Magnetic nano Fe3O4 and CuFe2O4 as heterogeneous catalysts: A green method for the stereo- and regioselective reactions of epoxides with indoles/pyrroles

Article abstract of DOI:10.1016/j.catcom.2012.09.030

In this paper, we report a new solvent-free catalytic method using the magnetic nano Fe₃O₄ and CuFe₂O₄ as competent heterogeneous catalysts for the stereo- and regioselective reactions of epoxides with indoles/p

Full text of DOI:10.1016/j.catcom.2012.09.030

Catalysis Communications 29 (2012) 118–121
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Catalysis Communications
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Short Communication
Magnetic nano Fe3O4 and CuFe2O4 as heterogeneous catalysts: A green method for
the stereo- and regioselective reactions of epoxides with indoles/pyrroles
⁎
Ramarao Parella, Naveen, Srinivasarao Arulananda Babu
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Knowledge City, Sector 81, SAS Nagar, Mohali, Manauli P.O., Punjab 140306, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 May 2012
Received in revised form 1 July 2012
Accepted 25 September 2012
Available online 3 October 2012
In this paper, we report a new solvent-free catalytic method using the magnetic nano Fe3O4 and CuFe2O4 as
competent heterogeneous catalysts for the stereo- and regioselective reactions of epoxides with indoles/pyrroles,
which gave the C-alkylated indoles/pyrroles. Chiral epoxides gave the alkylated indoles with a complete inversion
of stereochemistry.
© 2012 Elsevier B.V. All rights reserved.
Keywords:
C–C bond formation
Heterogeneous catalysts
Epoxides
Heterocycles
Nanoparticles
1. Introduction
In recent years, the magnetic nanoparticles-based catalysts have
been widely used as heterogeneous catalysts for achieving various
The development of efficient catalytic methods, facile recovery of
the catalyst from the reaction medium and recyclability of the catalyst
are very important tasks in modern synthetic chemistry. Indole and
pyrrole motifs are the core unit in various natural products and bio-
logically active molecules. Especially, the alkylated indoles/pyrroles
are potential synthetic intermediates as their synthesis has been the
subject of various studies [1–4]. The ring opening of epoxides with
N-, O- and S-based nucleophiles is well studied; however, the reac-
tions of epoxides with carbon nucleophiles (e.g. indole) are relatively
less explored [5]. The synthesis of alkylated indoles/pyrroles from the
reaction of epoxides with indoles/pyrroles is an atom economic con-
version. Generally this conversion has been carried out using strong
acidic/basic catalysts [6–8] or Lewis acids [9–12] or heterogeneous
catalysts [13–17]; notably, in this regard there exist only limited re-
ports based on eco-friendly conditions and heterogeneous catalysts
[16]. Further, there exist few reports [6,7,10] on the stereoselective
reactions of chiral epoxides with indoles/pyrroles [18,19].
Many of the reported methods are efficient; however, in some
methods the catalyst recovery/reuse is not possible and halogenated
solvent (DCM) or relatively expensive catalysts or high temperature/
pressure were employed [5–19]. Generally, indoles/pyrroles have rela-
tively low nucleophilicity for the direct attack at epoxides. Hence a
mild activation of the C-O bond of an epoxide is preferred as the strong-
ly acidic catalysts may cause isomerization of epoxides.
important chemical transformations [20,21]. Because of the magnetic
properties, a complete recovery of the catalyst from the reaction me-
dium is highly possible.
To the best of our knowledge, the reaction of epoxides with indoles/
pyrroles has not been reported using iron-based nanoparticles/catalysts.
We herein report the magnetic nano Fe3O4 and CuFe2O4 as proficient
heterogeneous catalysts for the stereo- and regioselective reaction of ep-
oxides with indoles/pyrroles.
2. Experimental
2.1. General
Solvents were purified by conventional methods. All reagents/
catalysts were purchased from Aldrich. The 1H and 13C NMR spec-
tra were recorded on a Bruker Avance-400 MHz spectrometer
(using CDCl3 with TMS as the standard). PXRD, HRTEM and HPLC
data sets were recorded on Rigaku Ultimia IV diffractometer, JEOL
JEM 2100 Instrument and Shimadzu HPLC system, respectively.
The copies of 1H and 13C NMR spectra of all the (known and new)
products obtained in this work have been given in the supplemen-
tary file.
2.2. General procedure for the magnetic nano Fe3O4-catalyzed reaction of
indoels/pyrroles with expoxides
A RB flask containing a mixture of styrene oxide (2a, 1 mmol), in-
dole (1a, 1 mmol) and magnetic nano Fe3O4 (b 50 nm, 10 mol%) was
⁎
Corresponding author. Fax: +91 172 2240266.
E-mail address: sababu@iisermohali.ac.in (S.A. Babu).
1566-7367/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.catcom.2012.09.030

R. Parella et al. / Catalysis Communications 29 (2012) 118–121
119
Table 2
stirred at rt for 24 h. The purification of the compound 3a and catalyst
Magnetic nano Fe3O4-catalyzed reaction of indoles with epoxides.
recovery were carried out as stated in the work-up method ‘A’ (for
the other work-up methods see the supplementary file).
R6 OH
R7
Work-up method ‘A’: Step 1. After the reaction period, EtOAc
(1–2 mL) was added to the reaction flask containing the crude reac-
tion mixture and stirred for 1–2 min. Step 2. A magnet was exter-
nally appended to the RB flask and the magnetic nano Fe3O4
catalyst was accumulated at the walls of the flask; the resulting
clear solution was transferred in to a fresh RB flask using a dropper.
Next, Steps 1 and 2 were repeated thrice. Then, the catalyst
containing flask was dried in an oven (at 100–110 °C, overnight)
and recycled. The combined organic layers were concentrated in
vacuum and purification of the resulting reaction mixture by col-
umn chromatography furnished the product 3a.
nano F e3O4
O
R3
R3
R6
R5
(10mol% )
neat
+
R2
R7
R5
R2
N
N
R4
R1
R4
R1
rt, 9 - 24 h
Entry
a
t(h) Isolated Yield (%)a
(1) Nucleophile
R1 R2
(2) Epoxide
R5 R6 R7
R3
H
R4
H
3b; 70
H
H
Cl
H
H
1a
2b
12
3c; 70
3d; 75
3e; 77
H
H
H
H
Me
Me
H
H
H
H
H
H
Br
H
2b Cl
H
H
H
H
H
H
b
c
d
1a
1b
1b
2c
2a
9
24
16
3f; 70
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
F
H
Cl
Br
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
e
f
g
h
i
j
k
l
1b
1b
1c
1c
1c
1c
1d
1d
2c
2d
2a
2b
2c
2d
2a
2b
18
24
24
24
24
24
24
24
3g; 63
3h; 71 (55)b
3i; 71
Me
Me
Me
Me
H
H
3. Results and discussion
3j; 74
3k; 70
3l; 71
H
H
H
H
H
H
OMe
OMe
H
Cl
At the outset, we performed the optimization reactions, which re-
vealed that 10 mol% of the magnetic nano Fe3O4 and solvent-free
condition as the best operative experimental conditions for the reac-
tion of indole with styrene oxide (Table 1).
The generality, scope and limitations of the magnetic nano
Fe3O4-catalyzed reaction of epoxides with indoles are shown in
Table 2. A variety of substituted indoles were reacted with various epox-
ides, which afforded the regioselective products 3b-v in very good yields.
Indoles containing electron-withdrawing substituents e.g. 5-NO2
and 5-CN were smoothly furnished the respective products 3o-s.
3m; 75
H
3n; 74
3o; 65
3p; 70
3q; 65
3r; 67c
3s; 63c
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
Br
Br
H
H
H
H
H
H
Et
Et
Br
H
2b Cl
2c Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
m
n
o
p
q
r
1d
1e
1e
1e
1f
1g
1h
1h
2c
2a
24
15
18
24
12
24
24
24
Br
CN
NO2
H
H
H
H
Cl
2a
2a
2a
2b
3t; 80 (74)b (45)d (75)e
3u; 74
s
t
H
3v; 74
H
H
H
H
Et
Br
H
H
u
v
1h
2c
16
OH
EtOOC
Ph
24
H
H
H
1a
2e
Ph
O
EtOOC
O
N
H
3w; 29
Table 1
H
H
H
H
H
H
H
H
w
xf
1a
1a
2f
3x; N.D
24
24
Magnetic nano Fe3O4-catalyzed alkylation of 1a.
PhO
OH
O
2g
PhO
O
Ph
catalyst (Xmol%)
OH
N
H
3y; 29
OH
+
N
H
solvent (2mL)
(or) neat
condition, 24h
yg
zg
1a
1c
2h
2h
24
24
N
H
H
H
H
H
H
H
H
O
O
1a (1 mmol) 2a (1 mmol)
3a
Yield (%)a
3z; 50
3aa; 56
Me
N
R1
Entry
Catalyst (mol %)
Solvent
Temp (°C)
OH
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Nil
Nil
Neat
rt
b5
b5
30
34
35
15
36
38
Neat
70–75
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
zag 1h
H
H
H
Et 2h
24
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (15)
Nano Fe3O4 (5)
Nano Fe3O4 (8)
Nano Fe3O4 (10)
Powder Fe3O4 (10)
Powder Fe3O4 (10)
Nano Fe2O3 (10)
Powder Fe2O3 (10)
Nano CuFe2O4 (10)
Nano CuFe2O4 (10)
Nano CuFe2O4 (5)
Nano CuFe2O4 (10)
Hexane
Toluene
THF
N
H
Ph
3ab; 60
Et
O
OH
zb
DMF
P h
N
H
MeOH
EtOH
1,4-Dioxane
MeCN
DCM
1a; 5g
2a; 6.15g
3a; 65
(6.57g)
N
H
Ph
37
65 (45)b
OH
57 (40)b
zch
O
1h
Ph
N
H
1,2-DCE
Neat
64 (45)b
3t
N
H
Et
66
68
2a
Et
Neat
rt
I recyclization = 75
II recyclization = 74
Neat
rt
76 (75)c (71)d
Neat
rt
50 (47)c (43)d
a All the reactions were done using 1 mmol of 1/2 unless otherwise stated and work up
Neat
Neat
70–75
rt
50
was carried out as given in method 'A'.
(20)c (22)e
b
Nano CuFe2O4 was used instead of nano Fe3O4.
s
t
u
v
w
Neat
rt
(20)c (21)e
c 2 mmol of 2 was used.
MeCN
Hexane
Neat
Reflux
rt
rt
59
34
54
70
d Powder Fe3O4 was used and the work up was carried out as given in method 'C' (see
the supplementary file).
e Nano Fe3O4 was used as a catalyst and the work up was carried out as given in method
'C' (see the supplementary file).
Neat
rt
a
f
Work up was carried out as given in method ‘A’ (see experimental Section 2.2 and
supplementary file) unless otherwise stated.
The reaction was done in MeCN at 80 °C.
g
2.2 mmol of 2h was used as 2h has a low Bp.
b
h
The reaction was carried out at rt and the corresponding yield is given in the pa-
The catalyst was recycled twice.
renthesis.
c
Work up was carried out as given in method ‘B’ (see the supplementary file).
Work up was carried out as given in method ‘C’ (see the supplementary file).
Work up was carried out as given in method ‘D’ (see the supplementary file).
d
e

120
R. Parella et al. / Catalysis Communications 29 (2012) 118–121
Table 3
with aliphatic epoxide 2-vinyloxirane successfully gave the respec-
tive homoallylic alcohols 3z, 3aa and 3ab. To demonstrate the recy-
clability of the magnetic nano Fe3O4, the reaction of 1h and 2a was
performed using the recovered magnetic nano Fe3O4, which gave
the product 3t in 75% (I recyclization) and 74% (II recyclization)
yields, respectively.
The FT-IR spectra and XRD patterns revealed the absence of any
characteristic peaks of organic impurities in the used magnetic nano
Fe3O4. Evaluation of the HRTEM images of the used magnetic nano
Fe3O4 revealed that the morphology of the used magnetic nano
Fe3O4 is considered to be stable (See the supplementary file for
FT-IR, PXRD and HRTEM data).
Magnetic nano Fe3O4-catalyzed alkylation of pyrrole and stereoselective reactions of
R-(2i) and S-(2j) with indoles.
t (h)
Entry
(2) Epoxide
Isolated Yield (%)
O H
(1) Nucleophile
R5
O
N
R5
N
H
H
1i
R5
N
H
O H
2a-c
R5=Cl; 4a (14%)
R5=Br; 4b (14%)
R5=F; 4c (23%)
R5=H; 4d (23%)
R5=Cl; 5a (43%)
R5=Br; 5b (42%)
R5=F; 5c (32%)
R5=H; 5d (35%)
a
b
c
24
24
24
24
d
Ph
Then, the reaction of pyrrole with styrene oxides (2a-d) in the
presence of the magnetic nano Fe3O4 (10 mol%) furnished the respec-
tive regioisomeric C-alkylated products 4a-d and 5a-d (Table 3). Finally,
we performed the stereoselective reactions of (R)-styrene oxide and
(S)-styrene oxide with various indoles using the magnetic nano Fe3O4
(10 mol%, Table 3).
O
OH
Ph
N
1a
R1=H; 3ac; 72 (99%ee)
R1=Me; 3ad; 71 (99%ee)
e
f
24
24
R1
2i; (R)
2i; (R)
N
1c
R1
Ph
O
O H
P h
2j; (S )
N
1c
R1=Me; 3ae; 72 (99%ee)
g
Interestingly, the chiral epoxides gave the alkylated indoles in very
good yields with a complete inversion of stereochemistry, which indicat-
ed the operation of a SN2-type mechanism and based on the X-ray struc-
ture of a representative product 3m [22], a plausible mechanistic
pathway for the magnetic nano Fe3O4-catalyzed reaction of epoxides
with indoles is proposed (Scheme 1).
All the reactions are clean, highly regio- and stereoselective as
the epoxide 2 underwent cleavage by indoles with preferential
attachment at the benzylic position and selectively furnished
the primary alcohols. Since the 3-position of indole is the pre-
ferred site for electrophilic substitution reactions, C3-alkylated
indole derivatives were exclusively obtained in all of the above
reactions.
2
R1
N
R1
P h
OH
Br
O
Br
Ph
N
H
3af; 66 (99%ee)
h
i
1e
24
2i; (R)
N
H
Ph
OH
O
Ph
Ph
N
H
N
H
3ag; 74 (99%ee)
1h
24
Et
Et
2i; (R)
Et
P h
OH
O
N
H
N
H
3ah; 75 (99%ee)
1h
j
24
2j; (S )
Et
aAll the reactions were done using 1 (1 mmol), 2 (1 mmol) and Fe3O4 (10 mol%).
4. Conclusion
In summary, we have shown that the magnetic nano Fe3O4- and
CuFe2O4 as competent heterogeneous catalysts for the highly stereo-
and regioselective reaction of epoxides with indoles/pyrroles. In the
case of chiral epoxides, the alkylated indoles were obtained with a com-
plete inversion of stereochemistry. This is an eco-friendly heteroge-
neous catalytic method in which no need of any solvent and high
temperature/pressure.
The reaction of indole with ethyl 3-phenylglycidate (2e, mixture of
trans and cis) afforded the product 3w in 29% yield. The reaction of
cyclohexene oxide with indole failed to give any product. The reac-
tion of indole and 2-(phenoxymethyl)oxirane (2 g) in MeCN at
refluxing temperature gave the product 3y in 29% yield. These lim-
itations are because, generally, the aliphatic epoxides are less reac-
tive than aryl epoxides [16]. Notably, the reaction of indoles 1a,c,h
Scheme 1. Ortep diagram of 3m and plausible mechanism.

R. Parella et al. / Catalysis Communications 29 (2012) 118–121
121
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Appendix A. Supplementary data
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.catcom.2012.09.030.
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