Recyclable graphite oxide catalyzed Friedel-Crafts addition of indoles to α,β-unsaturated ketones

Article abstract of DOI:10.1016/j.tetlet.2011.08.002

The Friedel-Crafts addition of indoles to α,β-unsaturated ketones, and nitro styrenes was studied with graphite oxide as catalyst. Various indole derivatives were synthesized in good to excellent yields. The preparation of graphite oxide catalyst from sim

Full text of DOI:10.1016/j.tetlet.2011.08.002

Tetrahedron Letters 52 (2011) 5188–5191
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Recyclable graphite oxide catalyzed Friedel–Crafts addition of indoles to
a,b-unsaturated ketones
⇑
A. Vijay Kumar, K. Rama Rao
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500 607, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The Friedel–Crafts addition of indoles to
a,b-unsaturated ketones, and nitro styrenes was studied with
Received 21 May 2011
Revised 27 July 2011
Accepted 2 August 2011
Available online 9 August 2011
graphite oxide as catalyst. Various indole derivatives were synthesized in good to excellent yields. The
preparation of graphite oxide catalyst from simple and readily available starting materials makes this
method more affordable. The heterogeneous graphite oxide can be easily recovered and recycled up to
five cycles without loss of activity.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Carbon catalysis
Friedel–Crafts reaction
Graphite oxide
Indoles
a,b-Unsaturated ketones
Indole moiety is the constituent of various natural products,
readily available graphite flakes by oxidation with KMnO4/H2SO4.6
We adopted a modified Hummers procedure for the preparation of
graphite oxide.6,7 The prepared GO was dialyzed in a dialysis bag
for 24 h to ensure the complete removal of residual metallic impuri-
ties. After the final purification procedure, we found that Mn was
present in less than 30 ppb by ICP–MS analysis. The other metals like
Fe, Co, Cu, Pb, etc. were below the detection limit. Thus ensuring that
GO was free of metal impurities, the prepared GO was characterized
completely with Raman, IR, XRD and TGA techniques to establish its
authenticity. The powder XRD has shown the complete disappear-
ance of the diffraction peak at 26.6° (3.34 Å) which is characteristic
biologically active compounds and drugs. Indole based molecules
are very important in drug discovery. Many indole ligands with
high-affinity for G-protein coupled receptors have been identified.1
Of these, the 3-substituted indoles show significant biological
activity and are precursors for the synthesis of various natural
and unnatural drug based structures.2 They are accessed by
Friedel–Crafts Michael type addition of indole to
a,b-unsaturated
ketones. Existing methods of synthesis require metal catalysts
and stoichiometric amounts of the reagents with cumbersome iso-
lation procedures and longer reaction times.3 The extra expenses
and efforts to process this inevitably generated toxic metal waste
hinders them from being adopted for large scale synthesis. In view
of these drawbacks, the synthetic protocols utilizing carbon and
modified carbon based catalysts devoid of metals are becoming
more important due to the growing concern for sustainable chem-
istry. Graphene, modified graphite has received much attention
owing to its interesting properties in material science with wide
range of applications.4 Graphene oxide, a delaminated layer of
graphite oxide is shown in Figure 1.
of graphite. The FTIR spectrum (KBr) has shown peaks at m = 3380 cm
ꢀ1 assigned to the hydroxyl group vibration of the C–OH, 1577 and
1381 cmꢀ1 assigned to the O–H deformation of the C–OH group
and 1048 cmꢀ1 strong band attributed to C–O stretching vibration.8
On the other hand pristine graphite was IR inactive and did not show
any of these characteristic peaks. Raman spectroscopy is another
OH
The modified graphite especially graphite oxide (GO), prepared
by the exhaustive oxidation of graphite is being explored as a cata-
lyst for various organic transformations.5 In this context, we present
herein the Friedel–Crafts addition of indoles to a,b-unsaturated ke-
tones catalyzed by graphite oxide (GO). The graphite oxide turns out
OH
HO
HOOC
O
OH
HO
O
COOH
HOOC
O
O
O
HO
HO
O
to be an economical catalyst as it can be prepared simply from the
HOOC
COOH
⇑
Corresponding author. Tel.: +91 40 27193164; fax: +91 40 27160512.
E-mail address: kakulapatirama@gmail.com (K. Rama Rao).
Figure 1. Schematic representation of graphene oxide.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.002

A. Vijay Kumar, K. Rama Rao / Tetrahedron Letters 52 (2011) 5188–5191
5189
Table 1
widely used noninvasive tool for the characterization of carbon. The
Raman spectra of GO showed two strong bands, one at 1359 and
1595 cmꢀ1 which can be attributed to D and G bands, respectively.
Graphite shows a weak D band at 1353 cmꢀ1, strong G band at
1580 cmꢀ1 and a broad D0 band at 2580 cmꢀ1. The increase in
intensity of the band at 1359 cmꢀ1 and disappearance of the D0 band
at 2580 cmꢀ1 in GO confirms the creation of sp3 domains due to ex-
treme oxidation of graphite.9 The IR and Raman analysis signifi-
cantly gratified the formation of GO from graphite. After having
established the authenticity of GO, we tested it for the catalysis of
Freidel–Crafts addition of indole to methyl vinyl ketone. Various sol-
vents and catalysts were screened for the optimum conditions to
obtain the maximum yield of the product. When only water was em-
ployed as solvent, 69% of the product conversion was observed,
whereas reaction with H2O/THF (7:3 ratios) with 20 wt % of GO gave
maximum yield of the product in 92% within 3 h at ambient condi-
tions. However, when 50 wt % of GO was used, the reaction time
has drastically reduced to 1 h with nearly the same yield. The reac-
tion proceeded smoothly at the b-position of indole to MVK without
any NH protection thus exemplifying the efficiency of the catalyst.
Other catalytic systems like PTSA, cyclodextrins, nano catalysts,
acidic Al2O3 were inferior in performance when compared with
GO. The reaction with mineral acids like HCl, H2SO4 also gave only
moderate yields of the product. However, graphite itself was not
able to catalyze the reaction, whereas 20% conversion was observed
in the case of activated charcoal (results summarized in Table 1).
With the reaction conditions being optimized, various substituted
indoles were checked for their conversion with methyl vinyl ketone
and nitro styrenes. Indoles with fluoro, bromo, iodo, cyano, nitro,
methyl, and methoxy substituents underwent reactions smoothly
in the addition to methyl vinyl ketone.
Screening of solvents for graphite oxide catalyzed indole addition to
a
,b-unsaturated
ketonesa
O
Catalyst
Methyl vinyl
ketone
N
H
N
H
Entry Catalyst
% of catalyst Solvent
t (h) Yieldb (%)
1
2
3
4
5
6
7
8
Graphite oxide
Graphite oxide
Graphite oxide
Graphite oxide
Graphite oxide
Graphite oxide
Graphite oxide
Graphite oxide
Graphite oxide
Graphite oxide
50 wt %
H2O
2.5
5.5
3
2
1
69
81
92
90
94
71
56
64
66
52
20
5
10 wt %
20 wt %
30 wt %
50 wt %
50 wt %
50 wt %
50 wt %
50 wt %
50 wt %
H2O/THF
H2O/THF
H2O/THF
H2O/THF
Toulene
3
1,4-Dioxane 3.5
CH3CN
CH2Cl2
MeOH
4
6
5
12
24
24
24
—
8
2
2
24
24
24
10
24
9
10
11
12
13
15
16
17
18
19
20
21
22
23
24
Activated charcoal 50 wt %
H2O/THF
H2O/THF
H2O/THF
H2O/THF
H2O
H2O/THF
H2O/THF
H2O/THF
H2O
Graphite
Fe2O3 nano
Fe3O4 nano
—
50 wt %
10 mol %
10 mol %
—
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
10 mol %
50 wt %
10 mol %
13
11
—
PTSAc
HCl
31
55
67
12
10
25
14
9
H2SO4
b-CDd
Sulfo-b-CDe
CuO nano
Al2O3 acidic
MgO nano
H2O
H2O/THF
H2O/THF
H2O/THF
a
Reaction conditions: indole (1 mmol), methyl vinyl ketone (1.1 mmol), H2O/THF
7:3 ratio, rt.
b
Isolated yield.
para-Toluene sulfonic acid.
b-Cyclodextrin.
c
d
e
The methoxy substituted indole gave the highest yield fol-
lowed by bromo, methyl, cyano, N-methyl, nitro, chloro, iodo,
and fluoro within 2.5–8 h for complete conversion with no poly-
merized or dimerized side products, whereas the reaction of in-
Carboxymethyl-b-cyclodextrin sodium salt.
Table 2
Graphite oxide catalyzed various indoles addition to
a
,b-unsaturated ketonesa
R2
Graphite
oxide
R
R1
R1
R2
R
N
H
+
R1 = COCH3, NO2
N
R2 = CH3, aryl
H
Entry
1
Indole
Acceptor
Product
t (h)
Yieldb (%)
Br
Br
O
O
2.5
89
N
H
N
H
NC
NC
O
O
O
O
O
O
2
3
4
4
81
92
N
H
N
H
MeO
Me
MeO
Me
3.5
4
N
H
N
H
83
N
H
N
H
(continued on next page)

5190
A. Vijay Kumar, K. Rama Rao / Tetrahedron Letters 52 (2011) 5188–5191
Table 2 (continued)
Entry
Indole
Acceptor
Product
t (h)
Yieldb (%)
79
F
F
O
O
5
6
4
N
H
N
H
I
I
O
O
O
3.0
73
N
H
N
H
O
O2N
7
8
9
6.5
5.5
6
77
80
76
N
H
O2N
N
H
O
O
O
N
N
O
N
H
N
Cl
H
Cl
Br
O
N
H
10
11
6.5
72
61
O
N
H
Br
O
O
O
8
N
H
N
H
O
COOH
COOEt
N
H
12
13
24
24
0
0
N
H
COOH
O
O
N
H
N
COOEt
NO2
H
O2N
O2N
4F-Ph
N
H
F
14
36
36
58
40
N
H
OMe
OMe
2,5OMePh
NO2
N
H
15
N
H
a
Reaction conditions: indole (1 mmol), acceptor (1.1 mmol), GO (20 wt %), H2O/THF 7:3 ratio, rt.
Isolated yield.
b
dole with the less reactive electron deficient nitro styrenes took
with indole, whereas, no reaction was observed with b-phenyl
vinyl ketone as well as simple styrene (results summarized in
Table 2).
To evaluate the reusability of GO, the catalyst after completion
of the reaction was filtered and washed with water, dried in a dess-
icator and employed for the next reaction. Likewise the catalyst
was found to be recyclable up to five cycles with no loss of activity.
The performance of GO in effectively catalyzing the reaction was
consistent without any activation and thus validates its recyclabil-
ity (Table 3).10
longer time to give moderate yields of the product. Though 4
and 7 substituted indoles do undergo the reaction, the more hin-
dered 4-substituted indole took much longer time than the 7-
substituted indole to afford the Michael adduct. However, there
was no reaction in the case of 4-bromoindole versus 3-pentene-
2-one, which might be due to steric crowding. No reaction was
observed in the case of indole with carboxylic acid and carboxylic
ester substituents at the
a-position of indole even after 24 h. In
the case of b-methyl vinyl ketone, the reaction did take place

A. Vijay Kumar, K. Rama Rao / Tetrahedron Letters 52 (2011) 5188–5191
5191
Table 3
Supplementary data
Recyclability of graphite oxidea
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.08.002.
O
Catalyst
Methyl vinyl
ketone
N
H
N
H
References and notes
Entry
GO recovered
t (h)
Product yieldb (%)
1. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
2. Radwan, M. A. A.; Ragab, E. A.; Sabry, N. M.; El-Shenawy, S. M. Bioorg. Med.
Chem. 2007, 15, 3832–3841.
Native
—
3
92
89
88
86
86
82
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
96%
94%
92%
92%
89%
3.2
3.5
3.5
4
3. (a) Hagiwara, H.; Sekifujib, M.; Hoshib, T.; Suzukib, T.; Quanxic, B.; Qiaoc, K.;
Yokoyamac, C. Synlett 2008, 608–610; (b) Das, B.; Chowdhury, N.; Damodhar,
K.; Reddy, K. R. Helv. Chim. Acta 2007, 90, 340–345; (c) Gu, Y.; Ogawa, C.;
Kobayashi, J.; Mori, Y.; Kobayashi, S. Angew. Chem. 2006, 118, 7375–7378.
Angew. Chem., Int. Ed. 2006, 45, 7217–7220; (d) Bartoli, G.; Bartolacci, M.;
Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org.
Chem. 2003, 68, 4594–4597; (e) Kantam, M. L.; Laha, S.; Yadav, J.; Choudary, B.
M.; Sreedhar, B. Adv. Synth. Catal. 2006, 348, 867–872; (f) Firouzabadi, H.;
Iranpoor, N.; Jafarpour, M.; Ghaderi, A. J. Mol. Catal. A 2006, 252, 150–155; (g)
Ma, J.; Ng, S.; Yong, Y.; Lou, X.-Z.; Wang, X.; Liu, X.-W. Chem. Asian. J. 2010, 5,
778–782.
4
a
Reaction conditions: indole (1 mmol), methyl vinyl ketone (1.1 mmol), H2O/THF
7:3 ratio, rt.
b
Isolated yield.
4. (a) Shin, H.-J.; Kim, K. K.; Benayad, A.; Yoon, S.-M.; Park, H. K.; Jung, I.-S.; Jin, M.
H.; Jeong, H.-K.; Kim, J. M.; Choi, J.-Y.; Lee, Y. H. Adv. Funct. Mater. 2009, 19,
1987–1992; (b) Wang, G.; Yang, J.; Park, J.; Gou, X.; Wang, B.; Liu, H.; Yao, J. J.
Phys. Chem. C 2008, 112, 8192–8195; (c) Mc Allister, M. J.; Li, J.-L.; Adamson, D.
H.; Schniepp, H. C.; Abdala, A. A.; Liu, J.; Herrera-Alonso, M.; Milius, D. L.; Car,
R.; Prud’homme, R. K.; Aksay, I. A. Chem. Mater. 2007, 19, 4396–4404; (d) Rao, C.
N. R.; Sood, A. K.; Subrahamanyam, K. S.; Govindaraj, A. Angew. Chem. 2009,
121, 7890–7916. Angew. Chem., Int. Ed. 2009, 48, 7752–7777; (e) The Nobel
Prize in Physics 2010 was awarded to Andre Geim, Konstantin Novoselov for
their contributions to graphene.
5. (a) Dreyer, D. R.; Jia, H.-P.; Bielawski, C. W. Angew. Chem. 2010, 121, 6965–6968.
Angew. Chem., Int. Ed. 2010, 49, 6813–6816; (b) Jia, H.-P.; Dreyer, D. R.;
Bielawski, C. W. Tetrahedron 2011, 67, 4431–4434; (c) Jia, H.-P.; Dreyer, D. R.;
Bielawski, C. W. Adv. Synth. Catal. 2011, 353, 528; (d) Dreyer, D. R.; Bielawski, C.
W. Chem. Sci. 2011, 2, 1233–1240.
6. (a) Hummers, W. S., Jr.; Offeman, R. E. J. Am. Chem. Soc. 1958, 80, 1339; (b)
Staudenmaier, L. Ber. Dtsch. Chem. Ges. 1898, 31, 1481; (c) Staudenmaier, L. Ber.
Dtsch. Chem. Ges. 1899, 32, 1394; (d) Nakajima, T.; Matsuo, Y. Carbon 1994, 32,
469.
7. Refer Supplementary data for detailed experimental procedure.
8. Bourlinos, A. B.; Gournis, D.; Petridis, D.; Szabo, T.; Szeri, A.; Dekany, I. Langmuir
2003, 19, 6050–6055.
In conclusion we have studied the Friedel–Crafts addition of
indoles to ,b-unsaturated ketones and nitro styrenes with graph-
ite oxide as catalyst. The graphite oxide was synthesized from the
inexpensive graphite with readily available reagents. The synthe-
sized GO was completely characterized. Graphite oxide was found
to be efficiently catalyzing the Friedel–Crafts reaction of indoles
a
with various electron rich and deficient
a,b-unsaturated ketones
affording good yields of products with simple adoptable proce-
dures at ambient conditions in H2O/THF solvent mixture with short
reaction times and no side product formation. In addition GO was
easily recoverable from the reaction mixture and was recyclable up
to five times with no loss of activity. Overall, graphite oxide turned
out to be an environmentally benign catalyst for the Friedel–Crafts
addition of indoles to a, b-unsaturated ketones and nitro styrenes.
Acknowledgments
9. Stankovich, S.; Dikin, D. A.; Piner, R. D.; Kohlhaas, K. A.; Kleinhammes, A.; Jia, Y.;
Wu, Y.; Nguyen, S. T.; Ruoff, R. S. Carbon 2007, 45, 1558–1565.
10. Though the powder XRD, Raman spectra of the catalyst after five cycles have
shown Graphitic peaks, the catalyst did not show any loss of activity. Refer
Supplementary data for spectra.
A.V.K. is grateful to the University Grants Commision, New Del-
hi for the research fellowship. The authors are thankful to Professor
Jonathan P. Rourke, University of Warwick, UK for his suggestions.