Friedel-Crafts Alkylation of Nitrogen Heterocycles Using [Bmim][OTf] as a Catalyst and Reaction Medium

Article abstract of DOI:10.1055/s-2008-1078423

Friedel-Crafts alkylation of nitrogen heterocycles, such as indoles and pyrroles, can be carried out in ionic liquids under mild conditions to afford the corresponding alkylated product in moderate to good yields.

Full text of DOI:10.1055/s-2008-1078423

LETTER
1449
Friedel–Crafts Alkylation of Nitrogen Heterocycles Using [Bmim][OTf] as a
Catalyst and Reaction Medium
F
riedel–Crafts Alkylat
.
ion of
N
itrog
L
en
H
eterocycle
a
s
kshmi Kantam,*a Rajashree Chakravarti,a B. Sreedhar,a Suresh Bhargavab
a
Inorganic & Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160921; E-mail: mlakshmi@iict.res.in
b
School of Applied Sciences, RMIT University, Melbourne, Australia
Received 19 March 2008
also as effective catalysts in many reactions.12 The
uniqueness of ionic liquids lies in their physical properties
such as low vapor pressure, wide liquid range, high ther-
mal stability, and highly conductive solvation ability for a
variety of organic substrates and catalysts including
Lewis acids and enzymes.13 In addition, they can be recy-
cled easily without any significant loss of activity. The use
of these ionic liquids have been well demonstrated for
various organic and biotransformations.14,15
Abstract: Friedel–Crafts alkylation of nitrogen heterocycles, such
as indoles and pyrroles, can be carried out in ionic liquids under
mild conditions to afford the corresponding alkylated product in
moderate to good yields
Keywords: nitrogen heterocycle, ring opening, indole, pyrrole,
ionic liquids, epoxide
Indole and pyrrole derivatives are important pharmaco-
logically and biologically active compounds.1 Alkylated
pyrroles are also used for the development of functional
organic materials.2 Therefore a direct synthesis of their
derivatives is desired.
In continuation of our interest to explore new reactions in
ionic liquids, herein we report Friedel–Crafts alkylation of
nitrogen heterocycles with indoles and pyrroles under am-
bient conditions in ionic liquids. This procedure allows a
facile reaction, followed by a simple workup procedure to
give the corresponding products in moderate to good
yields (Scheme 1).
Epoxides on the other hand are well-known carbon elec-
trophiles, which can undergo ring-opening reactions with
a number of nucleophiles to give rise to a vast array of
synthetically important products.3
The general method for ring opening of epoxides with ni-
trogen heterocycles has been reported by using high-pres-
sure conditions and acid catalysis.4
OH
O
[bmim][OTf]
Recently, lanthanide triflates5 and other Lewis acids such
+
N2, r.t., 1.5 h
6
7
N
N
as InBr3 and InCl3 have also been reported as mild cata-
lysts to facilitate this reaction. Enantioselective addition
of indoles to aromatic epoxides, catalysed by chromium–
salen complexes,8 has also been reported. Although the
Lewis acids initiate facile reactions under moderately
mild conditions, they have the problem of waste disposal
and high cost.
H
H
Scheme 1 Friedel–Crafts alkylation of indole with styrene oxide
A range of ionic liquids possessing different chemical
properties was screened for the alkylation of indoles with
styrene oxide. The ionic liquid [bmim][OTf] showed
maximum efficiency (Table 1, entry 1).
Industry favors catalytic processes induced by heteroge-
neous catalysts over homogeneous processes in view of
the ease of handling, simple workup, and regenerability.
Recently, our group reported the Friedel–Crafts alkylation
of indoles by using nanocrystalline titanium(IV) oxide.9
Bandgar et al.10 have reported fluoroboric acid adsorbed
on silica gel as a catalyst for ring opening of aryl epoxides
with nitrogen heterocycles. Very recently, Das et al. have
reported sulfated zirconia as a catalyst for these reac-
tions.11
Table 1 Screening of Different Ionic Liquids for Alkylation of In-
dolesa
Entry
Ionic liquid
[bmim][OTf]
[bmim][Br]
[bmim][PF6]
[bmim][BF4]
CH2Cl2
Time (h)
1.5
Yield (%)b
1
2
3
4
5
85
10
–
1.5
1.5
1.5
3
In the past decade, room-temperature ionic liquids
(RTILs) have emerged as one of the most attractive eco-
benevolent alternatives to volatile organic solvents and
1.5
–
a Reaction conditions: indole (1.2 mmol), styrene oxide (1.0 mmol),
ionic liquid (0.5 ml) stirred under N2 atmosphere at r.t.
b Isolated yields.
SYNLETT 2008, No. 10, pp 1449–1454
x
x
.x
x
.2
0
0
8
Advanced online publication: 19.05.2008
DOI: 10.1055/s-2008-1078423; Art ID: D08908ST
© Georg Thieme Verlag Stuttgart · New York

1450
M. L. Kantam et al.
LETTER
The other ionic liquids gave very low yields of the prod- liquid [bmim][OTf] as the reaction medium, the substrates
uct, whereas [bmim][PF6] did not give any product at all. were added to the reaction in different molar ratios. The
When the reaction was run in CH2Cl2, instead of ionic liq- highest yields of the products were obtained when indole
uid, no product was formed even after prolonged time. and epoxide reacted in the ratio 1.2:1, respectively.
The strong Lewis acid character of [bmim][OTf] may ac-
count for this increased activity. After choosing the ionic
tion of indoles, a wide range of structurally varied indoles
To widen the scope of the [bmim][OTf]-promoted alkyla-
Table 2 [Bmim][OTf]-Promoted Alkylation of Indoles with Styrene Oxidea,16
Entry
1
Nucleophile
Epoxide
Product
Time (h)
1.5
Yield (%)b
85, 82c
Ph
OH
O
N
H
N
H
Ph
OH
Me
Me
2
3
4
5
6
7
1.0
1.0
1.0
1.5
2.5
3.0
82
85
90
82
78
75
N
H
N
H
Ph
OH
MeO
MeO
N
H
N
H
Ph
OH
Me
N
H
Me
N
H
Ph
OH
N
Me
N
Me
Ph
OH
Br
Br
N
H
N
H
Ph
OH
Br
Br
N
H
N
H
Ph
OH
NC
8
9
NC
24
24
18
10
N
H
N
H
OH
O2N
Ph
N
H
a Reaction conditions: indole (1.2 mmol), epoxide (1 mmol), [bmim][OTf] (0.5 mL), stirred under nitrogen atmosphere at r.t. for an appropriate
time.
b Isolated yields.
c Yield after fourth cycle.
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LETTER
Friedel–Crafts Alkylation of Nitrogen Heterocycles
1451
were subjected to undergo this reaction under the opti- 3). The aromatic epoxides having electron-withdrawing
mised reaction conditions affording the corresponding groups reacted much faster (Table 3, entries 2 and 3).
products in moderate to good yields (Table 2).
However, no product was formed by aliphatic epoxides.
It was evident from the NMR spectral data that the aryl ep- In all cases, a single regioisomer was obtained and the
oxides underwent cleavage by indoles with preferential structure was established by IR, 1H NMR, and mass-spec-
attachment at the benzylic position, resulting in the forma- trometric studies. The reactions were highly regioselec-
tion of primary alcohols. Since the 3-position of indole is tive, affording good yields of products in a short period of
the preferred site for electrophilic substitution reactions, time.
3-alkyl indoles were obtained as the sole product in all re-
The methodology was further extended to the ring open-
actions. In general, indoles bearing electron-donating
ing of aromatic epoxides with pyrroles (Scheme 2) to af-
groups furnished higher reaction rates, affording the alco-
ford the corresponding products in moderate yields. The
hols in moderate to good yields (Table 2, entries 2–4). On
results are summarised in Table 4.
the other hand, the presence of electron-withdrawing
In all cases the reaction proceeded efficiently at ambient
groups on the indole significantly decreased the rate of the
temperatures with high regioselectivity. It was observed
reaction and a low yield of product was obtained even af-
that the epoxides also underwent cleavage selectively at
ter prolonged reaction time. In the case of 5-nitro- and 5-
the benzylic position to give the primary alcohol (Table
cyanoindoles, very low yields of the product were ob-
4). The products were obtained as a mixture of the 2-alkyl
and 3-alkyl pyrroles, which were separated by column
chromatography. Since 2-position of the pyrrole is the
served (Table 2, entries 9 and 10). Significantly greater re-
activity was observed in the case of N-methylindole,
which gave a higher yield in comparison with indole (Ta-
preferred site for the electrophilic substitution reaction, 2-
ble 2, entry 4). A variety of aromatic epoxides also under-
alkyl pyrrole was obtained as a major product in all cases.
went facile ring opening, resulting in the formation of the
These were characterised by IR, 1H NMR, and mass-spec-
trometric studies. The presence of an electron-withdraw-
corresponding products in moderate to good yields (Table
Table 3 [Bmim][OTf]-Promoted Ring Opening of Various Aromatic Epoxides with Indolea,17
Entry
Nucleophile
Epoxide
Product
Time (h)
1.5
Yield (%)b
85
Ph
OH
O
1
N
H
N
H
F
O
OH
2
3
4
1.0
1.0
2.5
82
80
78
F
N
H
Cl
O
OH
Cl
N
H
O
OH
N
H
a Reaction conditions: indole (1.2 mmol), epoxide (1 mmol), [bmim][OTf] (0.5 mL), stirred under nitrogen atmosphere at r.t. for an appropriate
time.
b Isolated yields.
Synlett 2008, No. 10, 1449–1454 © Thieme Stuttgart · New York

1452
M. L. Kantam et al.
LETTER
O
OH
[bmim][OTf]
N2, r.t., 2.5 h
+
OH
+
N
H
N
N
H
H
1
2
Scheme 2 Friedel-Crafts alkylation of pyrrole with styrene oxide
Table 4 [Bmim][OTf]-Promoted Alkylation of Pyrroles with Aromatic Epoxidesa
Entry
Nucleophile
Epoxide
Product
Time (h)
2.5
Yield (%)b
O
OH
N
H
1
80
80
N
H
O
OH
N
H
2
3
2.0
2.0
F
F
O
OH
N
H
80
Cl
Cl
O
OH
OH
N
H
4
5
3.5
2.5
78
82
O
N
Me
N
Me
a Reaction conditions: pyrrole (1.2 mmol), epoxide (1 mmol), [bmim][OTf] (0.5 mL), stirred under nitrogen atmosphere at r.t. for an appropriate
time.
b Isolated yields.
ing group in the epoxide gave a more facile reaction Et2O. The recovered ionic liquid was reused for several
(Table 4, entries 2 and 3).
cycles with minimal loss of catalytic activity.
All reactions proceeded smoothly at ambient temperature In summary, a simple, efficient, and recyclable protocol
with high regioselectivity, and good yields of the corre- for a facile alkylation of indoles and pyrroles with ep-
sponding products were obtained in a short period. It is oxides has been described. This occurs at ambient temper-
important to note that products arising from N-alkylation ature, via ring opening of aromatic epoxides using ionic
of indoles and pyrroles were not observed under these re- liquid [bmim][OTf] as an efficient catalyst and reaction
action conditions. Finally, upon completion of the reac- medium. The notable features of this novel procedure are
tion, the ionic liquid [bmim][OTf] was recovered almost mild reaction conditions, high regio- and chemoselectivi-
quantitatively by simple extraction of the product with ty, and simplicity in operation.
Synlett 2008, No. 10, 1449–1454 © Thieme Stuttgart · New York

LETTER
Friedel–Crafts Alkylation of Nitrogen Heterocycles
1453
G. Synlett 2005, 2003. (j) Rencurosi, A.; Lay, L.; Russo, G.;
Caneva, E.; Poletti, L. Carbohydr. Res. 2006, 341, 903.
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K.; Narsaiah, A. V. Tetrahedron Lett. 2003, 44, 1047.
(n) Xu, J.-M.; Wu, Q.; Zhang, Q.-Y.; Zhang, F.; Lin, X.-F.
Eur. J. Org. Chem. 2007, 1798.
Acknowledgement
R.C. thanks the Council of Scientific and Industrial Research
(CSIR), India, for research fellowship.
References and Notes
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Reddy, B. V. S.; Abraham, S.; Sabitha, G. Synlett 2002,
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J.; de Souza, R. F. Polyhedron 1996, 15, 1217. (b) Park, S.;
Kazlauskas, R. J. J. Org. Chem. 2001, 66, 8395. (c) Verma,
R. S.; Namboodiri, V. V. Pure Appl. Chem. 2001, 73, 1309.
(16) General Procedure for the Friedel–Crafts Alkylation of
N-Heterocycles Using [Bmim][OTf]
To a stirred solution of indole (1.2 mmol, 142 mg) in ionic
liquid (1.2 mmol, 0.5mL), styrene oxide (1.0 mmol, 120 mg)
was added under nitrogen atmosphere and stirred for 1.5 h at
r.t. After completion of the reaction, as monitored by TLC,
the crude product was extracted with Et2O (3 × 10 mL). The
combined ether extracts were concentrated in vacuo and the
resulting product was purified by column chromatography
on silica gel (100-200 mesh) with EtOAc–n-hexane (1:4) as
eluent to afford pure 2-(3-indolyl)-2-phenylethanol (Table 2,
entry 1); yield 85%. 1H NMR (200 MHz, CDCl3): d = 1.61
(br, 1 H), 4.18–4.23 (m, 2 H), 4.50 (t, J = 6.7 Hz, 1 H), 7.03–
7.48 (m, 10 H), 8.11 (br, 1 H). MS (EI): m/z = 237 (25), 206
(100), 178 (30), 128 (15), 102 (10), 77 (15), 63 (5), 51 (11).
Other known products were identified by comparison with
the data in the literature, see ref. 7 and 10. The ionic liquid
was dried under vacuum and preserved for the next run.
(17) Spectroscopic and analytical data of new compounds.
2-(3-Indolyl)-2-(4-flourophenyl)ethanol (Table 3, Entry
2)
Yield 82%. 1H NMR (300 MHz, CDCl3): d = 1.81 (1 H, br),
4.06–4.26 (2 H, m), 4.44 (1 H, t, J = 6.7 Hz), 6.90–7.37 (9 H,
m), 8.05 (1 H, br). 13C NMR (75 MHz, CDCl3): d = 44.83,
66.36, 111.28, 115.23, 115.53, 115.84, 119.30, 119.63,
121.90, 122.42, 126.84, 129.69 (2), 136.53, 137.43, 163.33.
MS (EI): m/z (rel. intensity) = 255 (13), 224 (100), 222 (14),
196 (10), 177 (7), 77 (12), 63 (13), 41 (14). IR (neat): 3578,
3419, 3069, 2885, 1623, 1556, 1501, 1462, 1412, 1351,
1250, 1106, 1070, 1017, 754 cm–1. Anal. Calcd for
C16H14FNO: C, 70.72; H, 5.19; N, 5.15. Found: C, 70.76; H,
5.24; N, 5.11.
2-(3-Indolyl)-2-(naphthyl)ethanol (Table 3, Entry 4)
Yield 78%. 1H NMR (300 MHz, CDCl3): d = 1.62 (1 H, br),
4.17–4.25 (2 H, m), 4.46 (1 H, t, J = 6.7 Hz), 7.00–7.47 (12
H, m), 8.10 (1 H, br). 13C NMR (75 MHz, CDCl3): d = 44.96,
66.41, 111.09, 115.36, 119.53, 119.84, 121.86, 122.18,
126.68, 126.82, 126.91, 128.22, 128.53, 129.14, 129.60,
136.61, 137.03, 141.73. MS (EI): m/z (rel. intensity) = 287
(16), 283 (19), 218 (7), 185 (9), 171 (10), 155 (12), 144 (13).
IR (neat): 3546, 3409, 3106, 2980, 1614, 1535, 1308, 1061,
1445, 1306, 1077, 1029,752 cm–1. Anal. Calcd for
C20H17NO: C, 83.59; H, 5.96; N, 4.87. Found: C, 83.62; H,
5.98; N, 4.80.
(9) Kantam, M. L.; Laha, S.; Yadav, J.; Sreedhar, B.
Tetrahedron Lett. 2006, 47, 6213.
(10) Bandgar, B. P.; Patil, A. V. Tetrahedron Lett. 2007, 48, 173.
(11) Das, B.; Thirupathi, P.; Kumar, R. A.; Reddy, K. R. Catal.
Commun. 2008, 9, 635.
(12) (a) Welton, T. Chem. Rev. 1999, 99, 2071. (b) Dupont, J.;
de Souza, R. F.; Saurez, P. A. Z. Chem. Rev. 2002, 102,
3667. (c) Wasserscheid, P.; Kiem, W. Angew. Chem. Int. Ed.
2000, 39, 3772. (d) Wasserscheid, P.; Welton, T. Ionic
Liquids in Synthesis; Wiley-VCH: Weinheim, 2003.
(13) (a) Gordon, C. M. Appl. Catal., A 2001, 222, 101.
(b) Sheldon, R. Chem. Commun. 2001, 2399. (c) Welton, T.
Coord. Chem. Rev. 2004, 248, 2459. (d) Jain, N.; Kumar,
A.; Chauhan, S.; Chauhan, S. M. S. Tetrahedron 2005, 61,
1015.
(14) (a) Song, C. E.; Shim, W. H.; Roh, E. J.; Lee, S.; Choi, J. H.
Chem. Commun. 2001, 1695. (b) Chen, S. L.; Ji, S. L.; Loh,
T. P. Tetrahedron Lett. 2003, 44, 2405. (c) Zerth, H. M.;
Leonard, N. M.; Mohan, R. S. Org. Lett. 2003, 5, 55.
(d) Fraile, J. M.; Garcia, J. I.; Herrerias, C. I.; Mayoral, J. A.;
Reiser, O.; Vaultier, M. Tetrahedron Lett. 2004, 45, 6765.
(e) Park, S. B.; Alper, H. Chem. Commun. 2004, 1306.
(f) Earle, M. J.; Katdare, S. P.; Seddon, K. R. Org. Lett.
2004, 6, 707. (g) Lancaster, N. L.; Welton, T. J. Org. Chem.
2004, 69, 5986. (h) Ranu, B. C.; Benerjee, S. Org. Lett.
2005, 7, 3049. (i) Li, W.-J.; Lin, X.-F.; Li, G.-L.; Wang, Y.-
2-(2-Pyrrolyl)-2-(4-fluorophenyl)ethanol (Table 4, Entry
2)
Yield 80%. 1H NMR (300 MHz, CDCl3): d = 1.52 (1 H, br),
3.92–4.05 (2 H, m), 4.07–4.10 (1 H, m), 5.91–5.93 (1 H, m),
6.10 (1 H, dd, J = 6.0, 3.0 Hz), 6.70 (1 H, m), 7.18 (2 H, d,
J = 8.8 Hz), 7.34 (2 H, d, J = 8.8 Hz), 8.16 (1 H, br). 13
C
NMR (75 MHz, CDCl3): d = 57.11, 67.78, 105.92, 108.20,
115.38, 117.41, 118.51, 129.66, 129.75, 129.83, 136.42,
161.76. MS (EI): m/z (rel. intensity) = 205 (15), 174 (100),
154 (5), 146 (17), 127 (14), 91 (27), 78 (18), 51 (16). IR
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M. L. Kantam et al.
LETTER
(neat): 3356, 3005, 1706, 1495, 1409, 1095, 1062, 1011,
831, 758 cm–1. Anal. Calcd for C12H12FNO: C, 70.23; H,
5.89; N, 6.82. Found: C, 70.26; H, 5.91; N, 6.79.
2-(2-Pyrrolyl)-2-(4-chlorophenyl)ethanol(Table 4, Entry
3)
Found: C, 65.06; H, 5.49; N, 6.29.
2-(2-Pyrrolyl)-2-(4-naphthyl)ethanol (Table 4, Entry 4)
Yield 78%. 1H NMR (300 MHz, CDCl3): d = 1.52 (1 H, br),
4.15 (1 H, dd, J = 5.7, 10.6 Hz), 4.25 (1 H, dd, J = 6.6, 10.6
Hz), 4.36 (1 H, t, J = 7.5 Hz), 6.0 (1 H, dd, J = 6.0, 3.0 Hz),
6.18 (1 H, m), 6.71 (1 H, m), 7.34–7.82 (7 H, m), 8.38 (1 H,
br). 13C NMR (75 MHz, CDCl3): d = 47.16, 66.39, 105.95,
107.03, 117.36, 125.36, 125.82, 125.91, 126.26, 126.40,
127.57, 127.74, 128.56, 132.63, 137.84. MS (EI): m/z (rel.
intensity) = 238 (75), 235 (28), 220 (28), 219 (15), 218 (9),
91 (27), 199 (6), 171 (12), 153 (11), 141 (19). IR (neat):
3498, 3349, 3040, 2995, 2925, 1692, 1490, 1241, 1090,
1058, 1015, 826, 711 cm–1. Anal. Calcd for C16H15NO: C,
80.98; H, 6.37; N, 5.90. Found: C, 80.95; H, 6.35; N, 5.92.
Yield 80%. 1H NMR (300 MHz, CDCl3): d = 1.52 (1 H, br),
3.90–4.04 (2 H, m), 4.05–4.12 (1 H, m), 5.91–5.94 (1 H, m),
6.08 (1 H, dd, J = 6.0, 3.0 Hz), 6.64 (1 H, m), 7.25 (2 H, d,
J = 8.8 Hz), 7.29 (2 H, d, J = 8.8 Hz), 8.13 (1 H, br). 13
C
NMR (75 MHz, CDCl3): d = 56.28, 67.14, 107.0, 109.05,
115.16, 119.08, 130.62, 133.17, 133.24, 156.02. MS (EI):
m/z (rel. intensity) = 221 (13), 190 (100), 154 (36), 141 (10),
127 (19), 97 (7), 73 (28), 57 (22), 43 (36). IR (neat): 3346,
2925, 1692, 1490, 1406, 1090, 1058, 1015, 826, 761 cm–1.
Anal. Calcd for C12H12ClNO: C, 65.02; H, 5.46; N, 6.32.
Synlett 2008, No. 10, 1449–1454 © Thieme Stuttgart · New York