Highly efficient one-pot three-component Betti reaction in water using reverse zinc oxide micelles as a recoverable and reusable catalyst

Article abstract of DOI:10.1039/c6ra28599f

An efficient synthesis of Betti bases via a one-pot three-component reaction of 2-naphthol, substituted aldehydes and anilines in aqueous media is reported. Through screening different catalysts, reverse zinc oxide nanomicelles show good activity and high

Full text of DOI:10.1039/c6ra28599f

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Highly efficient one-pot three-component Betti
reaction in water using reverse zinc oxide micelles
as a recoverable and reusable catalyst†
Cite this: RSC Adv., 2017, 7, 13868
ab
*
Jie Mou,‡
Gan Gao,‡ab Chen Chen,‡ab Jie Liu,ab Jian Gao,ab Yi Liuab
c
*
and Dongsheng Pei
An efficient synthesis of Betti bases via a one-pot three-component reaction of 2-naphthol, substituted
aldehydes and anilines in aqueous media is reported. Through screening different catalysts, reverse zinc
oxide nanomicelles show good activity and high selectivity. The catalyst retained activity after six cycles
of reuse and were recoverable. The method has the advantages of atom economy, short reaction time,
good yield, and easy work-up as well as being environmental friendly.
Received 23rd December 2016
Accepted 17th February 2017
DOI: 10.1039/c6ra28599f
rsc.li/rsc-advances
reaction is difficult to be initiated in water because the activity
of amine is inhibited by the strong hydrogen bond with water.
In recent years, rare earth and lanthanide triates,14 sulfanilic
Introduction
The Betti reaction, which is a typical Mannich reaction, is one of
the most important fundamental carbon–carbon bond-forming
reactions in organic chemistry.1 The Betti reaction provides 1-(a-
aminoalkyl)-2-naphthols, the so-called Betti bases. The optical
Betti base isomers are valuable ligands in asymmetric synthesis.2,3
Recently, the importance of Betti bases was well established in
pharmaceutical chemistry because of their bioactivities, including
anti-bacterial, antipain, antihypertensive and bradycardiac activ-
ities.4–6 The original Betti reaction is between an aldehyde,
ammonia or urea and b-naphthol in an ethanolic solution of
potassium hydroxide in two steps for a long time (9–36 h).7,8
However, the synthetic approach is plagued by a number of
serious disadvantages and has limited applications. Therefore,
numerous modern versions of Betti reaction have been developed
to overcome the drawbacks of the classical method. In general,
the preferable route is the use of a one-pot three-component
strategy that allows for a wide range of structural variations by
using quilinols,9 naphthols10 and alkyl amines to exchange
ammonia.11 However, these methods suffered from severe side
reactions and longer reaction times with lower yields.
acid-functionalized silica-coated magnetite nanoparticles,15
surfactants16 or iminium salts17,18 as catalysts for direct-type
Mannich reactions in water or under solvent-free conditions
have been successfully applied.19,20 In most cases the catalysts
are not used friendly and non-recoverable. To our knowledge, it
is still a challenge for aromatic primary amines are employed as
the substrates in water for their electron-withdrawing proper-
ties and steric hindrance. As a consequence, it is necessary to
develop environmentally benign reactions and atom-economic
catalytic processes for Betti reaction.
Nanocrystalline metal oxides nd excellent application as
active adsorbent for gas, for destruction of hazardous chem-
icals, and as catalyst in various organic reactions.21 Karmakar
et al. reported an efficient method for the preparation of Betti
base derivatives over nanocrystalline MgO in water.22 Unfortu-
nately, the yield of aniline's product is lower than 20%. More-
over, nanocrystalline metal oxides usually undergo
agglomeration when dispersed in solutions because of large
specic surface area and high surface activity. This behavior has
a major impact on their reactivity.23
Under the inspiration of metallomicelles,24,25 which were
utilized for their certain similarities with the natural enzymes,
we designed reverse zinc oxide nanomicelles as functional
catalyst to meet the dual requirements of the disperse stability
and nano-size control. Reverse micelles have been depicted as
passive nano-reactors that via their shapes template the
growing crystalline nuclei into narrowly dispersed or even
perfectly uniform nano-sized particles. Reverse micellar
systems containing metal oxide could possibly afford high local
reactant concentrations near the catalysts, helping enhance the
catalytic rate.26
In terms of green chemistry, the development and applica-
tion of multi-component coupling reactions in water is favour-
able, as they provide simple and rapid access to a large number
of organic molecules via a tolerable method.12,13 But the Betti
aSchool of Pharmacy, Xuzhou Medical University, Xuzhou 221006, China
bJiangsu Key Laboratory of New Drug and Clinical Pharmacy, Xuzhou Medical
University, Xuzhou 221006, China
cDepartment of Pathology, Xuzhou Medical University, Xuzhou 221006, China. E-mail:
dspei@xzhmu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra28599f
‡ Co-rst authors.
13868 | RSC Adv., 2017, 7, 13868–13875
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In this study, direct-type three-component Betti reaction
using water as the only solvent at room temperature catalyzed type instrument (Denki, Japan) using Cu Ka (1.54 A) radiation
by reverse ZnO nanomicelles is reported. Reverse ZnO nano- at a beam voltage 40 kV and a 30 mA beam current. The patterns
micelles are prepared starting from zinc acetate as a precursor, were obtained by continuous scans in a 2q range of 5–90ꢀ with
triethanolamine as the base and hexadecyl trimethyl ammo- a scan rate of 4 deg minÀ1 and step 0.02 deg. XRD sample was
nium bromide as the surfactant in cyclohexane. This route has obtained by centrifugation, washing, drying the micelles in
RSC Advances
X-ray diffractometer were employed on Rigaku D/max-III
˚
ꢀ
the advantages of atom-economy, operational-simplicity, eco- vacuum at 70 C in the vacuum drying oven.
friendliness and cost-efficiency.
Analytical thin layer chromatography (TLC) was performed
using glass backed TLC extra hard layer pre-coated with silica gel
˚
(0.25 mm, 60 A pore size) and visualized by exposure to ultraviolet
Experimental section
Materials
light (254/366 nm) using a Camag UV Lamp (Switzerland).
Proton nuclear magnetic spectra (1H NMR, 400 MHz) and
Unless otherwise noted, all reagents and solvents were carbon nuclear magnetic resonance spectra (13C NMR, 100
purchased from commercial suppliers and used without further MHz) were recorded on an JNM-ECZ400s/L spectrometer (Joel,
purication.
Japan) using CDCl3 or DMSO-d6 as a solvent and TMS as an
Preparation of reverse zinc oxide nanomicelles. Hexadecyl internal standard. IR spectra were recorded on a Jasco FT-IR
trimethyl ammonium bromide (CTAB, 0.3644 g, 1 mmol) was 4100 Series spectrophotometer (Perkin-Elmer, USA), v max
dissolved in cyclohexane (10 mL). The suspension was heated at (cmÀ1) are partially reported. HRMS analyses were carried out
ꢀ
80 C for 1 h and cooled to room temperature under stirring. using a Bruker micrOTOF-Q instrument (Bruker, USA).
Aer being stirred overnight, triethanolamine (5 mL) was added
dropwise under vigorous stirring until the milk white emulsion
was formed. Zinc acetate (Zn(CH3COO)2$2H2O) (2.19 g, 1 mmol)
was dissolved in distilled water (100 mL) whilst stirring to
Results and discussion
Preparation and characterization of reverse ZnO nanomicelles
obtain the 1 mol LÀ1 zinc solution. Zinc acetate solution (0.2 Reverse ZnO nanomicelles were prepared according to the
mL, 1 mol LÀ1) was injected into the above mentioned emulsion modied sol–gel based procedures27 using zinc acetate dehydrate
slowly under moderate stirring until the mixture turn cleared as precursor and cyclohexane as solvent. Reverse micelles were
and stirred for another 1 h. Then the solution was sonicated at formed by the self-assembly of the surfactant in apolar solvents.
200 W for 15 min in an ice bath. The reacted solution kept clear, Metal salts are solubilized within the interior of inverse micelles
and the reverse ZnO micelles were formed in solution and where were shield by the hydrophilic head groups of the surfac-
stabilized by surfactant.
tant from the oleic surroundings.28 Ionic surfactants as amphi-
Synthesis of Betti base derivatives. The catalytic activity of the philic molecules are oen used to form reverse micelles for
reverse ZnO nanomicelles was investigated by measuring their protein solubilization, such as anionic di-2-ethylhexyl sodium
ability to synthesis Betti base derivatives. To a mixture of aromatic sulfosuccinate (AOT)29 and cationic hexadecyl trimethyl ammo-
aldehydes (1 mmol), b-naphthol (1 mmol, 0.144 g) and aniline nium bromide (CTAB).30 In this case, CTAB was employed in the
(1 mmol, 0.094 g) in 10 mL water in a round bottom ask, catalytic preparation of reverse micelles. Its relatively polar head group
amount of reverse ZnO nanomicelles was added and stirred at regions solubilize and conne added zinc salts and act as reaction
room temperature for appropriate time. Aer completion of the cages when forced hydrolysis is initiated. The reaction sequence is
reaction as monitored by thin layer chromatography (TLC), the sustained by material exchange between reverse micelles and nal
aqueous layer was decanted to recycle the catalyst for another particle size is dependent on stabilization by the surfactant. In our
reaction. The crude product was ltered and puried by recrys- study, triethanolamine was used as base to maintain pH value and
tallization from ethanol (95%). The novel products were charac- sonication was applied to initiate the hydrolysis of zinc ions. The
terized by 1H NMR, 13C NMR, IR and HRMS.
Characterization methods. Dynamic light scattering (DLS) stabilized in solution by surfactant (Scheme 1).
reverse ZnO nanomicelles were formed which were sterically
measurements were performed on a NICOMP 380ZLS zeta
The particle size and distribution of reverse ZnO nano-
potential/particle size analyzer (PSS, USA) equipped with a He– micelles was measured with NICOMP 380ZLS and the
Ne laser at a wavelength of 660 nm. The experimental data were morphology was characterized using transmission electron
analyzed by the CONTIN method, which is based on an inverse- microscopy (TEM). The distribution of sphere diameters is
Laplace transformation of the data and provides access to a size shown in Fig. 1. The image revealed that the average diameter
distribution histogram for the analyzed micellar solutions. The was 120 nm and the size distribution was 80%.
z-potential of ZnO nanomicelles was determined by laser
Doppler anemometry using a NICOMP 380ZLS.
Fig. 2 illustrates the transmission electron microscopy
(TEM) micrograph of the reverse ZnO nanomicelles. It can be
Transmission electron microscopy (TEM) was performed on observed that the particles are highly dispersed, sub-
JEOL JEM 1230 (Joel, Japan) at an acceleration voltage of 120 kV. sphaeroidal and monodisperse on the TEM grid. The size
Then a drop of the reverse ZnO nanomicelle sample was applied range of them is approximate 200 nm. The particles displayed
onto a carbon-coated copper TEM grid. Aer solvent evapora- a homogeneous size distribution and the particle diameters
tion ZnO micelles remained dispersed on the carbon lm of the ranged from 20 to 500 nm, as evidenced by Zata-dimeter
TEM grid.
measurement.
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Scheme 1 Preparation process of reverse ZnO nanomicelles.
Fig. 1 Size distribution for reverse ZnO nanomicelles with average diameter of 120 nm.
The formation of ZnO nanomicelles was investigated by X- The peaks appeared at 2q value ranging from 31.73ꢀ, 34.38ꢀ,
ray diffraction (XRD). The XRD pattern of ZnO nanomicelles 36.22ꢀ, 47.50ꢀ, 56.56ꢀ, 62.81ꢀ, 66.34ꢀ, 67.91ꢀ, 69.03ꢀ, 72.6ꢀ and
aer centrifugation, washing and drying was shown in Fig. 3. 76.90ꢀ values corresponded to pure ZnO. All XRD diffraction
peaks of ZnO micelles are shown in a good agreement with
hexagonal structure of zincite phase reported in JCPDS le card
no. 05-0664. No peaks of impurity are observed, indicating that
ZnO precursor has been completely transformed into nano
ZnO. The result indicated that the sonication step is a key factor
in avoiding the fast precipitation and achieving a pure zinc
oxide.
Catalyst screening
Initially, the preparation of 4a from m-nitrobenzaldehyde (1
equiv.), naphthol (1.2 equiv.) and aniline (1 equiv.) in water was
investigated as a model system to search for the effective and
reusable catalytic system (Table 1).
It was found that the reaction failed in the absence of catalyst
from room temperature to 90 ꢀC for 24 h. Conventional basic or
acidic catalyst such as sodium hydroxide, triethylamine and
acetic acid only afforded Schiff base 6a as the terminal products
(Table 1, entry 1–4). Typical Lewis acid catalysts such as ZnCl2
and FeCl3 provided bis product 5a as a major product in low
Fig. 2 TEM image of reverse ZnO nanomicelles.
13870 | RSC Adv., 2017, 7, 13868–13875
yield whereas, 4a was formed as a minor product (<10% yield)
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surfactants (i.e. CTAB). Even though the mixture of ZnCl2 and
CTAB was added, there was no appreciable improvement in
yield (Table 1, entry 10–13). Meanwhile, it was found that the
smaller ZnO NPs (10 nm) can afford the desired product 4a,
which is better than ZnO NPs (100 nm) (Table 1, entry 14 and
15). The best result showed that exposure of the reaction
mixture to 10 mmol% reverse ZnO nanomicelles (100 nm) in 10
ꢀ
mL water at 70 C for 30 min provided 4a with excellent yield
(Table 1, entry 16). The larger size of nanomicelles (>500 nm)
did not give more satised results (Table 1, entry 18). The
normal ZnO nanomicelles catalyst is neither activity nor selec-
tivity to Betti reaction. Obviously, Betti reaction is sensitive to
the structure of the catalyst. All the results can be explained as
follows. In the catalytic process, the catalyst consists of small
metal oxide particles dispersed on an inert support which was
the key components of the catalyst. The activity of the catalyst
will generally depend on the size of the metal oxide particles
(active sites), where a catalyst with small particles will give high
activity due to the large number of atoms available on the metal
particles surfaces.31
Fig. 3 XRD graph of ZnO nanomicelle particles.
(Table 1, entry 5 and 6). In contrast, same test reaction was
carried out with different supported Lewis acid catalysts such as
ZnCl2–SiO2, BF3–SiO2 and TiO2–SiO2, the yields of desired
product 4a were increased from 23% to 42% (Table 1, entry 7–9).
To study the role of nanomicelles, the reaction was per-
formed with surfactants and ZnO nanoparticles (ZnO NPs).
Surprisingly, the reaction was not successful either with non-
ionic surfactants (i.e. PEG200–PEG2000) or with ionic
Solvent screening
To investigate the feasibility of the strategy, various solvents
such as dichloromethane, tetrahydrofuran, acetonitrile, ethanol
and dimethyl formamide were used to improve the yield of 4a
Table 1 Comparison of efficiency of various catalysts in one-pot synthesis of 4a
Entry
Catalysta
T (ꢀC)
Time (h)
4a yieldb (%)
5a yieldb (%)
6a yieldb (%)
1
2
3
4
5
6
7
8
20% NaOH
40% NaOH
CH3COOH
Et3N
FeCl3
ZnCl2
ZnCl2–SiO2
BF3–SiO2
TiO2–SiO2
PEG-200
PEG-2000
CTAB
90
90
90
90
90
90
90
90
90
90
90
90
90
90
90
70
70
70
70
8
8
8
8
8
8
8
8
8
8
8
8
8
1
1
—
—
—
—
4
60
20
—
40
10
—
—
—
—
—
—
—
65
61
47
43
41
—
—
—
47
7
23
29
42
—
—
—
Trace
43
12
98
96
41
27
9
10
11
12
13
14
15
16
17
18
19
—
—
Trace
ZnCl2 + CTAB
ZnO NPs (10 nm)
ZnO NPs (100 nm)
Reversed ZnO micelles (100 nm)
Reversed ZnO micelles (200 nm)
Reversed ZnO micelles (500 nm)
Normal ZnO micelles (100 nm)
—
—
—
—
19
—
—
—
—
—
0.5
0.5
0.5
8
a
Conditions: 1 (1.2 mmol), 2a (1 mmol), 3a (1 mmol), catalyst (3–6) (15 mol%), (7–11) (0.01 g mmolÀ1 substrate), (12–20) (10 mol%), solvent (water,
10 mL), 0.5–24 h. b Isolated yield.
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Table 2 Effects of solvent on the synthesis of 4aa
was obtained. In the presence of p-dodecylbenzenesulfonic acid
(DBSA) and sodium dodecyl sulfate (SDS), which acts both
Bronsted acid and anionic surfactant, only 19% and 23% of
desired product 4a was gained. CTAB acts as cationic surfactant.
CTAB based reverse ZnO nanomicelles proved to be the best
choice. It was known that the reverse micelles are small
molecular assemblies that encapsulate nanoscopic pools of
water.39 The results revealed that the interaction of the cationic
surfactant head groups and their BrÀ counter ions in water pool
is believed to play a major role in controlling the yields by
promoting the dehydration condensation in water.
Entry Solv.a
Temp. (ꢀC) Time (h) 4a yieldb (%) 5a yieldb (%)
1
2
3
4
5
6
7
CH2Cl2 25
CH3CN 60
24
24
8
8
8
7
12
6
34
46
87
96
14
26
12
28
22
—
—
THF
60
80
60
25
70
DMF
EtOH
Water
Water
0.15
1
a
Reactions were carried out in solvent 5.0 mL on a 1 mmol scale at the
special temperature using 10 mol% reverse ZnO nanomicelles as
catalyst. b Isolated yield.
Stability of the reaction system
The effect of reaction temperature was carefully examined
(Fig. 4). The reaction was smoothly promoted with the
increasing of temperature from room temperature to 70 ꢀC.
Aer 9 minutes, the highest yield was obtained at 70 ꢀC.
However, the catalyst acꢀtivity declined as the reaction temper-
ature increased over 70 C. Loss in surface area caused by the
dissociation of the micelles could be the reason for the
decreased activity. The effect of reaction time was also investi-
gated (Fig. 5). It was found that the reaction was started 2 min
later and maintained a stable state for a long period. The yield
did not increase signicantly from 8 min to 20 min.
and reduce the formation of 5a. In polar non-proton solvents
such as CH2Cl2, THF and CH3CN, both 4a and 5a were obtained
in poor yield. However, in polar protic solvents like C2H5OH and
DMF, 5a was obtained in higher yield in comparison to 4. It was
found that ethanol was superior to other examined solvents in
view of yield (Table 2, entry 5). However, with further consid-
eration on the development of environment-friendly chemistry,
we tried to conduct Betti reaction in water. To our delight, when
the reaction was performed in water at room temperature, only
product 4a was formed. With further studies by increasing
reaction temperature, the desired product 4a could be obtained
smoothly in 87% yield in a shortened reaction time 8 min (Table
2, entry 6). The results revealed that the reaction in aqueous
media condition produced the product in shortest reaction time
and highest yield (96%). Previously, reversible dehydration
condensation in water is in principle a difficult transformation
because the large excess of water pushes the equilibrium in
favor of the hydrated compounds.32 To date, dehydration reac-
tions in water have usually been achieved by employing the
novel catalyst.33–38 In this case, it was assumed that water can
favor the nucleophilic addition reaction between imine inter-
mediate and b-naphthol for the high polarity.
Recyclability of catalyst
Additionally, recycle and reusability of the catalyst was exam-
ined (Table 4). Aer the completion of the reaction, the aqueous
layer was decanted and the catalyst was reused for the next run
under the same conditions. As shown in Table 4, the desired
products yields remained essentially constant for the six
successive cycles, reecting high stability and reusability of the
catalyst. This is consistent with the characterization results for
this catalyst. Dynamic light scattering (DLS) measurements
Surfactant screening
To elucidate the role of nanomicelles, various non-ionic and
ionic surfactants (5 mol%) based ZnO reverse micelles (5 mol%)
were tested on the reaction of m-nitrobenzaldehyde, naphthol
and aniline in water. The results are summarized in Table 3.
The reaction was run in the presence of TX 10 at room
temperature for 8 h, as a result, only very low yield of product 4a
Table 3 Effect of surfactant-based reverse micelle on synthesis of 4aa
Entry
Surfactant
Catalyst
Time (h)
4a yieldb (%)
1
2
3
4
TX10
DBSA
SDS
ZnO
ZnO
ZnO
ZnO
8
—
19
23
96
48
48
0.15
CTAB
a
Fig. 4 Influence of reaction temperature on synthesis of 4a. Reactions
were carried out on a 0.1 mmol scale; reverse ZnO nanomicelles 20
mol%.
Conditions: 1 (1.2 mmol), 2a (1 mmol), 3a (1 mmol), surfactant (1–4) (5
mol%), catalyst (ZnO NPs, 5 mol%), solvent (water, 10 mL), room
temperature, 9 min to 48 h. Isolated yield.
b
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Table 5 Synthesized Betti base derivatives catalyzed by reverse ZnO
nanomicelles
Fig. 5 Effect of reaction time on yield of 4a. Reactions were carried
out on a 0.1 mmol scale; reverse ZnO nanomicelles 20 mol%.
results showed the particle diameters of ZnO nanomicelles
ranged from 120 to 250 nm and displayed a homogeneous size
distribution aer the ve successive runs. The increasing z-
potential indicated the catalytic system tend to be stable grad-
ually. No remarkable changes could be evidenced in the
recovery of the catalytic system.
a
Reactions were conducted with naphthol (1.2 mmol), benzaldehyde
Comparison of the substrates
(1 mmol), amine (1 mmol) and reverse ZnO nanomicelles (10 mol%)
b
in water (10 mL) at room temperature.
The products were
characterized by melting point, 1H, 13C NMR, IR and mass
spectroscopy. c Isolated yield.
To explore the generality and scope of the protocol, the reaction
of various aromatic aldehydes, amines and b-naphthol were
extended to prepare a series of Betti base derivatives and the
results are depicted in Table 5. It was found that both electron-
rich and electron-decient aromatic aldehydes could be con-
verted to the desired Betti base derivatives in the presence of
reverse ZnO nanomicelles (10 mol%) at 70 ꢀC in 1 h in good
yields (Table 5, 4a–4g). However, halogen or electron-
withdrawing groups at meta position accelerated the reaction
rather than electron-donating groups. Furthermore, the amine
component of the three-component reaction was surveyed. To
our delight, the reactions proceeded smoothly when aniline
thioacetamide were used as the substrates because the electron
density of amino group was reduced by the electron-
withdrawing conjugation effects of unsaturated bonds (Table
5, 4i, 4j, 4m and 4n).
Exploration of the possible mechanism
were used as substrate. Under the same reaction conditions, The mechanism of this multi-component reaction involves
when piperidine was used as an amine partner, the desired Knoevenagel condensation/Michael addition cascade
a
product 4h was obtained in 93% yield in 4 minutes (Table 5, 4h). process.40 A tentative mechanism for the zinc oxide-catalyzed
The results indicated that aliphatic amine and hydrazine were Mannich is proposed in Scheme 2 in the revised manuscript.
more active than aniline. In addition, a variety of Betti base Firstly, ZnO coordinates to benzaldehyde and generates the zinc
derivatives were obtained in moderate yields when amide or oxide-aldehyde intermediate 1, which reacts with aniline to
Table 4 The reuse of reverse ZnO micelles in the synthesis of 4aa
Cycle
Fresh
Reuse 1
Reuse 2
Reuse 3
Reuse 4
Reuse 5
Reuse 6
Yieldb (%)
Diameter (nm)
z (mV)
96
95
96
97
95
95
94
116 Æ 12
119 Æ 13
142 Æ 13
166 Æ 15
186 Æ 14
216 Æ 17
251 Æ 15
6.27 Æ 0.52
7.04 Æ 0.24
10.21 Æ 1.03
13.02 Æ 0.37
16.47 Æ 0.62
20.14 Æ 0.29
23.11 Æ 0.74
Conditions: 1 (1.2 mmol), 2a (1 mmol), 3a (1 mmol), catalyst (reverse ZnO nanomicelles, 10 mol%), solvent (water, 10 mL), 70 ꢀC, 1 h. b Isolated
a
yield.
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Scheme 2 Proposed mechanism for the synthesis of 4a.
generate the imine intermediate 2 aer the dehydration and nanoreactors and will nd more extensive applications in the
remove of zinc oxide. Subsequently, the imine intermediate is eld of green chemistry.
activated when ZnO binds to the nitrogen atom 3 which
promotes the following nucleophilic addition of b-naphthol to
give the desired product 4 and regenerates zinc oxide. Based
Acknowledgements
on the results obtained, the formation of the imine interme-
We are grateful for nancial support by National natural science
diate is likely the rate-determining step. ZnO, which is a Lewis
foundation of China (No. 81572349), the Natural Science
acid, provides efficient acidic sites to form coordinate bond
Foundation of Jiangsu Province (No. BK20141149, BK20140225)
between oxygen atom (or nitrogen atom) which can activate
the Science and technology project of Xuzhou city (No.
the formation of imine intermediate, followed by facilitating
KC16SY152) and the Director Found of the Jiangsu Province Key
the nucleophilic addition. Reverse micelles played an impor-
laboratory of New Drug Research and Clinic Pharmacy (ZR-
tant role in combining the substrates, stabilizing the imine
XY201403). This project was also sponsored by Innovation
intermediate and promoting the dehydration condensation
Project of Xuzhou Medical College.
under neutral conditions in water catalyzed by the cationic
water pool encapsulated in reverse micelles. The enhanced
surface area due to nano particle size is an added advantage
for its reactivity. Water promotes the nucleophilic addition
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