Zinc-proline complex: An efficient, reusable catalyst for direct nitroaldol reaction in aqueous media

Article abstract of DOI:10.1080/00397910701354731

Zinc-proline complex is an effective homogeneous catalyst for the nitroaldol reaction to afford 2-nitro alcohols in high yields at room temperature in water. The catalyst is reused for several cycles with consistent activity. Copyright Taylor & Francis Gr

Full text of DOI:10.1080/00397910701354731

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Zinc–Proline Complex: An Efficient, Reusable
Catalyst for Direct Nitroaldol Reaction in
Aqueous Media
a
a
a
K. Rajender Reddy , C. V. Rajasekhar & G. Gopi Krishna
a
Inorganic and Physical Chemistry Division , Indian Institute of Chemical
Technology , Hyderabad, India
Published online: 22 Jun 2007.
To cite this article: K. Rajender Reddy , C. V. Rajasekhar & G. Gopi Krishna (2007) Zinc–Proline Complex: An
Efficient, Reusable Catalyst for Direct Nitroaldol Reaction in Aqueous Media, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:12, 1971-1976
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Synthetic Communications , 37: 1971–1976, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701354731
Zinc–Proline Complex: An Efficient,
Reusable Catalyst for Direct Nitroaldol
Reaction in Aqueous Media
K. Rajender Reddy, C. V. Rajasekhar, and G. Gopi Krishna
Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad, India
Abstract: Zinc–proline complex is an effective homogeneous catalyst for the
nitroaldol reaction to afford 2-nitro alcohols in high yields at room temperature in
water. The catalyst is reused for several cycles with consistent activity.
Keywords: aqueous media, nitroaldol, reusable catalyst, zinc–proline
INTRODUCTION
Replacement of volatile organic solvents with environmentally benign solvents
has received considerable attention in organic synthesis as a result of increased
[
environmental regulations. Several solvent systems, for example, water,
1]
[2]
[
3]
[4]
[5]
supercritical fluids,
ionic liquids,
soluble polymers,
and fluorous
[
6]
liquids, have been exploited over the past several years as alternative
media for organic synthesis. In recent years, significant progress has been
made in the field of organic chemistry in aqueous media, and several organic
transformations, for example, aldol, allylation, Diels–Alder, Michael, Heck,
[7]
and Suzuki reactions, have been performed efficiently in water.
The nitroaldol or Henry reaction is one of the powerful C-C bond-forming
processes in organic chemistry, providing efficient access to valuable functio-
nalized structures such as 1,2-amino alcohols and a-hydroxy carboxylic
Received in India November 8, 2006
Address correspondence to Dr. K. Rajender Reddy, Inorganic and Physical
Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007,
India. E-mail: rajender@iict.res.in
1
971

1
972
K. R. Reddy, C. V. Rajasekhar, and G. G. Krishna
[
8]
acids. The classical nitroaldol reaction is performed in the presence of a base
in an organic solvent. Several bases, such as alkali metal hydroxides, carbon-
ates, bicarbonates, alkoxides, barium and calcium hydroxide, magnesium, and
aluminium ethoxides, and also organic bases such as primary, secondary, and
[9]
tertiary amines, have been reported in the literature. To overcome some of
the disadvantages associated with the homogeneous catalysts, such as tedious
workup procedures, large amounts of acids to neutralize bases, and lack of
reusability, several solid base catalysts also have been reported in recent
[
10]
years.
Depending on the nature of the substrate, these base catalysts
also catalyze the competitive aldol condensation and Cannizzaro reactions.
Furthermore, when aromatic aldehydes are employed as electrophiles, the
nitroaldol product may undergo base-catalyzed elimination of water to give
nitroalkenes. To prevent the formation of these side products, selective and
reusable catalysts are highly desirable.
Nitroaldol reactions may be run under aqueous conditions to avoid the use
of organic solvents and their associated environmental concerns. Ballini and
Bosica reported the use of cetyltrimethylammonium chloride as a phase-
transfer agent for the synthesis of 2-nitro alcohols in water containing
[
11]
sodium hydroxide.
Herein, we report an efficient synthesis of 2-nitro
alcohols under ambient conditions catalyzed by a zinc–proline complex
using the environmentally benign solvent, water, as the reaction medium.
RESULTS AND DISCUSSION
Zinc–amino acid complexes were readily prepared in methanol by reacting
the corresponding amino acids with zinc acetate in the presence of triethyl-
amine. The complexes were precipitated as white solids and readily isolated
by simple filtration. Spectroscopic characterization of the resulting products
have revealed that they form monomeric metal complexes with a general
[
12]
formula Zn(amino acid)2.
These complexes are initially screened as
catalysts for the nitroaldol reactions using p-nitrobenzaldehyde and nitro-
methane as reactants, and the results are summarized in Table 1. No
reaction occurred when simple zinc salts were used as the catalysts
(
Table 1, entries 1 and 2). However, when the reaction was performed with
the zinc–amino acid complexes as catalysts, the formation of nitroaldol
products was observed. Among the various zinc-amino acid complexes, the
zinc–proline catalyst showed higher activity (Table 1, entry 6) with an
exclusive formation of nitroaldol product. To evaluate the effect of solvent,
the experiments were conducted in dimethylformamide (DMF) and dichloro-
methane under identical conditions. In dimethyl sulfoxide (DMSO), the
product was formed in 96% yields after 9 h, whereas in dichloromethane,
no product formation was observed even after 24 h. These results indicate
that the nature of the amino acid and the solubility of the zinc complex play
important roles in the activity of the catalyst.

Zinc-Proline Complex
Table 1. Nitroaldol reaction between p-nitrobenzaldehyde and intro-
1973
a
methane with various zinccatalysts in water
b
S.no.
Zn catalyst
Yield
1
2
3
4
5
6
Zn(OAc)
ZnBr2
2
—
—
23
30
85
95
Zn(Phy-ala)
Zn(Gly)
Zn(Ala)2
Zn(Pro)
2
2
2
a
Reaction conditions: p-nitrobenzaldehyde (1 mmol), nitromethane
10 mmol), catalyst (10 mol%), H O (5 ml), rt.
(
2
b
NMR yields.
The nitroaldol reactions with various aldehydes were performed by taking
aldehyde (1 mmol), nitromethane (10 mmol), and zinc(proline)2 catalyst
(10 mol%) in water at room temperature, and the results are summarized in
Table 2. All the aldehydes investigated afforded very good yields of nitroaldol
products, from 71 to 98%. Aldehydes with strong electron-withdrawing
groups provided nitroaldol products in higher yields in shorter intervals of
time (Table 2, entries 1–4). whereas unsubstituted aldehydes and aldehydes
with electron-donating groups took longer times to provide higher conversions
of the products (Table 2, entries 6–8). Heteroaromatic aldehydes, such as fur-
furaldehyde and 3 pyridinecarboxaldehyde also resulted in higher conversions
(Table 2, entries 9 and 10). To check the influence of the present catalyst on
the diastereoselectivity, a reaction between p-nitrobenzaldehyde (1 mmol) and
nitropropane (5.6 mmol) with 10 mol% of the catalyst was performed in water
for 15 h. NMR spectrum of the resulting mixture confirms the quantitative
formation of a nitroaldol product with a 1:1 diastereomeric ratio.
Conventional methods generally use a large excess of the nitroalkanes,
which are not suitable for the large-scale preparation of nitroaldol products.
Ballini and Bosica reported the NaOH-catalyzed nitroaldol reactions using
1
:1 mixture of aldehydes and nitroalkanes in water under phase transfer
[
11]
conditions . The present catalyst also works well with 1:1 mixtures of
aldehydes and nitromethane. The reaction of p-itrobenzaldehyde with
nitromethane (1:1 ratio) resulted in the formation of 83% of the product after
1
8 h at room temperature, whereas under the same conditions 2-methoxybenzal-
dehyde, a substrate with an electron-donating group at the sterically hindered
ortho-position, provided 50% of the nitroaldol product. These results suggest
that the present catalyst can show appreciable activity with various aromatic
aldehydes for the nitroaldol reaction even in the absence of phase-transfer

1
974
K. R. Reddy, C. V. Rajasekhar, and G. G. Krishna
Table 2. Nitroaldol reaction of aromatic aldehydes with nitromethane catalyzed by
a
Zn(proline) complexin water
2
b
Yield (%)
Entry
1
Aldehyde
Time (h)
0.25
98
2
3
4
5
6
7
0.33
0.25
2.5
98
96
c
94
c
88
9.0
8.0
90
71
12.0
c
8
9
15.0
8.0
85
c
85
1
0
8.0
95
a
Reaction conditions: aldehyde (1 mmol), nitromethane (10 mmol), catalyst
10 mol%), H O (5 mL), rt.
NMR yield.
(
2
b
c
Isolated yield.
agents. The high activity of the present system could be associated with the
bifunctional nature of the catalysts, where pyrrolidine unit assists in the gener-
ation the carbanion and zinc ion in the activation of the carbonyl group. Unfor-
tunately, we did not observe any enantioselectivity in the present system.
To confirm that the present process can be recyclable, after the
completion of the reaction, the organic portion was extracted with ethyl

Zinc-Proline Complex
1975
acetate and the remaining aqueous solution was subjected for further recycling
experiments. Reaction between the p-nitrobenzaldehyde and nitromethane in
1
:10 ratio provided 98%, 96%, and 95% conversions in three consecutive
recycle experiments at room temperature in 1 h. Finally, the catalyst was
recovered by precipitating the aqueous layer by simple addition of acetone.
EXPERIMENTAL
General
Analytical-grade zinc salts and amino acids were purchased from S. D. Fine
Chemicals, India. Aromatic aldehydes, nitromethane, and nitroethane were
purchased from Aldrich or Fluka and used without further purification.
ACME silica gel (100–200 mesh) was used for column chromatography,
and thin-layer chromatography (TLC) was performed on Merck precoated
silica-gel 60-F254 plates. All the other solvents and chemicals were
obtained from commercial sources and purified using standard methods.
Preparation of the Catalysts
Zinc–amino acid complexes were synthesized according to the procedures
reported in the literature and used as such.
[12]
General Reaction Procedure and Reusability Protocol for
Nitroaldol Reaction
To a partially suspended Zn(amino acid)2 (10 mol%) in water (5 mL),
aromatic aldehyde (1 mmol) and nitromethane (0.5 mL, 10 mmol) were
added successively and stirred at room temperature for appropriate time.
After completion of the reaction, as monitored by TLC, the product was
extracted with ethyl acetate (3 Â 10 mL). The combined extracts were dried
over anhydrous Na SO , concentrated in vacuum, and the resulting product
2
4
was purified by column chromatography on silica gel with ethyl acetate and
n-hexane as eluent to afford the nitroaldol product. All the products gave sat-
1
isfactory H NMR and mass spectral data in accordance with litera-
[10d,13,14]
ture.
The aqueous layer after the ethyl acetate workup was used for
subsequent cycles. After the final cycle, the catalyst was recovered by preci-
pitating the aqueous layer by the addition of acetone.
CONCLUSION
In conclusion, Zn(proline) acts as an efficient, convenient, and reusable
2
catalyst for the nitroaldol reaction, providing the nitroaldol products

1
976
K. R. Reddy, C. V. Rajasekhar, and G. G. Krishna
exclusively in high yields. The advantages are high catalytic activity under
very mild conditions, easy operation, and recyclability. The superiority of
our method over the existing methods is the operation of nitroaldol reaction
with a 1:1 mixture of aldehyde and nitromethane in water to obtain the nitroal-
dol products in high yields.
ACKNOWLEDGMENT
We thank the Council of Scientific and Industrial Research (CSIR) for
financial support under the Task Force Project CMM-0005. C. V. R. and
G. G. K. thank the CSIR, India, for the award of research fellowship.
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