Bis[(L)prolinato-N,O]Zn in acetic acid-water: A novel catalytic system for the synthesis of β-amino carbonyls via Mannich reaction at room temperature

Article abstract of DOI:10.1002/aoc.1764

Zn[(L)proline]₂ was used as an efficient catalyst for the one-pot multicomponent reactions (MCR) of different aromatic amines, aromatic aldehyde and ketones in aqueous media. This method provides a novel and improved method for obtaining stereoselective β-amino carbonyl compounds in terms of good yield. Little catalyst loading, recyclability, easy accessibility of the catalyst and aqueous media are the main features of this protocol. Moreover column chromatography and recrystallization of product are not required as the crude product itself is very pure. Powder XRD and TEM images of the catalyst were taken for the first time.

Full text of DOI:10.1002/aoc.1764

Full Paper
Received: 31 August 2010
Revised: 6 November 2010
Accepted: 10 November 2010
Published online in Wiley Online Library: 26 January 2011
(wileyonlinelibrary.com) DOI 10.1002/aoc.1764
Bis[(L)prolinato-N,O]Zn in acetic acid–water:
a novel catalytic system for the synthesis
of β-amino carbonyls via Mannich reaction
at room temperature
Mazaahir Kidwai∗, Arti Jain, Roona Poddar and Saurav Bhardwaj
Zn[(L)proline]2 was used as an efficient catalyst for the one-pot multicomponent reactions (MCR) of different aromatic amines,
aromatic aldehyde and ketones in aqueous media. This method provides a novel and improved method for obtaining
stereoselective β-amino carbonyl compounds in terms of good yield. Little catalyst loading, recyclability, easy accessibility of
the catalyst and aqueous media are the main features of this protocol. Moreover column chromatography and recrystallization
of product are not required as the crude product itself is very pure. Powder XRD and TEM images of the catalyst were taken for
c
the first time. Copyright ꢀ 2011 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: bis[(L)prolinato-N,O]Zn; organometallic compound; nulticomponent reactions (MCRs); Mannich reaction; stereoselective;
recyclability
Introduction
Recently, the reported Mannich reactions have been catalysed
by HCl,[6] HBF4,[7] InCl3,[8] Y(OTf)3,[9] Yb(PFO)3,[10] Zn(BF4)2,[11]
Bi(OTf)3,[12] PS-SO3H,[13] chiral Brønsted acid,[14,15] phospho-
rodiamidic acid,[16] iminodiacetic acid,[17] heteropoly acid,[18]
copper(I)-Fesulphos Lewis acid,[19] dodecylbenzene sulfonic
acid,[20] nanoparticles,[21,22] Troger’s base[23] and enzymes.[24]
However, the catalysts suffer from the drawback of difficult sep-
aration after the reactions and therefore are incapable of being
recycled and reused. Most of the catalysts are not able to give
stereoselective products. Furthermore, some of them are corro-
sive, very expensive and volatile, and often cause environmental
problems; most of the methods also require high temperature
conditions. In almost every reaction column chromatography and
recrystallization are required, which consume a great deal of sol-
vent. Therefore it was thought worthwhile to develop a new
and mild methodology that overcomes the drawbacks of classical
catalysis. The development of novel reactivity as well as selectivity
that cannot be attained in conventional organic solvents is, thus,
one of the challenging goals of aqueous chemistry.
Zincisthemostubiquitousofalltraceelementsinvolvedinhuman
metabolism. More than 100 specific enzymes require zinc for their
catalytic function. For example, in the catalytic centre of human
carbonic anhydrase II, zinc (II) is coordinated by amino acids
and water, as zinc-bound water and hydroxide/hydroxyl ions are
excellent nucleophilic agents. The significance of Zn for all kinds
of life processes is generating new activities in the once-neglected
fieldofZncoordinationchemistry. Oneaspectofthisshouldbethe
study of Zn–amino acid complexes. Proline is the most prominent
amino acid for the coordination of Zn, as its secondary amino
group and carboxylate function are ideally suited for Zn2+ in low
coordination number, which makes Zn complex a moderately soft
Lewis acid. As part of our programme on green chemistry, we
have attempted to reveal the catalytic properties of Zn–proline
complex for organic reactions.
β-Amino carbonyl compounds are attractive targets for chem-
ical synthesis as they are widely used in biologically active
molecules as well as being important synthons for various
pharmaceuticals.[1]
Recently, organometallic catalysts emerged as a reagent class
representing a new methodology for green chemistry.[25–27] In our
effortstoexploretheapplicationofthisemergingarea, webecame
interested to determine the application of Zn[(L)proline]2 in the
presence of acetic acid for the Mannich reaction. Zn[(L)proline]2
has emerged as powerful catalyst for various transformations
The concept of ‘green chemistry’[2] has been widely adopted to
meet the fundamental scientific challenges of protecting human
health and the environment with commercial viability. One of
the thrust areas for achieving this target is to explore alternative
reaction conditions and reaction media to accomplish the desired
chemical transformation with minimum by-products and waste
generation as well as eliminating the use of hazardous solvents.[3]
Environmentally benign solvents like water are ‘green’ solvents,
being economical and eco-friendly for synthetic transformation.[4]
The Mannich reaction is one of the most important funda-
mental carbon–carbon bond-forming reactions in organic chem-
istry for the preparation of β- amino carbonyl compounds.[5]
∗
Correspondenceto:Mazaahir Kidwai, Green Research Laboratory, Department
of Chemistry, University of Delhi, Delhi 110 007, India.
E-mail: kidwai.chemistry@gmail.com
GreenResearchLaboratory,DepartmentofChemistry,UniversityofDelhi,Delhi
110 007, India
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Appl. Organometal. Chem. 2011, 25, 335–340
Copyright ꢀ 2011 John Wiley & Sons, Ltd.

M. Kidwai et al.
CHO
1
O
3
NH2
O
HN
Zn[(L)Proline]2
O
HN
Syn
+
+
+
CH3COOH
r.t
2
Anti
4
Scheme 1. Model reaction between aniline, benzaldehyde, and cyclohexanone at room temperature with Zn[(L)proline]2.
O
O
O
NH
O
O
N
H
NH
O
O
NH
O
NH
O
O
NH
O
N
O
H
NH
Ph
O
H
O
H
Ph
H
Ph
HC
N
Ph
CH3COOH
NH2 + Ph
Figure 1. Plausible mechanism for the Zn [(L)proline]2 catalysed reaction for β-aminocarbonyl compounds.
Ph
CHO
such as the aldol reaction[28] and the Hantzsch reaction.[29]
The Zn[(L)proline]2 complex is not dissociated under reaction
conditions.
reaction was carried out using equivalent amounts of aniline,
benzaldehyde and cyclohexanone. The reaction was refluxed at
100 ◦C in ethanol; even after 24 h, no product was obtained. The
same reaction was performed using Zn[(L)proline]2 as the catalyst
and acetic acid–water as reaction medium at room temperature.
Surprisingly 90% yield of desired product was obtained after
stirring the reaction mixture for 12 h (Scheme 1).
We investigated the influence of water with organic solvents
on reaction time and yield of the product. It was found that,
when acetic acid (only two drops) was used along with water
as a solvent, the reaction proceeded efficiently even at room
temperature. With this optimistic result in hand, we were curious
to know the reason for this. After applying so many hypotheses,
a proposed mechanism is reported in which acetic acid takes
part in the reaction. At room temperature acetic acid helps in
the synthesis of imine from aldehyde and amines (Fig. 1), which
ultimately participates in the reaction with cyclohexanone in
the presence of Zn[(L)proline]2. It was also found that, when
a water–ethanol system was used as the reaction medium, no
product was obtained even after refluxing the mixure for 24 h.
In continuation of our studies on developing economically
viable and environmentally benign methodologies for organic
reactions and to reveal the efficient utility of transition metals
and their derivatives,[30–32] we report herein for the first time
the Zn[(L)proline]2 catalysed three-component stereoselective
Mannich reaction in aqueous medium. Many advantages, such
as higher solubility in water, insolubility in organic solvents,
stereoselectivity, inexpensiveness, ecofriendly nature, uncom-
plicated handling, convenient workup and recyclability, make
Zn[(L)proline]2 as an efficient catalyst in organic synthesis.
Results and Discussion
To validate our hypothesis and achieve catalytic evaluation
of Zn[(L)proline]2, we took the synthesis 4a from aniline,
benzaldehyde and cyclohexanone as the model reaction. A blank
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Appl. Organometal. Chem. 2011, 25, 335–340

Bis[(L)prolinato-N,O]Zn in acetic acid–water
Table 1. Various catalyst and catalytic system Catalysed model
Table 2. Catalyst recycling studiesa
reactiona
Catalyst recycle
Yieldb (%)
1
2
3
4
5
Sample no.
Catalyst
Time
Yieldb (%)
98
94
91
85
70
a Reaction was performed with 1 mmol aniline, benzaldehyde, and
acetophenone in the presence of 5 mol% of Zn[(L)proline]2 at room
temperature. Reaction progress monitored by TLC.
b Isolated yield.
1
2
3
4
5
6
Zn(CH3COO)2
24
24
24
24
10
24
Trace
Trace
Zero
Zero
98
Zn(Lys)2
Zn(L-Pro)2 –water
Zn(L-Pro)2 –ethanol
Zn(L-Pro)2 –acetic acid
Acetic acid
Trace
a Reactions were performed with aniline (0.01 mol), benzaldehyde
(0.01 mol), acetophenone (0.01) and various catalytic system (5 mol%).
b Isolated yield.
Ar'
Ar'
NH
NH
O
O
Ha
Ha
Ar
Ar
Hb
Hb
Anti (J > 5.5 Hz)
Syn (J < 4.0 Hz)
Scheme 2. Identification of anti and syn isomers by 1H NMR spectroscopy.
Figure 2. Powder X-ray diffraction patterns of Zn[(L)proline]2.
Moreover, when only acetic acid was used, there was no formation
of desirable product. These findings support our mechanism and
confirmed that Zn[(L)proline]2 –acetic acid is important for the
smooth formation of desirable product (Table 1).
carbon atom, that is the most stable transition state produces the
anti-isomer.
One of the most important advantages for our reaction is the
purity of the products. All the separated products are of high
purity and do not require any further purification such as column
chromatography or recrystallization. The crude products are very
pure and give good NMR spectra.
We further investigated the optimum reaction conditions using
different amounts of Zn[(L)proline]2. An increase in the quantity of
Zn[(L)proline]2 from 2 to 5 mol% not only decreased the reaction
time from 12 to 10 hrs, but also increased the product yield slightly
from 93 to 98%. This showed that the catalyst concentration plays
a major role in optimization of the product yield.
Interestingly, the products formed showed excellent anti
selectivity.Theantiandsynisomerswereidentifiedbythecoupling
constants (J) of the vicinal protons adjacent to C O and NH in
their 1H NMR spectra. The J signal of the anti isomer is higher than
that of the syn one. The anti/syn ratio was determined by 1H NMR
judged by the intensity of the Ha,b. The JHa,Hb signal of the anti
isomer was higher than that of the syn isomer. According to the
1H NMR spectrum, the Ha signal for the anti isomer had a lower δ
value than that for the syn isomer. (Scheme 2)
A possible transition state is proposed in which interaction
between Zn, the imine and the enol form of cyclohexanone occurs
(Scheme 3, Fig. 1). Transition state I provides more space for the
aryl groups of the aldimine and less steric repulsion between
the methylene groups of cyclohexanone and aryl group on the
Catalyst recycling ability was also checked under the same
reaction conditions. Reaction of aniline, benzaldehyde, and cyclo-
hexanone in the presence of 5 mol% of catalyst in water–acetic
Zn
Ar'
O
O
H
N
Ar'
H
HN
H
H
H
Ar
Ar
I
H
Anti
Scheme 3. Possible transition state leading to anti product.
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Appl. Organometal. Chem. 2011, 25, 335–340
Copyright ꢀ 2011 John Wiley & Sons, Ltd.
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M. Kidwai et al.
Figure 3. TEM image of Zn[(L)proline]2.
R2
R2
CHO
NH2
O
O
HN
O
HN
+
Zn[(L)Proline]2
+
+
CH3COOH
r.t
R1
R2
R1
R1
Scheme 4. Synthesis of β-amino carbonyl compounds using substituted aniline, benzaldehyde, and cyclohexanone at room temperature with
Zn[(L)proline]2.
acid was considered as a model reaction for recycling studies. The
result is reported in Table 2. These results showed that the catalyst
exhibit good catalytic ability for up to five cycles.
complex was carried out. It was found that the peaks remained
the same, showing the recycling of the catalyst.
To check the crystalline nature of the catalyst, TEM images of the
catalystweretakenonacarbon-coatedgrid.Theimagesareshown
in Fig. 3. From these images it was found that the compound is
crystalline in nature. To the best of our knowledge, no information
regarding the shape and crystalline nature of the catalyst has
been reported before. With these encouraging results in hand, we
screened a variety of aromatic aldehydes and amines, including
electron-withdrawing and electron-donating groups (Scheme 4,
Table 3).
In the investigation of various benzaldehydes, it was found
that p-methylbenzaldehyde is most active in the reaction (Table 3,
entry 5). This is because the substituents on benzaldehyde have
a remarkable influence on the stability of intermediate RC6H4C+
Characterization of the catalyst
Powder XRD
X-ray patterns of the Zn[(L)proline]2 complex recorded in the
2θ = 0–100 range are shown in Fig. 2. The complex has specific
d values, which can be used for its characterization and peaks
obtained from powder XRD were matched with data card[33] 47-
1919JCDPS. These interpreted peaks revealed that the crystal is
orthorhombic in shape. Moreover to detect the recyclability of the
catalyst, powder X-ray diffraction of the recycled Zn[(L)proline]2
a
Table 3. Synthesis of various β-aminocarbonyl compounds using Zn[(L)proline]2
Sample no.
Product
Ketone
R1
R2
Yield (%)b
Time (h)
Anti/sync
1
2
3
4
5
6
7
4a
4b
4c
4d
4e
4f
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
Cyclohexanone
H
H
H
H
89
91
93
85
92
90
85
10
12
12
12
12
12
12
99 : 1
92 : 8
90 : 10
99 : 1
99 : 1
99 : 1
92 : 8
3-CH3
4-Cl
Ph
4-Cl
4-CH3
H
H
4-OCH3
H
4g
Furyl
a Reactions were performed with aniline (0.01 mol), benzaldehyde (0.01 mol), cyclohexanone (0.01) and Zn [(L)proline]2 (5 mol%) in aqueous acetic
acid by stirring the mixture at room temperature.
b Isolated yield.
c Diastereomeric ratio measured by 1H NMR spectroscopy analysis of the crude reaction mixture.
c
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Bis[(L)prolinato-N,O]Zn in acetic acid–water
O
R2
NH2
CHO
Zn[(L)Proline]2
O
HN
+
+
CH3COOH
r.t
R1
R2
R1
2
5
3
4(h-r)
Scheme 5. Synthesis of β-amino carbonyl compounds using substituted aniline, benzaldehyde and acetophenone at rt with Zn[(L)proline]2.
TLC. Aftercompletionofthereaction, thesolidproductwasfiltered
and the mother liquor was further used for consecutive runs. The
Table 4. Synthesis of various β –aminocarbonyl compounds using
Zn[(L)proline]2
a
structures of all the products were unambiguously established on
Sample
no.
Yield Time
(%)b (h)
1
the basis of their spectral analysis (IR, H NMR and GC/MS mass
Product
Ketone
R1
R2
spectral data). All the products are known compounds.
1
4h
4i
Acetophenone
Acetophenone
Acetophenone
Acetophenone
H
H
H
H
H
98
97
10
9
2
4-CH3
Conclusion
3
4j
3,4-(CH3)2 92
10
9
4
4k
4l
4-Cl
H
95
98
91
70
77
91
73
90
This procedure offers several advantages for the Mannich reaction,
such as using water as a green solvent, low loadings of cheap and
easily prepared catalyst, Zn[(L)proline]2, high yields and clean
reactions. In addition, product isolation is easily accomplished by
simple filtration, as the products are insoluble in water. There is
even no need for column chromatography and recrystallization as
our crude product is very pure. This simple work-up is of practical
importance, especially for large-scale operations.
5
Acetophenone 4-CH3
9
6
4m
4n
4o
4p
4q
4r
Acetophenone
Acetophenone
Acetophenone
H
H
H
4-OCH3
4-NO2
2-NO2
H
10
12
12
10
13
12
7
8
9
Acetophenone 4-OCH3
Acetophenone 4-NO2
Acetophenone 4-Br
10
11
H
H
a Reactions were performed with aniline (0.01 mol), benzaldehyde
(0.01 mol), acetophenone (0.01) and Zn [(L)proline]2 (5 mol%) in
aqueous acetic acid by stirring the mixture at room temperature.
b Isolated yield.
Acknowledgements
Theauthors(A. Jain, S. BhardwajandR. Poddar)arethankfultoUGC
and CSIR, New Delhi for their junior and senior research fellowship
respectively.
HNHC6H5 derived from the aldehyde and the amine. The rich
electron-donating substituents such as ‘–OCH3’ result in very low
stability of the intermediate (Table 3, entries 9 and 15). However,
electron-withdrawing groups such as –NO2 degrade the activity
of the intermediate and result in a very low yield (Table 3, entries
7 and 10).
Supporting information
Supporting information may be found in the online version of this
article.
In order to ascertain the scope and limitation of this
Zn[(L)proline]2-catalysed Mannich reaction, we extended the use
of the catalytic systems to the reaction of acetophenone with
various aldehydes and amines (Scheme 5, Table 4).
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Appl. Organometal. Chem. 2011, 25, 335–340
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