Hydrotalcite catalysis in ionic liquid medium: A recyclable reaction system for heterogeneous Knoevenagel and nitroaldol condensation

Article abstract of DOI:10.1016/j.tetlet.2004.02.103

Knoevenagel condensation proceeds efficiently in recyclable [bmim]PF ₆ and [bmim]BF₄ without any catalyst, and hydrotalcites in ionic liquid serve as a safe and recyclable reaction system for both Knoevenagel as well as nitroaldol condensations.

Full text of DOI:10.1016/j.tetlet.2004.02.103

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3055–3058
Hydrotalcite catalysis in ionic liquid medium: a recyclable reaction
system for heterogeneous Knoevenagel and nitroaldol condensation
Faiz Ahmed Khan,* Jyotirmayee Dash, Rashmirekha Satapathy and Sarasij K. Upadhyay
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Received 19 January 2004; revised 12 February 2004; accepted 19 February 2004
Abstract—Knoevenagel condensation proceeds efficiently in recyclable [bmim]PF6 and [bmim]BF4 without any catalyst, and
hydrotalcites in ionic liquid serve as a safe and recyclable reaction system for both Knoevenagel as well as nitroaldol condensations.
Ó 2004 Published by Elsevier Ltd.
Ionic liquids (ILs) are emerging as potential ÔgreenerÕ
alternatives to volatile organic solvents1 and in recent
years they have been used as environmentally benign
media for several important reactions.2 In continuation
of our interest in using ionic liquids as a recyclable, eco-
friendly alternative to organic solvents,3 we report
herein Knoevenagel reaction mediated by recyclable ILs
and hydrotalcites in ILs as a heterogeneous, reusable
catalyst system for Knoevenagel as well as nitroaldol
reactions.
methylene compounds, a classical synthetic transfor-
mation to prepare electrophilic alkenes,6 employing
catalyic Mg–Al HT in ILs [bmim]PF6 or [bmim]BF4
(Scheme 1, Tables 1 and 2). The condensation of benz-
aldehyde with malononitrile in either of the ionic sol-
vents [bmim][PF6] or [bmim]BF4 proceeded efficiently
resulting in near quantitative yields of the product
(Table 1, entries 1 and 3). A straightforward product
isolation was achieved by the addition of ether or tolu-
ene, which generates a biphasic medium with a clear
supernatant organic layer containing product and an
ionic catalyst phase, ready for next use. Thus, the
[bmim]BF4–Mg–Al HT system was successfully recycled
six times (entries 3–8) with no noticeable decrease in
reactivity or yield of the reaction. The reaction system
was equally efficient for the condensation of aldehydes
with ethyl cyanoacetate (entries 9, 15–17). Ni–Al
(Ni:Al ¼ 3:1) HT was also efficiently used for the same
purpose (Table 2, entry 6).
Heterogeneous catalysts are important not only from an
economical viewpoint but also due to ease of handling,
simple separation and reusability. Layered double
hydroxides (LDH) or hydrotalcites (HT)4 represent an
efficient basic catalyst system, for epoxidation,4a
Meerwein–Ponndorf–Verley reduction,4b cyanoethyl-
ation,4c aldol,4d nitroaldol4e and Knoevenagel4e con-
densations. The heterogeneous HT catalyst was
recovered by simple filtration and activated for further
use.4b–e We planned to devise a high-performance reus-
able reaction medium, with or without catalyst, that
could be directly recycled for subsequent batches,
without any activation.
To our surprise, we observed that the condensation of
aldehydes with malononitrile or ethyl cyanoacetate was
taking place smoothly without any added catalyst, in
either of the ionic solvents (Tables 1–3). In a typical
experiment, 4-nitrobenzaldehyde was dissolved in
[bmim]PF6 or [bmim]BF4 followed by the addition of
malononitrile and the reaction mixture was stirred at rt
Mg–Al (Mg:Al ¼ 3:1) HT was prepared according to the
original procedure of Miyata5 and used without any
pretreatment. Initially we carried out Knoevenagel
condensations of aldehydes and ketones with active
R1
R2
CN
Y
R1
R2
CN
With or without cat.
Ionic liquid, rt
O
+
Y
Keywords: Knoevenagel condensation; Nitroaldol condensation; Ionic
liquid; Hydrotalcite; Catalysis.
Cat. = Mg-Al (Mg:Al=3:1) HT
Y = CN, CO2Et
* Corresponding author. Tel.: +91-512-2597864; fax: +91-512-25974-
36; e-mail: faiz@iitk.ac.in
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.02.103

3056
F.A.Khan et al./ Tetrahedron Letters 45 (2004) 3055–3058
Table 1. Knoevenagel condensation of aromatic aldehydes (RCHO) in ionic liquids with or without Mg–Al HT
Entry
Substrate (R-CHO) R
Ph
Y
Ionic liquid
Time (h), Yield (%)a
No catalystc
With catalystb
1
2
CN
[bmim]PF6
[bmim]BF4
30 min, 98
30 min, 96 (2. run)
1, 99
1, 99
3
2, 98
4
1.5, 96 (2. run)
1, 97 (3. run)
2, 94 (4. run)
1, 94 (5. run)
1, 92 (6. run)
30 min, 94
5
6
7
8
9
10
Ph
4-O2NC6H4
CO2Et
CN
[bmim]PF6
[bmim]PF6
4, 98
3, 100
3, 96
4, 98
24, 98d
4, 98
3, 96
4, 94
1, 96
1, 98
20 min, 95
11
12
13
14
15
16
17
[bmim]BF4
3, 96
4-O2NC6H4
CO2Et
[bmim]PF6
[bmim]BF4
30 min, 94
3, 95
a Isolated yields of analytically pure products.
b All reactions were run using 0.5 mmol of aldehyde, 0.5 mmol of active methylene compound, 12 mg of Mg–Al HT in 1 mL of ionic liquid at rt.
c For [bmim]PF6 at rt and for [bmim]BF4 at 50 °C.
d At rt.
Table 2. Knoevenagel condensation of aldehydes and ketones with malononitrile in ionic liquids with or without Mg–Al HT
Entry
Substrate (R-CHO) R
Ionic liquid
Time (h), Yield (%)a
No catalystc
With catalystb
1
4-HOC6H4
[bmim]PF6
[bmim]BF4
[bmim]BF4
2, 91
4, 94
2
6, 91
2, 97
2, 98 (2. run)
3
3-BrC6H4
10, 95d
4
3, 98
2, 97
5
3,4,5-(MeO)3C6H2
[bmim]PF6
[bmim]BF4
6
3, 98e
2, 98e (2. run)
5, 93
4, 94
7
8
4-ClC6H4
4-PhC6H4
[bmim]BF4
[bmim]PF6
3, 96
2, 95
9
10
11
12
13
2, 96 (2. run)
C6H13
Me2CH
Cyclohexanone
[bmim]BF4
[bmim]BF4
[bmim]BF4
5, 93
5, 83
9, 91
O
14
[bmim]BF4
7, 93
a Isolated yields of analytically pure products.
b All reactions were run using 0.5 mmol of aldehyde, 0.5 mmol of active methylene compound, 12 mg of Mg–Al HT in 1 mL of ionic liquid at rt.
c For [bmim]PF6 at rt and for [bmim]BF4 at 50 °C.
d At rt.
e Using 15 mg of Ni–Al HT.
to furnish the product in near quantitative yield. While
the reaction was relatively slow at rt in [bmim]BF4
(Table 1, entry 11) as compared to [bmim]PF6, none-
theless an excellent yield of the product was obtained at
50 °C in a shorter reaction time (entries 12–14). To
ensure that the traces of protic or acidic impurities that
might be present in ILs are not responsible for the cat-
alyst-free reaction, the ILs were passed through basic
alumina, which gave essentially the same results. The
ionic solvent was economically recycled several times,

F.A.Khan et al./ Tetrahedron Letters 45 (2004) 3055–3058
3057
Table 3. Knoevenagel condensation of different aldehydes with malononitrile in recycled ionic liquids without any catalyst
Entry
Substrate, RCHO
Cycle
[bmim]PF6 rt, t/h, yield (%)a
[bmim]BF4 50 °C, t/h, yield (%)a
1
2
3
4
4-O2NC6H4
Ph
1
2
3
4
0.5, 99
1, 96
2, 93
2, 91
3, 98
7, 94
4, 98
4, 95
3,4,5-(MeO)3C6H2
4-HOC6H4
a Isolated yields of analytically pure products.
OH
and Table 3 presents the efficient reprocessing of
Knoevenagel condensations of different aldehydes in the
same IL. To the best of our knowledge, this is the first
report of a catalyst-free Knoevenagel reaction in ILs.7
OH
NO2
Mg-Al HT
+
R
CHO
R
R
[bmim][BF4], 60 oC
syn NO2
anti
NO2
R
time (h) cycle yield (%)a,b ratio
73 (92)
4-O2NC6H4
The condensation of malononitrile with substituted
benzaldehydes, aliphatic aldehydes and ketones, with or
without the catalyst were investigated and the results are
summarized in Table 2. The reactions using hydrotalcite
catalyst were somewhat faster than the catalyst-free
reactions.
48:52
46:54
5
1
2
85 (94)
8
84 (90)
82 (91)
45:55
45:55
10
10
3
4
3-BrC6H4
8
1
2
81 (90) 41:59
71 (81) 42:58
15
a isolated yields, b yields in parentheses is based on starting aldehyde
recovered.
We next examined the Henry reaction (nitroaldol) in IL
over solid base hydrotalcite catalysts. The Henry reac-
tion is a fundamental carbon–carbon bond forming
reaction providing convenient entry to important
building blocks such as nitro alkenes, b-amino alcohols
and a-hydroxy carbonyl compounds.8 To our knowl-
edge, there is no literature report on nitroaldol reactions
in ionic liquids, whereas aldol and asymmetric aldol
condensations have been well studied in this medium.9
Our results, summarized in Table 4, demonstrate that
both aromatic and aliphatic aldehydes give excellent
yields of products. Ni–Al (Ni:Al ¼ 3:1) HT was also
efficiently used and recycled to furnish the nitroaldol
products. The reaction system was efficiently recycled
for four cycles (Table 4, entries 4–7). Isobutyraldehyde
Scheme 2.
furnished a 27:83 mixture of the corresponding nitro-
alkene and nitro aldol product upon direct distillation
under reduced pressure from the reaction mixture. It is
interesting to note the significant alteration in the dia-
stereoselectivity, giving 48:52 of syn anti as compared to
0:100 reported4e for 4-nitrobenzaldehyde and nitro-
ethane (Scheme 2). The reaction medium was efficiently
recycled for four subsequent reactions without sub-
stantial change in diastereoselection.
In summary, we have developed an eco-friendly catalyst-
free reaction system for the Knoevenagel condensation.
The efficiency of hydrotalcites as solid base catalysts
in ILs as a safe and reusable media was demonstrated
for the Knoevenagel and Henry reactions. Significant
alteration in the diastereoselectivity was observed in the
case of the nitroaldol reaction with nitroethane. The
advantages include easy product isolation and catalyst
as well as ionic solvent recycling.
Table 4. Nitroaldol reaction using Mg–Al HT in [bmim][BF4]a
MeNO2
OH
Mg-Al (Mg:Al=3:1) HT
NO2
R
CHO
R
[bmim][BF4], 60 o
C
Entry
Substrate, R
Time (h)
Yieldb (%)
1
Ph
4-O2NC6H4
10
64
81
2
7
(2. run), 9
3
83
93
c
4
4-O2NC6H4
6
(2. run), 9
Acknowledgements
5
91
87
6
(3. run), 9
(4. run), 11
Financial support from the DST and CSIR is gratefully
acknowledged. J.D. and S.K.U. thank CSIR for a fel-
lowship. F.A.K. acknowledges the DST for a Swarna-
jayanti Fellowship.
7
85
81
43, 95d
8
4-IC6H4
3,4,5-(MeO)3C6H2
PhCH2
10
20
9
9
10
11
12
13
74
81
76e
CH3(CH2)2
Me2CH
CH3(CH2)5–
5
13
6
73
a All reactions were run using 0.5 mmol of aldehyde, 0.75 mmol of
nitromethane, 19–30 mg Mg–Al HT in 1 mL of ionic liquid.
b Isolated yields of analytically pure products.
c Using Ni–Al HT.
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