Rapid and general protocol towards catalyst-free friedel-crafts C-alkylation of indoles in water assisted by microwave irradiation

Article abstract of DOI:10.1002/ejoc.200901333

An efficient and simplified protocol for uncatalyzed FriedelCrafts alkylation of indoles using microwave irradiation in water is described. A series of functionalized indole derivatives has been synthesized in very short times with moderate to good yields. The combination of microwave irradiation and superheated water offers significant advantages over conventional methods, such as higher selectivities, simplicity, shorter reaction times, and no need for a catalyst.

Full text of DOI:10.1002/ejoc.200901333

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901333
Rapid and General Protocol towards Catalyst-Free Friedel–Crafts
C-Alkylation of Indoles in Water Assisted by Microwave Irradiation
Margherita De Rosa*[a] and Annunziata Soriente[a]
Keywords: Indoles / Friedel–Crafts reaction / Microwave irradiation / Superheated water / Synthetic methods / Nitrogen
heterocycles / Microwave chemistry / Alkylation
An efficient and simplified protocol for uncatalyzed Friedel–
Crafts alkylation of indoles using microwave irradiation in
water is described. A series of functionalized indole deriva-
tives has been synthesized in very short times with moderate
to good yields. The combination of microwave irradiation
and superheated water offers significant advantages over
conventional methods, such as higher selectivities, simplicity,
shorter reaction times, and no need for a catalyst.
could immediately trap the SN1 reaction intermediate and
thus annihilate the chance of π nucleophiles to intercept the
transient carbocation.
Introduction
The indole framework, identified as privileged structure,[1]
is a structural motif observed in various natural products
possessing different biological activities and in complex mo-
lecules with numerous applications, such as pharmaceuti-
cals and agrochemicals.[2] Among the various methods for
the introduction of functionalized alkyl frameworks at the
3-position of the indolyl core, Lewis and Brønsted acid pro-
moted Friedel–Crafts reactions (FC)[3] play a prominent
role. The classical Friedel–Crafts reaction suffers from rel-
evant drawbacks, such as chemical aspects (reactivity and
selectivity), environmental concerns associated with the use
of poorly manageable catalysts and the release of large
amounts of environmentally hazardous wastes, this also
combined with indole’s susceptibility to strong acid cata-
lysts. These disadvantages have encouraged the develop-
ment of numerous reaction variants with an ever increasing
attention to cleaner and environmentally more friendly stra-
tegies.[4]
Water-mediated reactions have attracted much attention
in organic synthesis in recent years,[5] not only because
water offers practical advantages over organic solvents from
economical, environmental and safety standpoints, but also
because reactions in aqueous media display reactivities and
selectivities different from those in conventional organic
solvents, and in many cases they exceed those in organic
solvents. Historically, the inability to perform the Friedel–
Crafts reaction under basic and even neutral aqueous con-
ditions is reported,[3,6d] since water, as a strong nucleophile,
Interesting advances in this field were made by Mayr et
al.[6] It was found that the alkylation reactions between
alkyl halides and π nucleophiles, such as indole, are possible
in water, a solvent considered prohibitive for such reactions,
without the use of any catalyst. The indole can compete
with the solvent system by trapping the intermediate carbo-
cation, provided that the nucleophilicity of the reaction in-
termediate is higher than that of the solvent system.[6] How-
ever, the method is not general and is limited by the ioniza-
tion rates of the corresponding alkyl halides – this has been
often reported for benzhydrylium and 4-methoxybenzyl cat-
ions (classical carbocations present in the Mayr’s list).[6]
Over the past years, the combination of water as reaction
medium with microwave irradiation as a nonclassical energy
source has been recognized as a viable environmentally
friendly alternative. The interest in this field is evidenced by
the increasing number of related publications and reviews,
which emerged in recent years.[7] The efficiency of micro-
wave irradiation with dramatically reduced reaction times
and increased product yields as well as selectivity improve-
ment is one of the key features of this approach, in addition
to the advantages of conducting organic reactions in water.
Furthermore, under microwave (M.W.) irradiation water is
rapidly heated to high temperatures (Ͼ100 °C, “super-
heated conditions”) enabling its behavior as a pseudo-or-
ganic solvent with favorable physical and chemical property
changes.
Based on the above reports and expecting beneficial mi-
crowave effects according to the reaction mechanism and
the polarity change of the system during the reaction pro-
gress, we envisioned the possibility of using a combination
of microwave irradiation and superheated water as an op-
[a] Dipartimento di Chimica, Università degli Studi di Salerno,
Via Ponte don Melillo, 84084 Fisciano (SA), Italy
Fax: +39-089-969296
E-mail: maderosa@unisa.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901333.
Eur. J. Org. Chem. 2010, 1029–1032
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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M. De Rosa, A. Soriente
SHORT COMMUNICATION
portunity to improve the Friedel–Crafts alkylation reaction tain the product in moderate yield, but with a low discrimi-
of indoles with different SN1-reactive benzyl halides, both nation between the N-alkylated product (25% yield) and
in terms of generality and efficiency (Scheme 1).
the C-alkylated product (37% yield). Interestingly, im-
proved yields and selectivities were obtained by the micro-
wave-assisted procedure within only a few minutes. The re-
action was performed in sealed microwave tubes under mi-
crowave irradiation by using a CEM Discover single mode
reactor (Table 1, Entry 3). Moreover, under microwave irra-
diation the reaction was clean and proceeded with increased
regioselectivity: the N-alkylation product was detected in
the crude mixture only in very low yield, and the C-alky-
lation occurred with high selectivity at position 3 of the
indole.
Prompted by this result, a series of experiments was per-
formed under microwave irradiation at various reaction
times, temperatures and power settings aimed to optimize
the reaction conditions. Raising the reaction temperature
from 150 °C to 170 °C had no effect on the yield (Table 1,
Entry 4), whereas temperatures below 150 °C decreased no-
ticeably the reaction efficiency (Table 1, Entries 5, 6). Simi-
larly, running the reaction for a shorter time led to a lower
conversion (Table 1, Entries 3, 7, 8). As shown in Table 1,
the best yield of adduct 3aa was achieved at 150 °C in 8 min
(Table 1, Entry 3) with an irradiation power of P = 200 W.
In order to investigate the role of water, the reaction was
performed neat under the optimized reaction conditions.
Under these conditions, only a trace amount of product
3aa was found with many side products. The influence of
different molar ratios of substrate/alkyl halide and reaction
Scheme 1. Catalyst-free microwave-promoted Friedel–Crafts alky-
lation of indoles with benzyl halides in water.
Bringing these two areas (chemistry in water and micro-
wave irradiation) together offers several advantages such as
higher selectivities, simplicity, shorter reaction times, and
no need to use a catalyst.
Results and Discussion
Initially, we examined the Friedel–Crafts alkylation of in-
dole (1a) with benzyl bromide (2a) in water without any
catalyst. Preliminary experiments were carried out both un-
der microwave irradiation and under conventional condi-
tions. When the reaction was run at room temperature
(Mayr’s conditions),[6f] it provided no conversion of starting
material, even after prolonged time (12 h), but instead
yielded side products, such as benzyl alcohol as a result of
alkyl halide hydrolysis in aqueous medium (Table 1, En-
try 1). However, upon increasing the reaction temperature
to reflux conditions (Table 1, Entry 2), we were able to ob-
Table 1. Microwave-enhanced Friedel–Crafts alkylation of indole
(1a) with benzyl bromide (2a).
Table 2. Microwave-enhanced Friedel–Crafts alkylation reactions
of indoles 1 with benzyl bromide (2a).
Entry[a]
R
R1
R2
Product
Yield
Ratio
(%)[b,d]
C-3/C-2[c]
1
2
3
4
5
6
7
8
9
H
H
Me
Me
H
H
H
H
H
H
Me
H
Me
H
H
Me
H
H
H
H
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
68
88
61
78
55
69
72
65
81
46
62
94:6
–
–
Entry[a] Time
[min]
T
[°C]
Yield of 3aa + 4aa Selectivity Yield of 5aa
(%)[b]
C-3/C-2
(%)[b]
1[c]
2[d]
3
720
720
8
r.t.
reflux
150
170
130
110
150
150
150
150
150
–
–
–
25
10
10
9
8
2
2
6
H
–
37
68
67
51
28
32
52
62
59
15
98:2
94:6
87:13
94:6
100:0
94:6
90:10
94:6
92:8
98:2
Me
OMe
OMe
Br
Cl
CN
H
98:2
100:0
–
95:5
–
4
8
5
8
6
8
Me
H
–
7
4
10
H
H
3ja
3ka
93:7
–
8
6
11 (3-Me-
indole)
9
10
10
16
10[e]
11[d]
5
5
[a] All the reactions were conducted on a 0.5 mmol scale under
microwave-irradiation conditions: P = 200 W, T = 150 °C, reaction
time = 8 min. [b] Isolated yield after column chromatography. [c]
The ratio was determined by 1H NMR peak integration of the
[a] Reaction conditions: indole (0.6 mmol) and benzyl chloride
(0.5 mmol) in water (1 mL) were irradiated in a monomode micro-
wave reactor (P = 200 W). [b] Based on the isolated yield of pure
product 3aa after column chromatography. [c] Reaction performed
under Mayr’s conditions as reported in ref.[6f] [d] Reaction per-
formed using conventional heating with an oil bath. [e] The reac-
tion mixture was irradiated at P = 125 W.
crude products. [d] All products were characterized by H and 13C
1
NMR spectroscopy and mass spectrometry (see Supporting Infor-
mation). The NMR spectra of the products 3aa,[8] 3ba,[8] 3ca,[9]
3da,[10] 3fa,[11] 3ha,[12] 3ja[11] and 3ka[13] are in accordance with
those in the literature.
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Catalyst-Free Friedel–Crafts C-Alkylation of Indoles in Water
concentration were screened, and it was found that only a
Encouraged by these results, we explored the general va-
1.2:1.0 ratio of indole/benzyl bromide was required for an lidity of the procedure. The optimized procedure was used
efficient conversion, thereby preventing the use of a large for the reaction of substituted indoles 1 with benzyl bro-
excess of reagents without any concentration influence.
mide (2a) (Table 2).
Since we wanted to determine whether our reaction
As can be seen from the Table 2, preferential or exclusive
could be equally well carried out by using conventional 3-attack generally occurred with some N-attack (5–12%
heating, we performed the reaction in a pre-heated oil bath yield) in the case of 2-unsubstituted indoles. The presence
at 150 °C under exactly the same set of conditions as in the of N-alkylated indole adducts can be reasonably attributed
M.W.-assisted reaction (sealed 10 mL microwave tube, same to the absence of steric hindrance in the position adjacent
quantities of reagents and water). After 16 min, the reaction to the site of electrophilic attack. Introduction of electron-
mixture was cooled to afford the adduct in only 15% to- donating and -withdrawing groups was tolerated as was
gether with a considerable amount of starting material substitution in the 3-position. When the C-3 position of the
(Table 1, Entry 11).
indole was blocked by a substituent (Table 2, Entry 11), the
nucleophilic attack occurred at the C-2 position, known to
be very difficult, to afford the adduct 3ka in moderate yield
under our conditions. In the same way, the reaction effi-
ciencies proved to follow the established order of nucleo-
philic reactivity from the weakest nucleophile, 5-cyanoin-
dole (1j), to the strongest ones, such as 2-methylindole (1b)
and 2-methyl-5-methoxyindole (1g).
Table 3. Microwave-enhanced Friedel–Crafts alkylation reactions
of indole 1a with different alkyl halides 2.
Finally, we probed the feasibility of the reaction with
various SN1-reactive benzyl halides 2a–2i by using the opti-
mized conditions (Table 3).
In all cases, moderate to good yields were achieved with
high degrees of selectivity. Since the 3-position is the pre-
ferred site for electrophilic substitution reactions, C-3-sub-
stituted indoles were formed almost exclusively with small
amounts of N-alkylated adduct (Ͻ10%). In general, alkyl
halides with more stabilized carbocations gave better yields.
In order to contribute to energy savings and therefore
to the sustainability of the microwave-heated experiments
compared to conventionally heated ones, we monitored the
energy consumption (kWh) during the course of the reac-
tion using a commercially available domestic electricity me-
ter (Table 4).[16]
Table 4. Comparison of the energy consumed by microwave irradia-
tion (M.W.) and oil bath (∆) for the Friedel–Crafts reaction be-
tween indole 1a and benzyl bromide 2a.
Entry Heating Scale
T
t
Yield
E
E
method [mmol] [°C] [min][a] (%)[b] [kWh][c] [kWh mol–1][d]
1
2
oil bath
oil bath
0.5
0.5
0.5
0.5
1.0
100
100
150
150
150
180
720
16
8
21
37
15
68
65
0.27
1.02
0.1
0.03
0.03
2571
5513
1333
88.23
46.15
3[e] oil bath
4
5
M.W.
M.W.
8
[a] Reaction time (t) is defined as the total heating time. For oil-
bath experiments, this includes the time required for heating the
bath to the desired temperature. [b] Isolated yield of pure product.
[c] Energy consumption as measured by the Watt meter for the
total heating time (t) specified. [d] Energy consumption calculated
on the basis of mol of product formed. [e] Run performed in a
sealed vessel.
[a] All the reactions were conducted on a 0.5 mmol scale under
microwave-irradiation conditions: P = 200 W, T = 150 °C, reaction
time = 8 min. [b] Isolated yield after column chromatography. [c]
All products were characterized by 1H and 13C NMR spectroscopy
and mass spectrometry (see Supporting Information). [d] The
NMR spectra of the products 3aa,[8] 3ab,[14] 3ad,[15] and 3ah[8] are
in accordance with those in the literature.
The collected data point out that conventional heating
consumes a large amount of energy (with longer reaction
times and lower product yields), whereas the microwave-
assisted process under sealed-vessel conditions led to sig-
Eur. J. Org. Chem. 2010, 1029–1032
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M. De Rosa, A. Soriente
SHORT COMMUNICATION
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Typical Microwave-Assisted Experimental Procedure: A sealed
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(0.5 mmol) and indole derivative (0.6 mmol) in distilled water
(1 mL) was introduced in the cavity of a microwave reactor (CEM
Co., Discover System, single-mode reactor) and irradiated for an
appropriate time and temperature under magnetic stirring. After
air-flow cooling to room temperature, the tube was removed from
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ethyl acetate and poured into a separating funnel. Water was added
and the organic material was extracted with ethyl acetate
(3ϫ4 mL). The combined extracts were dried with MgSO4, and –
after removal of the solvent – the mixture was purified by column
chromatography (hexane/AcOEt as eluent) to yield the expected
products. The identity and purity of the compounds were con-
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Received: November 19, 2009
Published Online: January 15, 2010
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Eur. J. Org. Chem. 2010, 1029–1032