Solid-liquid phase alkylation of n-heterocycles: Microwave-assisted synthesis as an environmentally friendly alternative

Article abstract of DOI:10.1080/00397910903226166

The solid-liquid phase alkylation of a variety of five-membered N-heterocycles (carbazole, imidazole, benzimidazole, and indole-3-carbaldehyde) was carried out under different conditions. The use of alkali carbonate in dimethylformamide or in MeCN (in the latter case, in the presence of a phase-transfer catalyst) is a suitable method to prepare the corresponding N-alkylated products in an efficient way. In most cases, the solventless, microwave-assisted reaction is an environmentally friendly alternative to traditional methods. Copyrigh

Full text of DOI:10.1080/00397910903226166

This article was downloaded by: [Duke University Libraries]
On: 26 May 2012, At: 08:46
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Solid–Liquid Phase Alkylation of N-
Heterocycles: Microwave-Assisted
Synthesis as an Environmentally Friendly
Alternative
a b
b c
b
a
Mátyás Milen
, Alajos Grün
, Erika Bálint , András Dancsó &
b
György Keglevich
a
EGIS Plc., Division for Chemical Research, Budapest, Hungary
b
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest, Hungary
c
Research Group of the Hungarian Academy of Sciences at the
Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics, Budapest, Hungary
Available online: 07 Jul 2010
To cite this article: Mátyás Milen, Alajos Grün, Erika Bálint, András Dancsó & György Keglevich (2010):
Solid–Liquid Phase Alkylation of N-Heterocycles: Microwave-Assisted Synthesis as an Environmentally
Friendly Alternative, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 40:15, 2291-2301
To link to this article: http://dx.doi.org/10.1080/00397910903226166
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary

sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

1
Synthetic Communications , 40: 2291–2301, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903226166
SOLID–LIQUID PHASE ALKYLATION OF
N-HETEROCYCLES: MICROWAVE-ASSISTED
SYNTHESIS AS AN ENVIRONMENTALLY
FRIENDLY ALTERNATIVE
1
,2
2,3
M a´ ty a´ s Milen, Alajos Gr u¨ n, Erika B a´ lint,
2
1
2
Andr a´ s Dancs o´ , and Gy o¨ rgy Keglevich
EGIS Plc., Division for Chemical Research, Budapest, Hungary
1
2
Department of Organic Chemistry and Technology, Budapest University of
Technology and Economics, Budapest, Hungary
3
Research Group of the Hungarian Academy of Sciences at the Department of
Organic Chemistry and Technology, Budapest University of Technology and
Economics, Budapest, Hungary
The solid–liquid phase alkylation of a variety of five-membered N-heterocycles (carbazole,
imidazole, benzimidazole, and indole-3-carbaldehyde) was carried out under different
conditions. The use of alkali carbonate in dimethylformamide or in MeCN (in the latter
case, in the presence of a phase-transfer catalyst) is a suitable method to prepare the
corresponding N-alkylated products in an efficient way. In most cases, the solventless,
microwave-assisted reaction is an environmentally friendly alternative to traditional
methods.
Keywords: N-Alkylation; N-heterocycles; microwave synthesis; phase-transfer catalysis; solid–liquid phase
INTRODUCTION
O-, N-, and C-alkylations form the basic means of chemical transformations in
organic chemistry. These basic processes are often applied in the pharmaceutical
[
1–3]
industry. There are many possibilities to accomplish alkylations.
The alkylation of CH-acidic compounds can be carried out under phase-
transfer catalytic (PTC) conditions. Regarding the solid–liquid phase alkylation
applying K CO , it was found that the onium salt used as PTC may be substituted
2
3
by microwave (MW) irradiation. Moreover, the alkylations could be realized under
solvent-free conditions, meaning that this method is doubly environmentally
[
4,5]
friendly. In the case of MW-assisted solid–liquid phase alkylation of phenols
within O-alkylations, it was found that the presence or absence of the onium salt
Received June 3, 2009.
Address correspondence to Gy o¨ rgy Keglevich, Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, H-1521 Budapest, Hungary. E-mail: gkeglevich@
mail.bme.hu
2
291

2292
M. MILEN ET AL.
[
6,7]
affects the chemoselectivity (O- versus C-alkylation).
of PTC and MW techniques have also been investigated in N-alkylations.
Effects of the combination
[
8]
In this article, the solid–liquid phase alkylation of N-heterocycles, such as
carbazole, imidazole, and benzimidazole, and an indole derivative is investigated.
We wished to develop a green procedure for these N-alkylations. After studying
the N-alkylation of similar heterocycles with a variety of alkyl halides under solvent-
less MW conditions, Bogdal et al. reported yields of 73–95%. The only drawback of
these results is that the alkylations were carried out in a domestic MW oven where
detection of the exact temperatures is impossible, and hence the reproduction is not
[
9]
easy.
RESULTS AND DISCUSSION
The first model was the alkylation of carbazole (1) with ethyl haloacetates. The
results are summarized in Table 1. Under classical conditions and with Cs CO in
2
3
ꢀ
acetone or in acetonitrile at 26 C, the completion required 1 day when ethyl bro-
moacetate was the alkylating agent (Table 1, entries 1 and 3). In the presence of
Table 1. Alkylation of carbazole (1) with ethyl haloacetates under different conditions
a
Temp.
ꢀ
Conversion
(%)
Yield of 2a
(%)
X
M
Solvent
TBAB
( C)
Time
Entry
Br
Br
Br
Br
I
Cs
Cs
Cs
Cs
Cs
Cs
Cs
Cs
K
Me
Me
2
CO
CO
—
10%
—
26
26
26
26
26
26
26
26
26
26
26
26
26
26
26
26
26
1 day
5 h
98
100
100
100
100
81
1
2
2
90
92
88
93
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
DMF
DMF
DMF
—
1 day
4 h
3
10%
—
4
1 day
1 day
8 h
5
Cl
I
—
6
10%
10%
—
100
100
48
88
91
7
Cl
Br
Br
Br
Br
Br
Cl
Br
Br
Br
8 h
8
1 day
1 day
1 day
1 day
2 h
9
Rb
K
—
59
60
10
11
12
13
14
15
16
17
10%
10%
—
Rb
Cs
Cs
K
86
100
100
76
98
96
—
—
8 h
1 day
1 day
2 days
K
Cs
10%
—
84
63
a
Determined on the basis of GC or LC.
Note. Because of the risk of explosion, the reaction of carbazole and ethyl halogenoacetates may be
ꢀ
dangerous above 100 C under MW conditions.

MICROWAVE-ASSISTED ALKYLATION OF N-HETEROCYCLES
2293
10% of tetrabutylammonium bromide, the alkylation proceeded faster: the reaction
times were 5 and 4 h, respectively (Table 1, entries 2 and 4). By applying the esters of
ꢀ
iodo- and chloroacetic acid, in acetonitrile at 26 C in the absence of onium salt, the
conversion was 100 and 81%, respectively, after 1 day (Table 1, entries 5 and 6). In
the presence of 10% of tetrabutylammonium bromide (TBAB), the reaction time
became shorter (Table 1, entries 7 and 8). When Cs CO was replaced by K CO
3
2
3
2
and Rb CO , the conversion was only 48 and 59%, respectively (Table 1, entries 9
2
3
and 10). The presence of onium salt was also beneficial in this case regarding reaction
time (Table 1, entries 11 and 12). The use of dimethylformamide (DMF) instead of
acetonitrile led to a shorter reaction time of 2 h (Table 1, entry 13), but when ethyl
chloroacetate was the alkylating agent, completion required 8 h (Table 1, entry 14).
When K CO was used instead of Cs CO in DMF, the alkylation became quite
2
3
2
3
slow, and the conversion was only 76% after a day of stirring (Table 1, entry 15).
Generally, Cs CO is more efficient in solid–liquid phase N-alkylations than
2
3
K CO (Table 1, entries 3 vs. 9 and entries 13 vs. 15). The use of TBAB did not help
3
2
too much (Table 1, entry 16). Complete conversions made possible the isolation of
ethoxycarbonylcarbazole (2a) mostly in yields greater than 91% (Table 1, entries
2
–5, 13, and 14). The best set of conditions includes 1.2 eq. of Cs CO in DMF.
2 3
DMF is, however, not a green solvent. Because of this, we investigated the alkylation
without the use of any solvent. The reaction slowed down: the conversion was only
6
the MW technique. However, we had to discard this idea, as a very vigorous reaction
3% after 2 days of stirring (Table 1, entry 17). At this point, we tried to make use of
ꢀ
was observed to take place between carbazole and ethyl bromoacetate above 100 C
ꢀ
under MW irradiation. Below 100 C, there was practically no reaction.
ꢀ
Then the best set of conditions (Cs CO =DMF at 26 C and Cs CO =MeCN=
2
3
2
3
ꢀ ꢀ
0% TBAB at 26 C), as well as applying Cs CO without solvent above 100 C
2 3
1
under MW irradiation, were tried out in alkylations using reagents such as allyl bro-
mide, benzyl bromide, and propyl iodide. K CO was also tested (Table 2). When 1.2
eq. of Cs CO in DMF and allyl bromide, benzyl bromide, and propyl iodide were
2
3
2
3
used as the reagents, completion of the reaction to afford products in order 2b, 2c,
and 2d required reaction times of 8 h, 8 h, and 1.2 day, respectively (Table 2, entries
1, 5, and 9, respectively). Isolated yields of the alkylcarbazoles 2 were in the range of
94–97%. By running the alkylations in acetonitrile in the presence of TBAB, the reac-
tion times in the previous order were 12.5, 13, and 24 h, respectively (Table 2, entries
, 6 and 10). In MW-assisted solventless reactions, in the order 2b, 2c, and 2d and
2
ꢀ
ꢀ
ꢀ
applying 120 C=3 h, 135 C=3 h, and 140 C=4 h, the conversions were 28, 72, and
6%, respectively (Table 2, entries 3, 7, and 11). The addition of 10% of triethylben-
zylammonium chloride (TEBAC) to the reaction mixture before irradiation was use-
5
ful, as, in the previous order, conversions of 75, ꢁ100, and 90% were obtained
(Table 2, entries 4, 8, and 12). It can be seen that the solid–liquid phase alkylation
of carbazole (1) can be carried out most efficiently in DMF. In most cases, the
MW-assisted solventless accomplishment may be a good alternative in the presence
of a phase-transfer catalyst, but the conversions are not always complete.
Then the alkylation of imidazole (3) with ethyl bromoacetate, benzyl bromide,
and propyl iodide was investigated using Cs CO in DMF and K CO under sol-
2
3
2
3
ventless and microwave conditions (Table 3). Because of the enhanced reactivity
of imidazole as compared to carbazole, significantly shorter reaction times were

2294
M. MILEN ET AL.
Table 2. Substitution of carbazole (1) with different alkylating agents under different conditions
a
Conversion Yield of
Temp. Mode of
ꢀ
RX
Solvent
DMF
Catalyst
—
MeCN 10% TBAB
( C)
heating
Time
(%)
2 (%)
Entry
BrCH
BrCH
BrCH
BrCH
BnBr
BnBr
BnBr
BnBr
PrI
2
2
2
2
CH=CH
CH=CH
CH=CH
CH=CH
2
2
2
2
26
26
8 h
12.5 h
3 h
100
97(2b)
93(2b)
1
2
100
28
—
—
—
10% TEBAC
—
120
120
26
MW
MW
3
3 h
8 h
75
4
DMF
100
100
72
94(2c)
91(2c)
5
MeCN 10% TBAB
26
13 h
3 h
6
—
—
—
10% TEBAC
—
135
135
26
MW
MW
7
3 h
ꢁ100
100
62
8
DMF
1.2 day
24 h
4 h
96(2d)
9
PrI
PrI
MeCN 10% TBAB
26
10
11
12
—
—
—
10% TEBAC
140
140
MW
MW
56
90
PrI
4 h
a
Determined on the basis of GC.
Table 3. Alkylation of imidazole (3) under different conditions
a
Temp. Mode of Time Conversion
ꢀ
Yield of
4 (%)
RX
M
Solvent TBAB
( C)
heating
(min)
(%)
Entry
BrCH
BrCH
BnBr
BnBr
BnBr
PrI
2
CO
CO
2
Et Cs
DMF
—
—
—
26
100
26
20
20
100
90
91 (4a)
1
2
3
4
5
6
7
8
2
2
Et
K
Cs
K
MW
DMF
—
—
—
25
25
100
100
100
100
100
100
79 (4c)
65 (4c)
90 (4c)
85 (4d)
85 (4d)
90 (4d)
100
100
26
MW
MW
Cs
Cs
—
—
25
40
DMF
PrI
PrI
Cs MeCN
K
10%
—
26
100
240
40
—
MW
a
Determined on the basis of GC.

MICROWAVE-ASSISTED ALKYLATION OF N-HETEROCYCLES
2295
necessary. In the first variation (Cs CO =DMF), the completion using bromoacetate,
2
3
benzyl bromide, and propyl iodide required 20, 25, and 40 min, respectively (Table 3,
entries 1, 3, and 6, respectively). Isolated yields of the alkylimidazoles (4a, 4c, and 4d)
fell in the range of 79–91% (Table 3, entries 1, 3, and 6). In the case of propyl iodide,
the PTC approach (using acetonitrile and 10% of TBAB) was also tried. The alky-
lation was rather slow (Table 3, entry 7). The alkylation of imidazole (3) was also
studied under MW-assisted and solventless conditions. When K CO was used as
2
3
ꢀ
ꢀ
the base for the systems of bromoacetate=100 C=20 min, benzyl bromide=100 C=
ꢀ
2
5 min, and propyl iodide=100 C=40 min, conversions of 90, 100, and 100% were
obtained, respectively (Table 3, entries 2, 4, and 8). By applying benzyl bromide,
the solventless MW-alkylation was also accomplished in the presence of Cs CO
2
3
ꢀ
at 100 C, giving product 4c in complete conversion (Table 3, entry 5). Regarding
the solid–liquid phase alkylation of imidazole (3), the solventless MW-assisted
approach may be a good alternative to the classical method using DMF. There is
no need for a PTC.
For the alkylation of benzimidazole (5), carrying out the reactions in DMF
using Cs CO as the base and ethyl bromoacetate, benzyl bromide, and propyl iod-
2
3
ide as the alkylating agents gave reaction times of 0.5, 0.75, and 1 h, respectively, to
afford the corresponding products (6) in 93, 92, and 84%, respectively (Table 4,
entries 1, 3, and 7). In these instances, the PTC method (using onium salt in acetoni-
trile) is another possibility, but the reaction times are longer (Table 4, entries 4 and
8
). With no solvent and using K CO , the MW approach also gave good results
2 3
(Table 4, entries 2, 5, and 9). In the case of benzylation, Cs CO was also tested
2 3
and proved to be a suitable base (Table 4, entry 6). The isolated yields were, in most
cases, greater than 92%. The solid–liquid phase alkylation of benzimidazole (5) may
be well accomplished under solventless MW conditions, and there is no need for a
Table 4. Alkylation of benzimidazole (5) under different conditions
a
Temp. Mode of Time Conversion
ꢀ
Yield of
6 (%)
RX
M
Solvent TBAB
( C)
heating
(h)
(%)
Entry
BrCH
BrCH
BnBr
BnBr
BnBr
BnBr
PrI
2
CO
CO
2
Et Cs
Et
DMF
—
DMF
26
100
26
0.5
0.5
0.75
3.5
0.75
0.5
1
100
100
100
100
100
100
100
100
100
93 (6a)
95 (6a)
92 (6c)
96 (6c)
98 (6c)
95 (6c)
84 (6d)
94 (6d)
95 (6d)
1
2
3
4
5
6
7
8
9
2
2
K
Cs
MW
Cs MeCN
10%
10%
26
K
Cs
Cs
—
—
100
100
26
MW
MW
DMF
PrI
PrI
Cs MeCN
K
26
100
7
—
MW
1
a
Determined on the basis of GC.

2296
M. MILEN ET AL.
Table 5. Alkylation of indole-3-carbaldehyde (7) under different conditions
a
Temp. Mode of Time Conversion
ꢀ
Yield of
8 (%)
RX
M
Solvent TBAB
( C)
heating
(h)
(%)
Entry
BrCH
BrCH
BnBr
BnBr
PrI
2
CO
CO
2
Et Cs
K
DMF
—
26
100
26
0.5
0.5
0.75
0.75
1
100
92 (8a)
1
2
3
4
5
6
7
2
2
Et
MW
MW
95
100
Cs
Cs
Cs
DMF
—
DMF
96 (8c)
100
26
100
100
82 (8d)
92 (8d)
80 (8d)
PrI
PrI
Cs MeCN
K
10%
26
100
8
100
ꢁ100
—
MW
3
a
Determined on the basis of GC.
PTC. Hence, the N-alkylations carried out in DMF may be substituted by a more
environmentally friendly method.
Finally, the alkylation of indole-3-carbaldehyde (7) was studied. The use of
Cs CO in DMF and the usual set of alkylating agents led to quite similar results
as obtained with benzimidazole (Table 5, entries 1, 3, and 5). The solventless MW
2
3
ꢀ
synthesis using K CO or Cs CO at 100 C was a good alternative. There was no
2
3
2
3
need to use a PTC (Table 5, entries 2, 4, and 7).
In conclusion, the solid–liquid phase N-alkylation of simple N-heterocycles,
such as carbazole, imidazole, benzimidazole, and indole-3-carbaldehyde with ethyl
bromoacetate, allyl bromide, benzyl bromide, or propyl iodide may be well
accomplished using DMF or MeCN (the latter together with a PTC) as the solvent.
In most cases, the solventless MW-assisted accomplishment is a suitable alternative
to replace the traditional methods. If the substrate is reactive enough, there is no
need to use a PTC.
EXPERIMENTAL
General
Melting points were determined on a Kofler Bo e¨ tius micro-apparatus and were
not corrected. The Fourier transform–infrared (FT-IR) spectra were recorded on a
Bruker Vector 22 spectrometer, using KBr pellets of solids or films of liquids.
Gas chromatography (GC) was carried out on an HP 4890A instrument with a
column of HP5 15 m ꢂ 0.53 mm and N as carrier gas. GC–mass spectrometry (MS)
2
was carried out on an Agilent 6890 N-GC-5973 N-MSD instrument with a column of
3
0 m ꢂ 0.25 mm (Restek, Rtx-5SILMS) and He as carrier gas.
1
13
H NMR (500 MHz) and C NMR (125 MHz) spectra were taken on a Varian
Unity Inova 500-MHz spectrometer or a Varian Mercury Plus 200 instrument, where

MICROWAVE-ASSISTED ALKYLATION OF N-HETEROCYCLES
2297
1
13
the H frequency was 200 MHz and the C frequency was 50 MHz. Chemical shifts
are downfield to tetramethylsilane (TMS). The couplings are given in hertz.
Cesium carbonate was obtained from Chemetall GmbH Special Metals
Division Frankfurt am Main, Germany.
General Procedure for the Alkylation of N-Heterocycles (1, 3, 5, and
ꢀ
7) in Acetone, Acetonitrile, or Dimethylformamide Solution at 26 C
To a solution of 1.80 mmol of the heterocyclic compound and 2.16 mmol of
anhydrous alkali carbonate in 10–30 ml of dry acetone, acetonitrile or dimethylfor-
mamide was added 1.98 mmol of the alkylating agent, and in certain cases also 58 mg
ꢀ
(
0.18 mmol) of TBAB. The reaction mixture was stirred at 26 C for the appropriate
time shown in the tables. After that, the inorganic salts were filtered off, and the
filtrate was concentrated. Then the residue was taken up in DCM or, if it had con-
tained a PTC, in diethyl ether or ethyl acetate, and the mixture was washed with
water twice. Finally the organic phase was dried (MgSO ), filtered, and concentrated
4
to afford the alkylated heterocycles (2, 4, 6, and 8).
Carbazol-9-yl-acetic Acid Ethyl Ester (2a)
ꢀ
[10]
ꢀ
1
Yield 98%, white crystals, mp 93–95 C (lit. 97 C); H NMR (CDCl ) d 8.06
3
(
d, J ¼ 7.7, 2H), 7.42 (ꢁt, J ¼ 7.7, 2H), 7.28 (d, J ¼ 8.1, 2H), 7.23 (t, J ¼ 7.7, 2H), 4.91
1
3
(
(
s, 2H), 4.14 (q, J ¼ 7.1, 2H), 1.16 (t, J ¼ 7.1, 3H); C NMR (CDCl ) d 168.4
3
COOꢃ), 140.5 (C=), 125.8 (CH=), 123.1 (C=), 120.4 (CH=), 119.5 (CH=), 108.3
(
1
CH=), 61.5 (CH ), 44.7 (CH ), 14.0 (CH ); IR (KBr) 1739, 1489, 1326, 1228,
2
2
3
ꢃ1
209, 745, 724 cm
.
9-Allyl-carbazole (2b)
ꢀ
[11]
ꢀ
1
Yield 97%, white crystals, mp 54–55 C (lit. 55–56 C); H NMR (CDCl ) d
3
8
5
.08–8.10 (m, 2H), 7.42–7.45 (m, 2H), 7.34–7.35 (m, 2H), 7.21–7.24 (m, 2H),
1
3
.92–6.00 (m, 1H), 5.12–5.14 (m, 1H), 5.00–5.03 (m, 1H), 4.85–4.87 (m, 2H);
C
NMR (CDCl ) d 140.4 (C=), 132.3 (CH=), 125.6 (CH=), 122.9 (C=), 120.3
3
(
CH=), 119.0 (CH=), 116.7 (H C=), 108.7 (CH=), 54.2 (CH ); IR (KBr) 1453,
1
2
2
ꢃ1
326, 750, 723 cm .
9
-Benzyl-carbazole (2c)
Yield 94%, white crystals, mp 112–115 C (lit.
CDCl ) d 8.11–8.12 (m, 2H), 7.39–7.42 (m, 2H), 7.33–7.34 (m, 2H), 7.19–7.25 (m,
ꢀ
[12]
ꢀ
1
112–113 C); H NMR
(
3
1
3
5
1
1
H), 7.10–7.12 (m, 2H), 5.47 (s, 2H); C NMR (CDCl ) d 140.6 (C=), 137.2 (C=),
3
28.7 (CH=), 127.4 (CH=), 126.4 (CH=), 125.8 (CH=), 123.0 (C=), 120.4 (CH=),
ꢃ1
19.2 (CH=), 108.9 (CH=), 46.5 (CH ); IR (KBr) 1450, 1329, 750, 722 cm
.
2
9
-Propyl-carbazole (2d)
Yield 96%, white crystals, mp 47–48 C (lit.
00 MHz) d 8.10 (d, J ¼ 7.7, 2H), 7.37–7.49 (m, 4H), 7.18–7.25 (m, 2H), 4.27 (t,
ꢀ
[11]
ꢀ
1
49–50 C); H NMR (CDCl ,
3
2

2298
M. MILEN ET AL.
1
3
J ¼ 7.2, 2H), 1.91 (ꢁhx, J ¼ 7.3, 2H), 0.97 (t, J ¼ 7.5, 3H); C NMR (CDCl ) d 140.5
3
(
(
C=), 125.5 (CH=), 122.8 (C=), 120.3 (CH=), 118.7 (CH=), 108.7 (CH=), 44.6
CH ), 22.3 (CH ), 11.8 (CH ); IR (KBr) 1450, 1326, 1220, 747, 723 cm
2
ꢃ1
.
2
3
Imidazole-1-acetic Acid Ethyl Ester (4a)
1
Yield 91%, oil; H NMR (CDCl , 200 MHz) d 7.49 (s, 1H), 7.07 (t, J¼ 1.1, 1H),
3
[
13] 1
6
.95 (t, J ¼ 1.5, 1H), 4.70 (s, 2H), 4.23 (q, J¼ 7.1, 2H), 1.28 (t, J ¼ 7.1, 3H) [lit.
H
NMR (CDCl ) d 7.42 (s, 1H), 6.92 (s, 1H), 6.82 (s, 1H), 4.68 (s, 2H), 4.12 (q, 2H),
3
1
3
1
(
.23 (t, 3H)]; C NMR (CDCl ) d 167.2 (COOꢃ), 137.7 (CH=), 129.3 (CH=), 119.8
3
ꢃ1
CH=), 61.8 (CH ), 47.7 (CH ), 13.8 (CH ); IR (film) 3385, 1749, 1510, 1217, 759cm .
2
2
3
1-Benzyl-1H-imidazole (4c)
ꢀ
[14]
ꢀ
1
70 C); H NMR (CDCl ,
Yield 79%, white crystals, mp 70–71 C (lit.
3
2
1
00 MHz) d 7.51 (s, 1H), 7.27–7.39 (m, 3H), 7.09–7.17 (m, 2H), 7.07 (ꢁt, J ¼ 1.0,
1
3
H), 6.88 (t, J ¼ 1.2, 1H), 5.08 (s, 2H); C NMR (CDCl ) d 137.2 (CH=), 136.0
3
(
CH=), 129.6 (CH=), 128.7 (CH=), 128.0 (CH=), 127.0 (CH=), 119.1 (CH=),
ꢃ1
5
0.5 (CH ); IR (KBr) 1506, 1449, 1233, 1071, 906, 827, 715, 663 cm
2
.
1-Propyl-1H-imidazole (4d)
1
Yield 85%, oil; H NMR (CDCl , 200 MHz) d 7.45 (s, 1H), 7.04 (s, 1H), 6.90 (t,
3
[
14]
J ¼ 1.2, 1H), 3.89 (t, J ¼ 7.0, 2H), 1.81 (ꢁhx, J ¼ 7.2, 2H), 0.92 (t, J ¼ 7.3, 3H) [lit.
1
H NMR (CDCl ) d 7.44 (s, 1H), 7.00 (s, 1H), 6.90 (s, 1H), 3.87 (t, J ¼ 7, 2H), 1.80
3
1
3
(
1
1
m, J ¼ 7, 2H), 0.90 (t, J ¼ 8, 3H)]; C NMR (CDCl ) d 136.9 (CH=), 129.1 (CH=),
3
18.6 (CH=), 48.4 (CH ), 24.2 (CH ), 10.9 (CH ); IR (film) 2968, 1671, 1511, 1231,
2 2 3
ꢃ1
080, 756 cm
.
Benzimidazole-1-acetic Acid Ethyl Ester (6a)
ꢀ
[15]
ꢀ
1
Yield 93%, white crystals, mp 61–63 C (lit. 62–63 C); H NMR (CDCl ) d
3
7
1
1
.91 (s, 1H), 7.80–7.83 (m, 1H), 7.27–7.32 (m, 3H), 4.86 (s, 2H), 4.22 (q, J ¼ 7.1, 2H),
1
3
.25 (t, J ¼ 7.2, 3H); C NMR (CDCl ) d 167.1 (COOꢃ), 143.5, 143.3, 133.9 (C=),
3
23.3 (CH=), 122.4 (CH=), 120.4 (CH=), 109.1 (CH=), 62.1 (CH ), 46.0 (CH ), 14.0
2
2
ꢃ1
CH ); IR (KBr) 1730, 1498, 1230, 1023, 737 cm .
3
(
1
-Benzyl-1H-benzimidazole (6c)
Yield 92%, white crystals, mp 114–115 C (lit.
CDCl ) d 7.91 (s, 1H), 7.82–7.83 (m, 1H), 7.20–7.33 (m, 6H), 7.14–7.16 (m, 2H),
ꢀ
[16]
ꢀ
1
113–115 C); H NMR
(
3
1
3
5
.30 (s, 2H); C NMR (CDCl ) d 143.9, 143.1, 135.4, 133.8, 128.9 (CH=), 128.1
3
(
CH=), 127.0 (CH=), 122.9 (CH=), 122.1 (CH=), 120.3 (CH=), 109.9 (CH=),
ꢃ1
4
8.7 (CH ); IR (KBr) 1494, 1265, 731 cm
2
.
1-Propyl-1H-benzimidazole (6d)
1
Yield 84%, oil; H NMR (CDCl , 200 MHz) d 7.86 (s, 1H), 7.79–7.84 (m, 1H),
3
7
.36–7.41 (m, 1H), 7.25–7.30 (m, 2H), 4.10 (t, J ¼ 7.0, 2H), 1.89 (ꢁhx, J ¼ 7.2, 2H),

MICROWAVE-ASSISTED ALKYLATION OF N-HETEROCYCLES
2299
[
17] 1
0
7
0
1
.93 (t, J ¼ 7.3, 3H) [lit.
H NMR (CDCl ) d 7.82 (s, 1H), 7.77–7.81 (m, 1H),
3
.32–7.37 (m, 1H), 7.21–7.29 (m, 2H), 4.05 (t, J ¼ 7.0, 2H), 1.77–1.92 (m, 2H),
1
3
.89 (t, J ¼ 7.3, 3H)]; C NMR (CDCl ) d 143.8, 142.9, 133.7 (C=), 122.6 (CH=),
3
21.8 (CH=), 120.2 (CH=), 109.6 (CH=), 46.6 (CH ), 23.0 (CH ), 11.2 (CH ); IR
2
2
3
ꢃ1
(
film) 1496, 1214, 751 cm .
3-Formyl-indole-1-acetic Acid Ethyl Ester (8a)
ꢀ
[18]
ꢀ
80–81 C); H NMR (CDCl ,
3
1
Yield 92%, white crystals, mp 78–79 C (lit.
00 MHz) d 10.02 (s, 1H), 8.30–8.34 (m, 1H), 7.73 (s, 1H), 7.26–7.37 (m, 3H), 4.89
2
1
3
(
(
(
(
s, 2H), 4.24 (q, J ¼ 7.2, 2H), 1.27 (t, J ¼ 7.1, 3H); C NMR (CDCl ) d 184.7
3
CHO), 167.2 (COOꢃ), 139.1 (CH=), 137.4 (C=), 125.0 (C=), 124.3 (CH=), 123.1
CH=), 122.2 (CH=), 119.0 (C=), 109.4 (CH=), 62.2 (CH ), 48.1 (CH ), 14.0
2
2
ꢃ1
CH ); IR (KBr) 1743, 1656, 1204, 1171 cm
3
.
1-Benzyl-1H-indole-3-carbaldehyde (8c)
ꢀ
[19]
Yield 96%, pale yellow crystals, mp 107–108 C (lit. 108–109 C); H NMR
ꢀ
1
(
CDCl , 200 MHz) d 9.93 (s, 1H), 8.29–8.34 (m, 1H), 7.63 (s, 1H), 7.26–7.32 (m, 6H),
3
1
3
7
1
1
.11–7.15 (m, 2H), 5.27 (s, 2H); C NMR (CDCl ) d 184.5 (CHO), 138.5 (CH=),
3
37.3 (C=), 135.2 (C=), 128.9 (CH=), 128.2 (CH=), 127.1 (CH=), 125.3 (C=),
24.0 (CH=), 122.9 (CH=), 122.0 (CH=), 118.3 (C=), 110.3 (CH=), 50.7 (CH );
2
ꢃ1
IR (KBr) 1661, 1536, 1393, 1195, 1075, 744 cm
.
1-Propyl-1H-indole-3-carbaldehyde (8d)
1
Yield 89%, oil; H NMR (CDCl , 200 MHz) d 10.01 (s, 1H), 8.29–8.34 (m, 1H),
3
7
.72 (s, 1H), 7.26–7.40 (m, 3H), 4.15 (t, J ¼ 7.0, 2H), 1.93 (ꢁhx, J ¼ 7.3, 2H), 0.98 (t,
1
3
J ¼ 7.3, 3H); C NMR (CDCl ) d 184.4 (CHO), 138.3 (CH=), 137.1 (C=), 125.4
3
(
C=), 123.8 (CH=), 122.7 (CH=), 122.0 (CH=), 117.9 (C=), 110.0 (CH=), 48.8
[20] 13
(
1
1
CH ), 23.0 (CH ), 11.3 (CH ) [lit.
C NMR (DMSO-d6) d 184.4, 140.7, 137.0,
24.6, 123.4, 122.3, 120.9, 116.9, 111.0, 47.7, 22.6, 10.9]; IR (film) 1659, 1533,
2
2
3
ꢃ1
401, 751 cm
.
General Procedure for the Alkylation Carbazole, Imidazole,
Benzimidazole, and Indole-3-carbaldehyde Under Microwave
Conditions
A mixture of 1.5 mmol of imidazole (0.10 g), indole-3-carbaldehyde (0.22 g),
benzimidazole (0.18 g) or carbazole (0.25 g), 1.8 mmol of K CO (0.25 g) or Cs CO
3
2
3
2
(0.59 g), 1.8 mmol of alkyl halide (0.18 ml of BrCH CO Et, 0.20 ml of BnBr, 0.14 ml
2 2
of BrCH CH=CH or 0.16 ml of PrI), and, if it was necessary, 0.034 g (0.15 mmol) of
2
2
TEBAC was irradiated in a microwave reactor (40–60 W) for the appropriate time.
The reaction mixture was taken up in 25 ml of ethyl acetate, and the suspension was
filtered. Evaporation of the volatile components provided the crude product, which
was passed through a thin layer of silica gel using 3% MeOH in CHCl as the eluant
3
and then analyzed by GC or GC-MS.

2300
M. MILEN ET AL.
ACKNOWLEDGMENTS
This project was partially supported by the Hungarian Scientific Research
Fund (OTKA T067679). The authors are grateful to Fanni Daruny Sypaseuth for
participating in a part of the project.
REFERENCES
1
2
3
. Stefanidakis, G.; Gwyn, J. E. Alkylation; In Chemical Processing Handbook;
J. J. McKetta (Ed.); CRC Press: Boca Raton, FL, 1993; pp. 88–138.
. D o¨ rwald, F. Z. Side Reactions in Organic Synthesis: A Guide to Successful Synthesis
Design; Wiley-VHC: Weinheim, 2005; Ch. 6, pp. 229–251.
. Price, C. C. The alkylation of aromatic compounds by the Friedel–Crafts method;
In Organic Reactions; R. Adams (Ed.); John Wiley: New York, 1946; Vol. 3, Ch. 1,
pp. 1–82.
4
5
6
7
8
9
. Keglevich, G.; Nov a´ k, T.; Vida, L.; Greiner, I. Microwave irradiation as an alternative to
phase transfer catalysis in the liquid-solid phase, solvent-free C-alkylation of active meth-
ylene containing substrates. Green Chem. 2006, 8, 1073–1075.
. Keglevich, G.; Majrik, K.; Vida, L.; Greiner, I. Microwave irradiation as a green alterna-
tive to phase transfer catalysis: Solid–liquid phase alkylation of active methylene contain-
ing substrates under solvent-free conditions. Lett. Org. Chem. 2008, 5, 224–228.
´
. Keglevich, G.; B a´ lint, E.; Karsai, E.; Gr u¨ n, A.; B a´ lint, M.; Greiner, I. Chemoselectivity in
the microwave-assisted solvent-free solid–liquid phase benzylation of phenols: O-versus
C-alkylation. Tetrahedron Lett. 2008, 49, 5039–5042.
´
. Keglevich, G.; B a´ lint, E.; Karsai, E.; Varga, J.; Gr u¨ n, A.; B a´ lint, M.; Greiner, I. Hetero-
geneous phase alkylation of phenols making use of phase transfer catalysis and microwave
irradiation. Lett. Org. Chem. 2009, 6, 535–539.
´
. Keglevich, G.; Sypaseuth, F. D.; Gr u¨ n, A.; Karsai, E.; Greiner, I. The role of phase trans-
fer catalyst in the microwave-assisted N-benzylation of amides, imides, and N-hetero-
cycles. Lett. Org. Chem. 2009, 6, 529–534.
. Bogdal, D.; Pielichowski, J.; Jaskot, K. Remarkably fast N-alkylation of azaheterocycles
under microwave irradiation in dry media. Heterocycles 1997, 45, 715–722.
1
1
1
1
0. Hoechster Farbw. Procedure for the preparation of N-methylcarbazole. DE Patent
55304, 1912.
2
1. Kricka, L. J.; Ledwith, A. Reactions of condensed N-heteroaromatic molecules, part I:
Alkylation by thallium(I) ethoxide. J. Chem. Soc., Perkin Trans. 1 1972, 2292–2293.
2. Buu-Ho €ꢀ , N. G. P. H.; Royer, R. Potential nitrogen-heterocycle carcinogens, XI:
Substitution reaction of N-alkylcarbazoles. J. Org. Chem. 1951, 16, 1198–1205.
3. Pellicciari, R.; Curini, M.; Spagnoli, N.; Ceccherelli, P. Reaction of alkoxycarbonylcarbe-
noids with imidazole: An improved preparation of ethyl imidazole-1-ylacetate and the first
synthesis of diethyl imidazole-1-ylmalonat. Synthesis 1981, 8, 629–631.
1
1
4. Begg, C. G.; Grimmett, M. R.; Wethey, P. D. The thermally induced rearrangement of
1-substituted imidazoles. Aust. J. Chem. 1973, 26, 2435–2446.
5. Cacace, F.; Giuliano, R.; Inam-ul-Haq. The N-acetyl-benzimidazole acid and its
auxinic activity. Atti Accad. Naz. Lincei, Rend. Classe Sci. Fis. Mat. Nat. 1957, 22,
510–513.
1
6. Forrester, J.; Ray, V. H.; Newton, L.; Preston, P. N. Synthesis and reactivity of benzylic
sulfonium salts: Benzylation of phenol and thiophenol under near-neutral conditions.
Tetrahedron 2001, 57, 2871–2884.
17. Fawaz, A.; Russel, B. W. Radical cyclisation onto imidazoles and benzimidazoles.
Tetrahedron 1999, 55, 4109–4122.

MICROWAVE-ASSISTED ALKYLATION OF N-HETEROCYCLES
2301
1
1
2
8. Zhigachev, V. E.; Suvorov, N. N. Darzens condensation of indoles. Tr. Mosk.
Khim.-Tekhnol. Inst. 1969, 61, 150–153.
9. Kurihara, T.; Fujimoto, T.; Harusawa, S.; Yoneda, R. Simple N-alkylation and
N-acylation of 3-acetylindole and 3-indolecarbaldehyde. Synthesis 1987, 4, 396–397.
0. Bouerat, L. M. E.; Fensholdt, J.; Nielsen, S. F.; Liang, X.; Havez, S. E.; Andersson, E. C.;
Jensen, L.; Hansen, J. R. Novel therapeutic use of indolinone derivatives. WO Patent
2005=058309 A1, 2005.