An FeCl3-catalyzed highly C3-selective Friedel-Crafts alkylation of indoles with alcohols

Article abstract of DOI:10.1016/j.tetlet.2007.07.208

The FeCl₃-catalyzed C3-selective Friedel-Crafts alkylation of indoles using allylic, benzylic and propargylic alcohols has been developed. The reaction was performed in the presence of a catalytic amount of inexpensive anhydrous FeCl₃

Full text of DOI:10.1016/j.tetlet.2007.07.208

Tetrahedron Letters 48 (2007) 7160–7163
An FeCl3-catalyzed highly C3-selective Friedel–Crafts
alkylation of indoles with alcohols
Umasish Jana,* Sukhendu Maiti and Srijit Biswas
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
Received 19 June 2007; revised 27 July 2007; accepted 30 July 2007
Available online 3 August 2007
Abstract—The FeCl3-catalyzed C3-selective Friedel–Crafts alkylation of indoles using allylic, benzylic and propargylic alcohols has
been developed. The reaction was performed in the presence of a catalytic amount of inexpensive anhydrous FeCl3 (10 mol %) in
nitromethane under mild conditions. This method can also be used for the alkylation of pyrrole.
Ó 2007 Elsevier Ltd. All rights reserved.
The indole framework is a versatile and important struc-
tural motif frequently found in natural products,
pharmaceuticals, and other synthetic compounds.1
Modification of the indole structure is an emerging field
of research. Among the various methods to synthesize
substituted indoles, substitution at C-3 with alcohol
derivatives is important.2 However, the substitution
with derivatives of alcohols produces large amounts of
salt waste as a by-product and many reactions require
stoichiometric amounts of base or Lewis acids. Thus,
in view of the demand for efficient, atom-economic3
and economically valuable processes, the direct catalytic
substitution of indoles with alcohols is highly desirable,
as water is the only by-product (Scheme 1).
hols. Therefore, the development of a more general and
practical method under mild conditions and preferably
using environmentally friendly and inexpensive reagents
is highly desirable.
During the course of our investigations on the catalytic
activation of alcohols using FeCl3,7 as an inexpensive
and environmentally friendly Lewis acid, we herein
report the direct regioselective C-3 alkylation of indoles
using alcohols.
First, we investigated the Friedel–Crafts allylic alkyl-
ation between indole 1a and allyl alcohol 2a in order
to develop the reaction conditions. We found that in
the presence of FeCl3 (10 mol %) at room temperature
in nitromethane as solvent, the reaction proceeded effi-
ciently to afford the allylated product 3a8 in 70% yield.
The reaction was clean and complete within 2 h without
the need for an inert atmosphere, and gave the C3-sub-
stitution product exclusively. Among various solvents,
nitromethane was found to be the best in terms of the
efficiency of the reaction.
Recently, a few reports4–6 have appeared on the direct
catalytic substitution of indole with alcohols. However,
the harsh reaction conditions and the use of expensive,
toxic and moisture sensitive reagents in most of the
above methods limits their practical utility in large-scale
synthesis. Moreover, these methods are not general for
substrates such as benzylic, allylic and propargylic alco-
R3
R4
OH
Catalyst
+
H2O
R2
+
R2
R4
R3
N
R1
N
R1
Scheme 1. Catalytic substitution of indoles.
Keywords: Indole; Ferric chloride; Alkylation; Alcohols; Atom-economical.
*
Corresponding author. Tel.: +91 33 2414 6223; fax: +91 33 2414 6584; e-mail: jumasish2004@yahoo.co.in
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.208

U. Jana et al. / Tetrahedron Letters 48 (2007) 7160–7163
Table 1. FeCl3-catalyzed substitution of indoles 1 with allylic alcohols 2a
7161
Entry
Nucleophile
Alcohol
Product
Time (h)
2
Yieldb (%)
Me
OH
1
70
N
H
OMe
+
1a
N
MeO
2a
H
3a
Me
HO
2
1a
3
56c
Me
N
H
3b
2b
N
H
Cl
Me
OH
3
4
1a
1a
2
3
60c
+
Cl
N
Me
Cl
H
2c
3c
N
H
Ph
OH
Ph
58d
N
H
2d
3d
Me
5
6
2a
2b
2
2
72
65
N
OMe
Me
N
1b
Me
3e
3f
Me
1b
1b
N
Me
Ph
7
8
2d
2a
3
3
72
71
N
Me
3g
Me
Me
N
OMe
H
Me
Me
1c
N
H
3h
Ph
9
1c
2b
2d
2
2
70
N
H
3i
10
60e
N
1d
N
H
H
Ph
3j
a Reaction conditions: Nucleophile 1 (1 mmol), alcohol 2 (1 mmol), FeCl3 (0.1 mmol), nitromethane (3 mL), rt.
b The yield refers to pure isolated product characterized from spectral data.
c Mixture of regioisomers ꢀ3:2 (1H NMR).
d The reaction mixture was stirred at room temperature for 2 h, then alcohol 2 (0.3 mmol) was added and the reaction heated at 55 °C for 1 h.
e Toluene was used as the solvent at room temperature.

7162
U. Jana et al. / Tetrahedron Letters 48 (2007) 7160–7163
The reactions of various indoles with different alcohols
were examined next and the results are summarized in
Table 1. In general, the reactions proceeded smoothly
with high selectivities for various secondary allylic alco-
hols 2a–d with indole in very good yields within very
short periods of time at room temperature. The process
also worked efficiently for N-methylindole and afforded
the desired products in good yields (Table 1, entries
5–7). This result differed from the allylation of indoles
catalyzed by palladium in the presence of trialkylbo-
rane.4a The sterically demanding indole 1c (Table 1, en-
tries 8 and 9) reacted with alcohols 2a and 2b effectively
under these conditions with excellent regioselectivity to
give 3h and 3j in good yields. Unsymmetrical allylic
alcohols without any activating group (Table 1, entries
2 and 3) produced mixtures of regioisomers. The acid
and air sensitive pyrrole 1d (Table 1, entry 10) could also
be allylated using the present method in moderate yield
without any side product formation. Allylation occurred
selectively at the 2-position of pyrrole.9 Although the
present procedure is very useful for reaction with sec-
ondary allylic alcohols, unfortunately, primary allylic
alcohols produced mixtures of products, therefore, these
reactions were not persued further.
Next, we attempted to synthesize 3-benzylated indoles
using this method (Table 2). Both free indole (Table 2,
entry 1) and N-methylindole (Table 2, entries 2–5)
underwent smooth coupling with benzyl alcohol deriva-
tives efficiently and selectively. In the presence of
Table 2. FeCl3-catalyzed substitution of various indoles 1 with benzylic alcohols 4a
Entry
Nucleophile
Alcohol
OH
Ph
Product
Time (h)
3
Yield (%)
75b
Ph
1
N
H
N
1a
H
4a
5a
Me
OH
Me
2
3
4
5
6
4
1
1
1
3
80b
N
Me
1b
N
4b
Me
5b
5c
Me
OH
Me
1b
1b
1b
OMe
92
MeO
N
4c
Me
Me
OH
Me
Me
98
Me
N
4d
S
Me
5d
Me
OH
S
Me
95
N
4e
5e Me
Ph
OH
89b
Ph
N
1e
Ts
N
5f
4f
Ts
a Reaction conditions: Nucleophile 1 (1 mmol), alcohol 2 (1 mmol), FeCl3 (0.1 mmol), MeNO2 (3 mL), room temperature.
b Reaction was performed at 60 °C in the presence of alcohol (1.3 equiv).
OH
FeCl3 (10 mol%)
+
MeNO2, rt, 1 h
then 1 h at 55 oC
N
R
N
R
6
7a: R = H 48%
7b: R = Me 40%
1a: R = H
1b: R = Me
Scheme 2. FeCl3-catalyzed propargylation of indoles.

U. Jana et al. / Tetrahedron Letters 48 (2007) 7160–7163
7163
7. Jana, U.; Biswas, S.; Maiti, S. Tetrahedron Lett. 2007, 48,
4065–4069.
Brønsted or Lewis acid, secondary and tertiary benzylic
alcohols possessing b-hydrogen atoms are very sensitive
to dehydration, but the present method could also be
applied to both secondary and tertiary alcohols (Table
2, entries 3–5). This reaction also proceeded smoothly
with the thiophene derivative 4e (Table 2, entry 5),
affording a hybrid heterocycle in 95% yield. Moreover,
this method could also be applied to N-tosylindole 1e
(Table 2, entry 6) and furnished product 5f in 89% yield.
8. Representative experimental procedure: To a stirred solution
of indole 1a (116 mg, 1 mmol) and allylic alcohol 2a
(178 mg, 1 mmol) in dry nitromethane (3 mL) was added
anhydrous FeCl3 (16 mg, 0.1 mmol). The resulting reaction
mixture was stirred at room temperature for 2 h, and
monitored by TLC. The reaction mixture was then
concentrated under reduced pressure and the residue was
purified by silica gel column chromatography to afford the
alkylated indole 3a (194 mg, 0.7 mmol) as a brown solid,
mp 145 °C; Rf = 0.5 (petroleum ether/EtOAc, 9:1).
Spectral data for novel compounds are given below: 3-[3-(4-
Methoxyphenyl)-1-methyl-allyl]-1H-indole (3a): IR (neat)
Finally, we investigated the FeCl3-catalyzed propargyl-
ation of indoles with propargyl alcohol 6 (1.3 equiv)
using the present method, which afforded alkynes 7a
and 7b in moderate yields (Scheme 2).
1
3409, 2959, 1608, 1512 cmÀ1. H NMR (300 MHz, CDCl3)
dH 1.56 (d, J = 7.0 Hz, 3H), 3.80 (s, 3H), 3.88–3.95 (m, 1H),
6.30–6.49 (m, 2H), 6.83 (d, J = 8.7 Hz, 2H), 7.03–7.39 (m,
6H) 7.69 (d, J = 7.8 Hz, 1H), 7.96 (br s, 1H); 13C NMR
(75 MHz, CDCl3) dC 20.9, 34.3, 55.4, 111.3, 114.0, 119.3,
119.8, 120.5, 120.7, 123.0, 126.9, 127.4, 127.6, 130.8, 133.5,
136.7, 158.8; HRMS: m/z Calcd for C19H19NO: 277.1467;
found, 277.1631.
In summary, we have developed an efficient and atom-
economical method for the direct alkylation of indoles
with various alcohols in the presence of the inexpensive
and non-toxic Lewis acid FeCl3, under mild conditions.
Functional groups that could coordinate to the Lewis
acid, such as an ether, chloride and tosyl remained unaf-
fected under the reaction conditions. Sensitive molecules
such as thiophene and pyrrole also survived under the
reaction conditions. The reaction did not proceed at all
without FeCl3. Although the exact mechanism is uncer-
tain at this moment, presumably, the reaction proceeded
through an aromatic electrophilic substitution, where the
alcohol is activated by coordination with FeCl3. Further
investigation on the reaction mechanism and the scope of
this reaction are currently underway in our laboratory.
3-[3-(4-Chlorophenyl)-1-methyl-allyl]-1H-indole (3c): Mix-
ture of regioisomers (3:2); IR (neat) 3415, 2964, 1489,
1456 cmÀ1 1H NMR (300 MHz, CDCl3) dH 1.57 (d,
;
J = 7.10 Hz, 1.8H), 1.73 (d, J = 6.30 Hz, 1.2H), 3.92–
3.95 (m, 0.6H), 4.87 (d, J = 3.68 Hz, 0.4H), 5.48–5.57
(m, 0.5H), 5.89–5.97 (m, 0.5H), 6.44–6.45 (m, 1H), 6.89–
7.42 (m, 8H), 7.66 (d, J = 7.90 Hz, 1H), 7.99 (br s, 1H);
HRMS: m/z Calcd for C18H16ClN: 281.0971; found,
281.1708.
3-[3-(4-Methoxyphenyl)-1-methyl-allyl]-1-methyl-1H-indole
(3e): IR (neat) 3006, 1606, 1506, 1509, 1467 cmÀ1; 1H NMR
(300 MHz, CDCl3) dH 1.57 (d, J = 7.0 Hz, 3H), 3.77 (s,
3H), 3.81 (s, 3H) 3.91–3.96 (m, 1H), 6.30–6.51 (m, 2H),
6.83–6.90 (m, 3H), 7.10 (t, J = 7.3 Hz, 1H), 7.22–7.33 (m,
4H), 7.70 (d, J = 7.9 Hz, 1H); 13C NMR (75 MHz, CDCl3)
d 21.1, 32.7, 34.3, 55.4, 109.3, 113.8, 114.0, 118.8, 119.2,
119.8, 121.6, 125.4, 127.3, 127.5, 129.4, 130.8, 133.6, 137.4,
158.8; HRMS:m/z Calcd for C20H21NO: 291.1623; found
291.1679.
Acknowledgements
We are pleased to acknowledge financial support from
Jadavpur University. S.B. is thankful to UGC for his
fellowship.
3-[3-(4-Methoxyphenyl)-1-methyl-allyl]-2-methyl-1H-indole
(3h): IR (neat) 3407, 2963, 1680, 1606, 1510 cmÀ1; 1H NMR
(300 MHz, CDCl3) dH 1.57 (d, J = 7.0 Hz, 3H), 2.41 (s,
3H), 3.80 (s, 3H), 3.83–3.92 (m, 1H), 6.36–6.51 (m, 2H),
6.83 (d, J = 8.6 Hz, 2H), 7.06–7.18 (m, 2H), 7.29 (d,
J = 8.5 Hz, 3H), 7.63 (d, J = 7.7 Hz, 1H), 7.75 (br s, 1H);
13C NMR (75 MHz, CDCl3) dC 12.3, 20.5, 33.7, 55.4, 110.4,
114.0, 119.0, 119.4, 120.8, 127.2, 127.3, 127.7, 130.9, 133.2,
135.4, 158.7; HRMS: m/z Calcd for C20H21NO: 291.1623;
found, 291.0237.
References and notes
1. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science: Oxford, 2000; (b) Sundberg, R. J.
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Z. J. Org. Chem. 2006, 71, 9865–9868, and reference cited
therein.
2-(1,3-Diphenylallyl)-1H-pyrrole (3j): IR (neat) 3429, 3026,
1598, 1492, 1450 cmÀ1 1H NMR (300 MHz, CDCl3) dH
;
3. (a) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259–
281; (b) Trost, B. M. Science 1991, 254, 1471.
4.84 (d, J = 7.4 Hz, 1H), 5.96 (s, 1H), 6.16 (d, J = 2.42 Hz,
1H), 6.40–6.67 (m, 3H), 7.19–7.36 (m, 10H), 7.81 (br s, 1H);
13C NMR (75 MHz, CDCl3) dC 48.2, 106.9, 108.5, 117.4,
126.5, 126.9, 127.0, 127.6, 128.5, 128.7, 128.8, 131.2, 131.4,
133.1, 137.1, 142.2; HRMS: m/z Calcd for C19H17N:
259.1361; found, 259.3190.
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Am. Chem. Soc. 2005, 127, 4592–4593; (b) Smith, J. J. K.;
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ruthenium/NH4BH4 system, see: (c) Nishibayashi, Y.;
Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S. J. Am.
Chem. Soc. 2002, 124, 11846–11847; Inada, Y.; Yoshikawa,
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Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem., Int. Ed.
2006, 45, 793–796.
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K. S. N. Tetrahedron Lett. 2007, 48, 3295–3298.
3-Benzhydrol-1-(toluene-4-sulfonyl)-1H-indole
(5f):
IR
(neat) 3059, 3024, 1598, 1494 cmÀ1 1H NMR (300 MHz,
;
CDCl3) d 2.37 (s, 3H), 5.51 (s, 1H), 6.93 (s, 1H), 7.06–7.31
(m, 15H), 7.67 (d, J = 8.14 Hz, 2H), 7.96 (d, J = 8.36 Hz,
1H); 13C NMR (75 MHz, CDCl3) d 21.7, 48.6, 114.0, 120.6,
123.3, 124.9, 125.9, 126.9, 128.3, 128.7, 128.8, 128.9, 129.1,
129.6, 129.9, 142.2, 144.9; HRMS: m/z Calcd for
C28H23NO2SNa: 460.1347; found, 460.1363.
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Tamaru, Y. Heterocycles 2006, 67, 535–541.