Friedel-Crafts alkylation of indoles with epoxides catalyzed by nanocrystalline titanium(IV) oxide

Article abstract of DOI:10.1016/j.tetlet.2006.06.163

Friedel-Crafts alkylation of indoles with epoxides to afford 3-alkyl indole derivatives at room temperature with moderate to good yields and high regioselectivity using nanocrystalline titanium(IV) oxide catalyst is described.

Full text of DOI:10.1016/j.tetlet.2006.06.163

Tetrahedron Letters 47 (2006) 6213–6216
Friedel–Crafts alkylation of indoles with epoxides catalyzed
by nanocrystalline titanium(IV) oxide
M. Lakshmi Kantam,* Soumi Laha, Jagjit Yadav and B. Sreedhar
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
Received 18 April 2006; revised 20 June 2006; accepted 29 June 2006
Abstract—Friedel–Crafts alkylation of indoles with epoxides to afford 3-alkyl indole derivatives at room temperature with moderate
to good yields and high regioselectivity using nanocrystalline titanium(IV) oxide catalyst is described.
Ó 2006 Elsevier Ltd. All rights reserved.
3-Alkylindole derivatives have significant biological and
pharmacological importance1,2 and can be prepared by
Friedel–Crafts alkylation of indoles using epoxides.
Epoxide ring opening with different nucleophiles3 is gen-
erally carried out with acid or base catalysts.
Titanium dioxide is a prominent material for various
kinds of industrial applications related to catalysis, e.g.
in the selective reduction of NOx in stationary sources,
photocatalysis for pollutant elimination or organic syn-
thesis, photovoltaic devices, sensors, and paints.15
Epoxide ring opening with indoles has been reported
We herein report the use of recyclable, nanocrystalline
titanium(IV) oxide (nano TiO2) catalyst for the Fri-
edel–Crafts alkylation of indoles with epoxides affording
3-alkyl indole derivatives at room temperature with
moderate to good yields and high regioselectivity. Treat-
ment of indole with styrene oxide resulted in the forma-
tion of 2-(3-indolyl)-2-phenylethanol in 64% yield using
10 mol % nano TiO2 (Scheme 1).
using high-pressure conditions4 or SiO2 or lanthanide
5
triflate catalysts.6 In recent years, indium reagents have
emerged as mild Lewis acids, which can promote several
7
8
organic transformations. InCl3 as well as InBr3 have
been used in the Friedel–Crafts addition of indoles with
epoxides. Recently, highly enantioselective addition of
indoles with aromatic epoxides catalyzed by chromium
salen complexes was reported.9
Various types of nanocrystalline metal oxides (nano
TiO2, nano ZnO, nano CuO) as well as commercially
available bulk TiO2 were evaluated for the Friedel–
Crafts alkylation of indoles with styrene oxide. Nano
TiO2 was found to be more active when compared to
the other metal oxides tested (Table 1, entries 5–8).
Among the different solvents used, dichloromethane
gave the optimum yield (Table 1, entries 1–5).
Industry favors catalytic processes induced by heteroge-
neous catalysts over homogeneous processes in view of
the ease of handling, simple work-up, and regenerabil-
ity. Nanocrystalline metal oxides have attracted atten-
tion due to their unusual magnetic, physical and
surface chemical and catalytic properties.10–12 These
materials can exist with numerous surface sites with en-
hanced surface reactivity such as crystal corners, edges
or ion vacancies.13 Recently, Choudary et al. reported
asymmetric Henry and Michael addition reactions cata-
lyzed by nanocrystalline magnesium oxide (MgO) with
good to excellent enantioselectivity.14
To test the generality and scope of this nano TiO2
catalyzed reaction, an array of structurally divergent
Ph
O
OH
Nano TiO2
+
N
H
DCM, RT, 12 h
N
H
Keywords: Nano TiO2; Epoxide; Indole; Heterogeneous catalyst.
*
Scheme 1. Nano TiO2 catalyzed Friedel–Crafts alkylation reaction of
Corresponding author. Tel./fax: +91 40 27160921; e-mail:
indole with styrene oxide.
mlakshmi@iict.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.163

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M. L. Kantam et al. / Tetrahedron Letters 47 (2006) 6213–6216
Table 1. Screening of reaction parameters for addition of indoles to
epoxides and substituted indoles were tested. From
NMR spectral data it was evident that aryl epoxides
underwent cleavage by indole with preferential attach-
ment at the benzylic position, resulting in the formation
of primary alcohols (Table 2, entries 1–10) or secondary
alcohols (Table 2, entries 11 and 12). Since the 3-
position of indole is the preferred site for electrophilic
substitution reactions, 3-alkyl indole derivatives were
obtained exclusively in all reactions.
aromatic epoxidesa
Entry
Solvent
Time
(h)
Catalyst
Yield
(%)b
1
2
3
4
5
6
7
8
MeCN
CH3NO2
THF
Toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
24
24
24
24
12
24
24
24
Nano TiO2
Nano TiO2
Nano TiO2
Nano TiO2
Nano TiO2
Commercial TiO2
Nano ZnO
Nano CuO
43
30
20
52
64, 62c
Trace
>5
In general, indoles bearing electron-donating groups
furnished higher reaction rates, affording the alcohols
in moderate to good yields. On the other hand, the pres-
ence of electron withdrawing groups on the indole sig-
nificantly decreased the rate of the reaction and a low
yield of product was obtained even after prolonged reac-
10
a Reaction conditions: Indole (2.25 mmol), styrene oxide (1 mmol),
catalyst (10 mol %), solvent (3 mL), room temperature.
b Isolated yields.
c Isolated yield after the fifth cycle.
a
Table 2. Alkylation of indoles with epoxides using nano TiO2
Entry
Nucleophile
Epoxide
Product
Time (h)
12
Yield (%)b
64, 62c
O
Ph
Ph
1
OH
N
H
N
H
O
O
OH
Ph
2
3
10
32
68
43
N
H
N
H
NC
OH
NC
N
H
N
H
Ph
Br
O
O
OH
Br
4
5
18
10
68
62
N
H
N
H
Ph
MeO
OH
MeO
N
H
N
H
Ph
O
O
O
OH
6
7
8
12
62
12
67
21
68
N
H
N
H
Ph
O2N
OH
O2N
N
H
N
H
Ph
OH
N
N
Me
Me

M. L. Kantam et al. / Tetrahedron Letters 47 (2006) 6213–6216
6215
Table 2 (continued)
Entry
Nucleophile
Epoxide
Product
Time (h)
10
Yield (%)b
Cl
O
9
72
OH
N
H
Cl
N
H
Cl
O
OH
10
12
66
N
H
Cl
N
H
Ph
OH
O
O
Ph
11
12
18
21
68
61
Ph
N
H
N
H
Ph
OH
COOMe
COOMe
N
H
N
H
a Reaction conditions: Indole (2.25 mmol), epoxide (1 mmol), all the reactions were carried out in anhydrous dichloromethane (3 mL) at room
temperature, employing 10 mol % of nano TiO2.
b Isolated yields.
c Isolated yield after the fifth cycle.
tion time. In the case of 5-nitro- and 5-cyanoindoles very
low yields of the product were observed. In all cases, a
single regioisomer was obtained and the structure was
established by IR, 1H NMR and mass spectroscopic
studies. This method does not require anhydrous sol-
vents or stringent reaction conditions. The reactions
were highly regioselective affording good yields of prod-
ucts in a short period of time. It is interesting to note
that the presence of strongly coordinating groups in this
reaction is well tolerated (Table 2, entries 3 and 7).
its well-defined shape and size (10–20 nm) and higher
specific surface area shows higher activity than other
catalysts.
Acknowledgements
We wish to thank the CSIR for financial support under
the Task Force Project CMM-0006, and S.L. and J.Y.
thank CSIR for the award of research fellowships.
Nanocrystalline metal oxide samples were purchased
from Nanoscale Materials Inc., Manhattan, KS 66502,
USA.
To understand the reason behind the increased activities
of nano TiO2 over the other nanocrystalline metal oxi-
des used, ammonia temperature programmed desorp-
tion (TPD) tests of the samples were run. In the
ammonia TPD test, nano TiO2 (16.150 mL/g) showed
greater desorption of ammonia over commercial TiO2
(0.1422 mL/g), nano ZnO (15.5947 mL/g) and nano
CuO (14.5028 mL/g).
References and notes
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Therefore, the increased activities of nano TiO2 over the
other samples tested may be due to increased acidity.
Besides this, nano TiO2 has higher surface area
(500 m2/g) and higher porosity than commercial TiO2
(SA: 10.69 m2/g), which may contribute to its increased
chemical reactivity.
2. Dirlam, J. P.; Clark, D. A.; Hecker, S. J. J. Org. Chem.
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To conclude, we have shown that nano TiO2 is a highly
active, reusable16 catalyst for the Friedel–Crafts reac-
tions of indoles with epoxides. Thus nano TiO2 with
4. Kotsuki, H.; Nishiuchi, M.; Kobayashi, S.; Nishizawa, H.
J. Org. Chem. 1990, 55, 2969.

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M. L. Kantam et al. / Tetrahedron Letters 47 (2006) 6213–6216
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solution of NaHCO3 (3 mL) and extracted with ether. The
combined organic layers were separated and dried over
Na2SO4. The resultant organic layer was concentrated to
give crude 2-(3-indolyl)-2-phenylethanol (Table 2, entry 1)
and unreacted indole. Column chromatography was
performed using silica gel (100–200 mesh) to afford the
pure product after removing the unreacted indole.8 Yield:
H. J. Org. Chem. 1996, 61, 984.
6. Kotsuki, H.; Teraguchi, M.; Shimomoto, N.; Ochi, M.
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8. Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi,
A. J. Org. Chem. 2002, 67, 5386.
1
64%, H NMR (200 MHz, CDCl3): d 1.61 (br, 1H), 4.18–
9. Bandini, M.; Cozzi, P. G.; Melchiorre, P.; Umani-Ronchi,
A. Angew. Chem., Int. Ed. 2004, 43, 84.
10. Itoh, H.; Utamapanya, S.; Stark, J. V.; Klabunde, K. J.;
Schlup, J. R. Chem. Mater. 1993, 5, 71.
4.23 (m, 2H), 4.50 (t, J = 6.7 Hz, 1H), 7.03–7.48 (m, 10 H),
8.11 (br, 1H); EIMS m/z: 237 (25), 206 (100), 178 (30), 128
(15), 102 (10), 77 (15), 63 (5), 51 (11). The reusability of the
catalyst was assessed after activating the catalyst at 250 °C
for 1 h. The nano TiO2 was reused for five cycles with
consistent activity. All the products (except those from
entries 9 and 10, Table 2) are reported compounds which
11. (a) Jiang, Y.; Decker, C.; Mohs, C.; Klabunde, K. J. J.
Catal. 1998, 180, 24; (b) Guzman, J.; Gates, B. C. Nano
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Am. Chem. Soc. 2003, 125, 2020; (b) Choudary, B. M.;
Kantam, M. L.; Ranganath, K. V. S.; Mahender, K.;
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Zaikovski, V.; Volodin, A.; Rieker, T. J. Am. Chem. Soc.
2000, 122, 4921.
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M. L.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 13167.
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16. General experimental and recycling procedure: Nano TiO2
(10 mol %) was added to a mixture of indole (2.25 mmol)
and styrene oxide (1 mmol) in anhydrous dichloromethane
(3 mL) and the mixture was stirred at room temperature
for 12 h. After completion of the reaction as monitored by
TLC, the catalyst was centrifuged and washed with ether
and DCM. The reaction was quenched with a saturated
1
were identified by IR, H NMR and mass spectroscopic
data.8,9 Spectroscopic and analytical data of new com-
pounds. 2-(2-Methyl-1H-indol-3-yl)-2-(4-chlorophenyl)-
ethanol (Table 2, entry 9): Yellow oil. Yield: 72%, 1H
NMR (200 MHz, CDCl3): d 2.35 (br, 1H), 2.42 (s, 3H),
4.05–4.12 (m, 2H), 4.36 (t, J = 7.5 Hz, 1H), 6.87–7.30 (m,
8H), 7.52 (br, 1H). EI-MS m/z (relative intensity) 285 (20),
254 (100), 204 (18), 176 (28), 110 (12), 77 (15), 52 (18).
IR(neat) 3530, 3397, 3055, 2924, 1616, 1590, 1566, 1488,
1459, 1300, 1092, 1015, 749. Anal. Calcd for
(C17H16ClNO): C, 71.45, H, 5.64, N, 4.90. Found: C,
71.54; H, 5.67; N, 4.85. 2-(1H-Indol-3-yl)–2-(4-chlorophen-
yl)-ethanol (Table 2, entry 10): Yellow oil. Yield: 66%, 1H
NMR (200 MHz, CDCl3): d 2.50 (br, 1H), 3.96–4.17
(m, 2H), 4.34 (t, J = 6.6 Hz, 1H), 6.86–7.40 (m, 9H), 8.08
(br, 1H). EI-MS m/z (relative intensity) 271 (6), 241 (41),
204 (25), 121 (19), 117 (64), 84 (16), 43 (100), 37 (22).
IR(neat) 3544, 3411, 3055, 2879, 1619, 1547, 1490, 1456,
1415, 1340, 1249, 1092, 1045, 1012, 746 Anal. Calcd for
(C16H14NO): C, 70.72; H, 5.19; N, 5.15. Found: C, 70.78,
H, 5.22, N, 5.10.