Imidazolium salts as phase transfer catalysts for the dialkylation and cycloalkylation of active methylene compounds

Article abstract of DOI:10.1016/j.tetlet.2004.11.141

The efficient synthesis of 1,1-disubstituted derivatives and the construction of cyclopropane and cyclopentane ring systems via dialkylation and cycloalkylation reactions of active methylene compounds using imidazolium salts as phase transfer catalyst is described. The dialkylation and cycloalkylation reactions of active methylene compounds in the presence of readily available imidazolium salts (ionic liquids) as phase transfer catalysts were performed to afford the respective dialkylated or cycloalkylated products. This method is very efficient for the synthesis of 1,1-disubstituted derivatives and cyclopropane and cyclopentane ring systems in a facile manner.

Full text of DOI:10.1016/j.tetlet.2004.11.141

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 635–638
Imidazolium salts as phase transfer catalysts for the
dialkylation and cycloalkylation of active methylene compounds
*
Sengodagounder Muthusamy and Boopathy Gnanaprakasam
Central Salt and Marine Chemicals Research Institute, Bhavnagar 364 002, India
Received 19 August 2004; revised 15November 2004; accepted 26 November 2004
Available online 13 December 2004
Abstract—The dialkylation and cycloalkylation reactions of active methylene compounds in the presence of readily available imida-
zolium salts (ionic liquids) as phase transfer catalysts were performed to afford the respective dialkylated or cycloalkylated products.
This method is very efficient for the synthesis of 1,1-disubstituted derivatives and cyclopropane and cyclopentane ring systems in a
facile manner.
ꢀ
2004 Elsevier Ltd. All rights reserved.
Cyclopropane and cyclopentane derivatives are very
1
cycloalkylation reactions to synthesize 1,1-disubstituted
products and cycloalkane ring systems.
important intermediates in the pharmaceutical industry
2
and for natural product synthesis. Phase transfer cata-
lysts (PTCs) are powerful reagents in chemical transfor-
To study the dialkylation processes, we synthesized the
ionic liquids [bmim]BF4, [bbim]BF4, [bmim]Br,
[bmim]PF , [mmim]BF and [mmim]I as described in
3
mations, the characteristics of which include mild
reaction conditions, safety, operational simplicity and
selectivity. Thus, finding a new phase transfer catalyst
to promote various organic transformations is of con-
siderable interest. Phase transfer catalysts are often used
in nucleophilic displacement reactions to facilitate reac-
tions between organic reactants and ionic inorganic
6
4
7
the literature (Fig. 1). Initially, we carried out the dialk-
ylation reaction of ethyl acetoacetate, allyl bromide and
potassium carbonate in the presence of [bmim]BF as a
4
phase transfer catalyst using dimethylformamide as sol-
vent. The reaction mixture was stirred at room temper-
ature for 2 h to give a white suspension, which
3
salts. Although many phase transfer catalysts are
3,4
8,9
known quaternary salts formed from ammonia are
only used for alkylation reactions. The presence of
bulky substituents on quaternary salts results in good
phase transfer catalysts for nucleophilic displacement
subsequently turned orange. Work-up furnished the
product 2a in 96% yield (Scheme 1). Interested by this
result, further dialkylation reactions were carried out
using [bmim]BF to furnish the products 2b–d. The dialk-
4
3
reactions. Thus, we planned to use imidazolium salts
generally known as ionic liquids) having bulky cations
ylation reaction was then performed with an equimolar
mixture of different alkyl halides under the above exper-
imental conditions to afford the products 2e,f having dif-
ferent alkyl groups in very good yield (Scheme 1).
(
as phase transfer catalysts for alkylations. Recently,
ionic liquids have played increasing roles in organic
chemistry and have been used in various organic trans-
5
formations as solvent, reagent or Brønsted acid. To
the best of our knowledge, only N-methylimidazolium
6
bromide has been indirectly implicated as a phase
transfer catalyst. We herein report a range of ionic liq-
uids as phase transfer catalysts for dialkylation and
+ N Bu
BF4
+ N Bu
BF4
+ N Bu
Br
N
N
N
Me
Bu
Me
[bmim]BF4
[bbim]BF4
[bmim]Br
Bu
PF6
+ N Me
N
Me
+ N
+
N
N
N
Keywords: Phase transfer catalysts; Ionic liquid; Alkylation; Imidazo-
Me
Me
BF4
Me
I
lium cations.
*
[bmim]PF6
[mmim]BF4
[mmim]I
Corresponding author. Tel.: +91 278 256 7760; fax: +91 278 256
562; e-mail: muthu@csmcri.org
7
Figure 1. Ionic liquids synthesized for phase transfer catalysis.
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.141

636
S. Muthusamy, B. Gnanaprakasam / Tetrahedron Letters 46 (2005) 635–638
O
O
O
O
the weak acidity of the substrate due to the phenyl
group. This reaction was repeated with strong bases
such as 7 N NaOH or KOH in aqueous media to furnish
1-phenylcyclopropanecarboxylic acid in 76% yield.
RX, K2CO3
H3C
OEt
H3C
OEt
[
Bmim]BF4 (cat.)
DMF, rt
R1 R2
1
2
1
2
RX= methyl iodide, 2a; R , R =allyl, 96%
The use of excess active methylene compound in the
above process would lead only to cyclopropane ring for-
mation without any side reactions. This shows that the
cyclopropanation formation was facile rather than
mono-alkylation or intermolecular bis-nucleophilic dis-
placement to give compound of type 6. Representa-
tively, the reaction of ethyl acetoacetate was
allyl bromide,
1
2
2
2
2
2
2
b; R , R =CH3, 94%
propargyl bromide
or benzyl bromide
1
2
c; R , R =propargyl, 95%
1
2
d; R , R =benzyl, 96%
1
2
e; R =CH3, R =propargyl, 87%
1
2
f; R =CH3, R =allyl, 88%
Scheme 1. Dialkylation of ethyl acetoacetate with various alkyl
halides.
performed in [bmim]BF as solvent without addition
4
of any organic solvent like DMF to afford the product
3a in 30% yield after 7 h duration. However, the same
reaction was carried out in DMF as a control experi-
In order to extend the utility of this method, we investi-
gated the cycloalkylation of active methylene
compounds using imidazolium salts. Initially, we
performed the cyclopropanation using ethyl acetoace-
tate, 1,2-dibromoethane and K CO in the presence of
1
0
ment without adding any imidazolium salt as a cata-
lyst affording the product 3a in only 63% yield.
Similarly, the reaction with other active methylene com-
pounds (ethyl cyanoacetate, diethyl malonate, acetylac-
etone) in the absence of the imidazolium salt furnished
the corresponding products in the range of only 60–
70% yields. This result demonstrates that imidazole
based PTCs give the products with improved yields.
2
3
a catalytic amount of [bmim]BF at room temperature
4
8
,9
to furnish 3a in 86% yield via an intramolecular dialk-
ylation reaction (Scheme 2). To generalize this process,
reactions of 1,2-dibromoethane with various active
methylene compounds (acetylacetone, diethyl malonate,
dimethyl malonate and ethyl cyanoacetate) in the pres-
ence of a catalytic amount of several imidazolium salts
Next, we investigated the role of imidazolium salts as
PTCs in cyclopentane ring formation using 1,4-dibro-
mobutane via cycloalkylation. We carried out the reac-
tion of ethyl acetoacetate, 1,4-dibromobutane, K CO
(
[bmim]BF4, [bmim]PF6, [bmim]Br, [bbim]BF4) in
DMF were studied (Table 1). Analysis of the results re-
vealed that all four imidazolium salts were effective
phase transfer catalysts for the cycloalkylation reac-
tions. However, the reaction of phenylacetic acid ethyl
ester under similar experimental conditions did not fur-
nish the cyclopropane derivative 3f (Table 1) because of
2
,9
3
8
and a catalytic amount of [bmim]Br to deliver the
cyclopentane derivative 4a in 94% yield (Scheme 3).
Cyclopentane ring formation was generalized with
several active methylene compounds and a catalytic
amount of imidazolium salts (Table 2). Reactions in
Br
Br
( )3 , K2CO3
Br
Br
, K2CO3
X
Y
X
Y
imidazolium salt
cat.), DMF, rt
X
Y
imidazolium salt
cat.), DMF, rt
X
Y
(
(
1
4
1
3
3
3
3
3
3
3
a; X= COMe, Y= COOEt
4a; X= COMe, Y= COOEt
b; X= COOMe, Y= COOMe
c; X= COOEt, Y= COOEt
d; X= CN, Y= COOEt
4b; X= COOMe, Y= COOMe
4c; X= COOEt, Y= COOEt
4d; X= CN, Y= COOEt
4e; X= COMe, Y= COMe
4f; X= Ph, Y= COOEt
e; X= COMe, Y= COMe
f; X= Ph, Y= COOEt
Scheme 2. Cyclopropane ring formation in the presence of a catalytic
amount of various imidazolium salts.
Scheme 3. Cyclopentane ring formation in the presence of a catalytic
amount of imidazolium salts.
Table 1. Cyclopropanation of active methylene compounds using different ionic liquids
Entry
X
Y
[bmim]BF
4
[bmim]PF
6
[bbim]BF
4
[bmim]Br
a
Yield (%)
a
Yield (%)
a
Yield (%)
a
Yield (%)
Time (h)
Time (h)
Time (h)
Time (h)
3a
3b
3c
3d
3e
3f
COMe
COOMe
COOEt
CN
COOEt
COOMe
COOEt
COOEt
COMe
86
92
92
89
759
0
6
6
856
87
89
854
9
83
7
7
92
92
4
88
7
6
b
94
b
6
8
6
7
6
94
4
86
73
12
89
74
12
4
9
COMe
Ph
74
12
8
COOEt
0
0
0
12
a
Yields (unoptimized) refer to isolated and chromatographically pure compounds 3.
Potassium carbonate (20.0 mmol) and imidazolium salt (2.0 mmol) was additionally added and the reaction heated to 70 ꢁC for 3 h for complete
conversion.
b

S. Muthusamy, B. Gnanaprakasam / Tetrahedron Letters 46 (2005) 635–638
Table 2. Cyclopentanation of active methylene compound using different ionic liquids
637
Entry
X
Y
[bmim]BF
4
[bmim]PF
6
[bbim]BF
4
[bmim]Br
a
Yield (%)
a
Yield (%)
a
Yield (%)
a
Yield (%)
Time (h)
Time (h)
Time (h)
Time (h)
4a
4b
4c
4d
4e
4f
COMe
COOMe
COOEt
CN
COOEt
COOMe
COOEt
COOEt
COMe
96
957
93
96
858
0
6
90
8
92
7
6
96
6
94
6
7
94
6
94
7
6
7
88
4
90
590
7
93
594
86
12
93
86
12
5
COMe
Ph
7
84
12
8
0
COOEt
0
0
12
a
Yields (unoptimized) refer to isolated and chromatographically pure compounds 4.
the presence of different imidazolium salts furnished the
cyclopentane derivatives 4 in 90–96% yields. However,
the reaction of acetylacetone afforded only in 84% yield
of product 4e (Table 2). The formation of cyclopentane
ring systems was also observed when the reactions were
repeated with excess active methylene compounds. This
result showed that cyclopentane ring formation is a fac-
ile reaction under these experimental conditions.
Table 4. Representative reactions of active methylene compounds in
the presence of tetrabutyl ammonium halides salts
a
Yield (%)
Entry
PTC
Time (h)
Product
1
TBAI
TBAB
TBAI
TBAB
6
2
2
6
7
2a
2a
3a
3a
4a
4a
96
94
88
85
93
96
2
3
4
5TBAB
6
TBAI
5
We also studied the cycloalkylation reactions in the
presence of imidazolium salts using different solvents.
Thus, the reaction was repeated with solvents such as
benzene, acetone and toluene to furnish the cyclopro-
pane derivatives in 80–88% yields and cyclopentane
derivatives in 90–96% yields employing potassium or so-
dium carbonate as base under reflux conditions (Table
a
Yields (unoptimized) refer to isolated and chromatographically pure
compounds.
Br
Br
( )2 , K2CO3
X
X
Y
Br
3
). Further, we investigated the dialkylation and cyclo-
alkylation reactions using the known PTC catalysts
TBAB and TBAI) instead of imidazoium salts under
imidazolium salt
(cat.), DMF, rt
Y
1
5
(
5
5
5
a; X= COMe, Y= COOEt, 94%
b; X= COOMe, Y= COOMe, 90%
c; X= COOEt, Y=COOEt, 96%
similar experimental conditions and the results are
shown in Table 4. This result indicates that the imidazo-
lium salts act as PTC catalysts like TBAB and TBAI.
5d; X= CN, Y= COOEt, 87%
e; X= COMe, Y= COMe, 80%
5
Finally, we studied the role of imidazolium salts in the
3
c
Scheme 4. Mono-alkylation of active methylene compounds with 1,3-
formation of the cyclobutane ring system. The initial
study with ethyl acetoacetate, 1,3-dibromopropane and
K CO in the presence of a catalytic amount of
dibromopropane in the presence of imidazolium salts.
2
3
[
bmim]BF showed that the unexpected mono-alkylated
4
product 5a was formed in 96% yield rather than the
cyclobutane. Cyclobutane ring formation also failed
with other active methylene compounds, even at ele-
vated temperatures and with excess K CO (Scheme 4)
dinucleophilic displacement and mono-alkylated prod-
ucts 5 (10–20%) under these experimental conditions
(Scheme 5).
2
3
in the presence of imidazolium salts and furnished only
the mono-alkylated compounds 5b–e in good yields.
Further, the use of excess active methylene compound
in the above reaction afforded the corresponding
bis-alkylated products 6 (56–65%) via intermolecular
In conclusion, we have demonstrated that environmen-
tally benign imidazolium salts can be used as phase
transfer catalysts for the dialkylation and cycloalkyl-
ation reactions of active methylene compounds
under mild conditions. Notably, cyclopropane and
Table 3. Reaction of ethyl acetoacetate in different solvent media in the presence of ionic liquids
Solvent
Conditions
Catalyst
Cyclopropanation
a
Cyclopentanation
a
4a (yield, %)
3
a (yield, %)
Benzene
Benzene
Benzene
Benzene
Acetone
Acetone
Acetone
Toluene
Reflux, 7 h
Reflux, 7 h
Reflux, 7 h
Reflux, 7 h
Reflux, 6 h
Reflux, 6 h
Reflux, 6 h
Reflux, 6 h
[bmim]BF
4
83
80
94
93
[bmim]PF
[bmim]Br
[mmim]I
6
8594
86
96
94
96
92
90
[bmim]BF
[mmim]I
4
88
88
[mmim]BF
[bmim]BF
4
86
86
4
a
Yields (unoptimized) refer to isolated and chromatographically pure compounds 3a and 4a.

638
S. Muthusamy, B. Gnanaprakasam / Tetrahedron Letters 46 (2005) 635–638
Y
J. E. L.; Einloft, S.; De Souza, R. F.; Dupont, J.
Polyhedron 1996, 15, 1217.
. General procedure for the dialkylation and cycloalkyl-
ation reactions using imidazolium salts as PTCs: To a
vigorously stirred solution of active methylene compound
X
Br
Br
( )2 , K2CO3
Y
X
8
X
Y
6
5
(major)
+
imidazolium salt
(excess) (cat.), DMF, rt
1
(minor)
(
20.0 mmol) and powdered anhydrous potassium carbon-
6
6
6
a; X=COOEt, Y=COOEt, 60%
b; X=COOCH3, Y=COOCH3, 65%
c; X=CN, Y=COOEt, 56%
ate (50.0 mmol) in DMF (50.0 mL) was added the
appropriate dihaloalkane (22.0 mmol). To this reaction
mixture a catalytic amount of imidazolium salt (2.0 mmol)
was added and the mixture stirred at room temperature
for the appropriate time. The reaction mixture was filtered
and the solid washed with diethyl ether. The filtrate was
diluted with water (200 mL) and extracted with diethyl
ether (4 · 75mL). The organic layers were combined and
washed with brine solution. Finally, evaporation of the
organic layer afforded the crude product, which was
chromatographed through a short alumina column (10%
EtOAc/hexane) to yield the respective pure products.
. All compounds exhibited spectral data consistent with
their structures. Selected spectral data: Compound 2a:
colourless liquid; IR (neat) 3080, 2982, 2935, 1739, 1714,
Scheme 5. Intermolecular dialkylation of active methylene compounds
in the presence of imidazolium salts.
cyclopentane derivatives were obtained in very good
yields at room temperature.
Acknowledgements
9
This research was supported by the Department of Sci-
ence and Technology, New Delhi. B.G. thanks DST,
New Delhi for the award of a research Fellowship.
À1
1
1
641, 1442, 1358, 1279, 1211, 1181, 1141, 922 cm ; H
NMR (200 MHz, CDCl ) 5.67–5.50 (m, 2H, CH), 5.14–
), 4.25–4.15 (q, J = 7.0 Hz, 2H, OCH ),
.67–2.59 (m, 4H, CH ), 2.13 (s, 3H, CH ), 1.30–1.23 (t,
3
5
2
.06 (m, 4H, CH
2
2
2
3
1
3
References and notes
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03.8 (C@O), 171.6 (C@O), 132.1 (CH), 118.9 (CH ), 62.9
(quat-C), 61.2 (OCH ), 35.9 (CH ), 26.7 (CH ), 13.9
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2
1
2
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2
+
3
+
10
(CH ); MS (FD ) m/z 210 (M ). Compound 3a:
3
Colourless liquid; IR (neat) 2984, 2937, 1725, 1702,
1628, 1417, 1398, 1362, 1312, 1187, 1121 cm ; H NMR
À1
1
(200 MHz, CDCl ) 4.26–4.16 (q, J = 7.0 Hz, 2H, OCH ),
3
2
2.47 (s, 3H, CH ), 1.46 (s, 4H, CH ), 1.33–1.27 (t,
3 2
1
J = 7.0 Hz, 3H, CH3); C NMR (50.3 MHz, CDCl3)
3
204.4 (C@O), 170.7 (C@O), 61.0 (OCH ), 59.2 (quat-C),
2
+
29.5( CH ), 18.8 (CH ), 13.9 (CH ); MS (FD ) m/z 156
3
2
3
+
(M ). Compound 4c: Colourless liquid; IR (neat) 2980,
À1
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;
1
3
5
1
OCH ), 2.22–2.15(m, 4H, C H ), 1.72–1.65(m, 4H, C H ),
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2
2
1
3
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2 2 3
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2242, 1742, 1450, 1368, 1297, 1193, 1025 cm ; H NMR
À1
1
(200 MHz, CDCl ) 4.32 (q, J = 7.0 Hz, 2H, OCH ), 2.30–
3
2
2.24 (m, 4H, CH ), 1.91–1.84 (m, 4H, CH ), 1.37–1.30 (t,
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2
+
37.5( CH ), 25.0 (CH ), 13.8 (CH ); MS (FD ) m/z 167
4
5
2
2
3
+
(M ). Compound 6b: White solid; mp 48–50 ꢁC; IR (KBr)
2960, 2927, 2863, 1744, 1468, 1440, 1349, 1270, 1250, 1221,
À1
1
1161 cm
OCH ), 3.40–3.32 (t, J = 8.0 Hz, 2H, CH), 2.0–1.91 (q,
3
; H NMR (200 MHz, CDCl ) 3.74 (s, 12H,
3
1
3
J = 8.0 Hz, 4H, CH ), 1.38–1.22 (m, 2H, CH ); C NMR
2
2
(50.3 MHz, CDCl ) 169.5( C@O), 52.4 (OCH ), 51.2
3
3
+
(CH), 28.2 (CH ), 25.0 (CH ); MS (FD ) m/z 304 (M );
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2
2
6
7
. Dehmlow, E. V.; Fastabend, U. Synth. Commun. 1993, 23,
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79.
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