257
Synlett 2815 (2009)
(2003)
[8] K. Akagawa, T. Yamashita, S. Sakamoto, K. Kudo, [20] W. Zhou, L.W. Xu, L. Yang, P.Q. Zhao, C.G. Xia,
Tetrahedron Lett. 50, 5602 (2009)
J. Mol. Catal. A: Chem. 249, 129 (2006)
[21] H. Yamamoto, K. Futatsugi, Angew. Chem. Int. Ed.
44, 1924 (2005)
[9] H.M. Meshram,
D.A. Kumar, B.C. Reddy,
Helv. Chim. Acta 92, 1002 (2009)
[10] M. Bandini,
P.G. Cozzi,
M. Giacomini,
[22] H. Yamamoto, Tetrahedron 63, 8377 (2007)
P. Melchiorre, S. Selva, A. Umani-Ronchi, J. Org. Chem. [23] J. Heinze, Angew. Chem. Int. Ed. 23, 831 (1984)
67, 3700 (2002) [24] P.L. Boulas, M. Gómez-Kaifer, L. Echegoyen,
[11] G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, Angew. Chem. Int. Ed. 37, 216 (1998)
L. Sambri, P. Melchiorre, Org. Lett. 9, 1403 (2007) [25] K. Daasbjerg, H. Svith, S. Grimme, M. Gerenkamp,
[12] M. Agnusdel, M. Bandini, A. Melloni,
C. Muck-Lichtenfeld, A. Barchuk, F. Keller, Angew.
Chem. Int. Ed. 45, 2041 (2006)
A. Umani-Ronchi, J. Org. Chem. 68, 7126 (2003)
[13] H. Firouzabadi, N. Iranpoor, F. Nowrouzi, Chem.
Commun. 789 (2005)
673