ZnO nanoparticles as an efficient catalyst for the one-pot synthesis of α-amino phosphonates

Article abstract of DOI:10.1055/s-0028-1088135

Zinc oxide nanoparticles (ZnO NPs, ca. 22 nm) were used as an effective catalyst in the solvent-free, three-component couplings of aldehydes, aromatic amines and dialkyl phosphites at room temperature to produce various α-amino phosphonates. Compared to known methods, satisfactory results were obtained with high yields through a simple experimental procedure. The catalyst was recycled and reused five times with minor decrease in its catalytic activity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1088135

1326
LETTER
ZnO Nanoparticles as an Efficient Catalyst for the One-Pot Synthesis of
a-Amino Phosphonates
ZnO Nanoparticles as
o
E
fficient Cat
h
alyst for the
a
S
ynthesis
o
m
f
a
-Amino Phospho
mnates ad Zaman Kassaee,* Farnaz Movahedi, Hassan Masrouri
Department of Chemistry, Tarbiat Modares University, P. O. Box 14155-4838, Tehran, Iran
Fax +98(21)8006544; E-mail: kassaeem@modares.ac.ir
Received 21 December 2008
defects are associated with some of these reported proce-
Abstract: Zinc oxide nanoparticles (ZnO NPs, ca. 22 nm) were
used as an effective catalyst in the solvent-free, three-component
couplings of aldehydes, aromatic amines and dialkyl phosphites at
room temperature to produce various a-amino phosphonates. Com-
dures including the requirement of solvent, additional
reagents, special apparatus, costly and moisture-sensitive
catalysts, and environmental disposal problems which en-
pared to known methods, satisfactory results were obtained with courage scientists to explore better routes for the synthesis
high yields through a simple experimental procedure. The catalyst
was recycled and reused five times with minor decrease in its cata-
lytic activity.
of a-amino phosphonates.
In this report, we disclose the ZnO NPs as an efficient
heterogeneous catalyst for the synthesis of a-amino phos-
Key words: ZnO nanoparticles, a-amino phosphonates, hetero-
phonates in the solvent-free conditions, through three-
geneous catalyst, solvent-free, three-component reaction
component reaction of aldehydes, amines, and dialkyl
phosphites (Scheme 1).
In the last few years, literature has highlighted the impor-
tance of nanosized materials in several scientific and tech-
R2
NH2
nological areas, including the catalytic activity of metal
R1CHO
oxide nanoparticles.1,2 The high surface to volume ratio of
NH
R2
ZnO NPs (20 mol%)
OR3
1
+
2
metal oxide nanoparticles is mainly responsible for their
enhanced catalytic properties.3 The catalytic influence of
nanocrystalline zinc oxide was customarily utilized in the
gas sensors and photocatalysts. Currently, application of
this nanocatalyst in organic and inorganic reactions has
emerged as a rapidly growing field.4–7 Zinc oxide nano-
particles (ZnO NPs) have been used in the synthesis of b-
phosphono malonates,8 Knoevenagel condensation,9
Dakin–West reaction,10 degradation of acid red B and
rhodamine B,11 etc.
R1
P
solvent-free, r.t.
OR3
HP(O)(OR3)2
O
3
4
Scheme 1
For this purpose, at first we prepared ZnO NPs through a
solid-state reaction method which has been reported by
Zhu and co-workers.35 The XRD patterns of the ZnO NPs
(Figure 1), could be indexed to the hexagonal wurtzite
structure (space group: P63mc; a = 3.249 Å, c = 5.206 Å,
JCPDS card no. 36–1451). No impurities are involved in
the synthesized ZnO NPs sample for which an average
size of 20 nm is estimated by the Scherrer equation: Dh,k,l
= kl/b cosq, where k is a constant, generally considered as
0.89 for ZnO, l is the wavelength of Cu Ka, 1.54 Å, b is
the full width at half maximum of diffraction line, and q is
the corresponding angle.36
On the other hand, a-amino phosphonates have attracted
much interest as important biologically active com-
pounds, and their synthesis has been a focus of consider-
able attention in the synthetic and medicinal
chemistry.12,13 They act as antibiotics, herbicides,14 inhib-
itors of the enzymes renin, EPSP synthase and HIV pro-
tease.15,16 In addition a-amino phosphonates have broad
applications due to their antifungal17 and antibacterial ac-
tivities.18 Various synthetic approaches have been report-
ed for the synthesis of a-amino phosphonates, among
which the most convenient are the Kabachnik–Fields19,20
synthesis and Pudovik reaction catalyzed by a base or an
acid. In addition Lewis acid catalysts such as ZnCl2,
SnCl2, SnCl4, BF3·Et2O, LiClO4,21,22 MgBr2,23 InCl3,24
28
TiO2,25 Sc(O3SOC12H25)3,26 TiCl4,27 TaCl5–SiO2,
CF3CO2H,29 PhMe3NCl,30 metal triflates31 and
Mg(ClO4)32 as well as chiral catalysts33,34 have been ex-
amined. However, in spite of their aptitudes, a number of
Figure 1 X-ray diffraction pattern of the synthesized ZnO nanopar-
ticles
SYNLETT 2009, No. 8, pp 1326–1330
x
x.
x
x.
2
0
0
9
Advanced online publication: 08.04.2009
DOI: 10.1055/s-0028-1088135; Art ID: G37308ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
ZnO Nanoparticles as Efficient Catalyst for the Synthesis of a-Amino Phosphonates
1327
Figure 2 SEM of the synthesized ZnO nanoparticles
Figure 3 TEM image of ZnO nanoparticles and the corresponding
electron diffraction pattern
The morphology and grain size of the ZnO NPs were in-
vestigated by SEM and TEM (Figures 2 and 3, respective-
ly). They have spherical and hexagonal morphology
including a narrow distribution of sizes from 18 nm to 36
nm, and the mean grain size of 22 nm, appearing consis-
tent with the results calculated from the Scherrer equation.
The prepared ZnO NPs were investigated as a catalyst in
the synthesis of a-amino phosphonates. This study was
performed by treatment of benzaldehyde, aniline, and
dimethyl phosphite in solvent-free conditions in the pres-
ence of ZnO NPs (20 mol%) at room temperature.
Table 1 Zinc Oxide Nanoparticles (ZnO NPs) Catalyzed Three-Component Synthesis of a-Amino Phosphonatesa
Entry
1
Aldehyde
Amine
Phosphite
Product
4a
4b
4c
Time (h)
9
Yield (%)b
90
benzaldehyde
aniline
HP(O)(OMe)2
HP(O)(OEt)2
HP(O)(OMe)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OMe)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OMe)2
HP(O)(OMe)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
HP(O)(OEt)2
2
benzaldehyde
aniline
9
90
3
p-chlorobenzaldehyde
p-chlorobenzaldehyde
m-chlorobenzaldehyde
o-chlorobenzaldehyde
p-nitrobenzaldehyde
p-methylbenzaldehyde
p-methoxybenzaldehyde
butyraldehyde
aniline
10.5
11
12
14
9
86
4
aniline
4d
4e
87
5
aniline
85
6
aniline
4f
81
7
aniline
4g
4h
4i
89
8
aniline
13
10
18
12
12
8
87
9
aniline
85
10
11
12
13
14
15
16
17
18
19
aniline
4j
78
furfuraldehyde
aniline
4k
4l
84
cinnamaldehyde
aniline
72
benzaldehyde
p-anisidine
p-anisidine
p-anisidine
p-anisidine
p-anisidine
p-bromoaniline
p-toluidine
4m
4n
4o
4p
4q
4r
91
p-methylbenzaldehyde
p-chlorobenzaldehyde
furfuraldehyde
9
90
10
12
11
14
12
86
83
p-methoxybenzaldehyde
p-methoxybenzaldehyde
p-methoxybenzaldehyde
85
81
4s
82
a Reaction conditions: aldehyde (1.0 mmol), amine (1.0 mmol), dialkyl phosphite (1.0 mmol), catalyst (20 mol%) at r.t. under solvent-free con-
ditions.
b Isolated yields.
Synlett 2009, No. 8, 1326–1330 © Thieme Stuttgart · New York

1328
M. Z. Kassaee et al.
LETTER
To our delight, we observed the formation of dimethyl
phenyl(phenylamino)methylphosphonate (4a). Complete
conversion and 90% isolated yield were obtained after
nine hours.37 A wide range of structurally varied alde-
hydes and aromatic amines were coupled together by this
procedure to produce the corresponding a-amino phos-
phonates (Table 1).
Table 2 Synthesis of a-Amino Phosphonate through the Reaction
of Benzaldehyde, Aniline, and Dimethyl Phosphite under Various
Conditions
Entry Solvent
Catalyst (mol%)
Temp
(°C)
Time
(h)
Yield
(%)a
1
2
CH2Cl2
MeCN
THF
H2O
EtOH
neat
ZnO NPs (20)
ZnO NPs (20)
ZnO NPs (20)
ZnO NPs (20)
ZnO NPs (20)
no catalyst
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
80
r.t.
80
r.t.
r.t.
r.t.
80
r.t.
13
10
15
18
15
24
24
20
12
10
9
30
42
23
trace
25
30
45
45
63
71
76
90
89
90
The reaction can tolerate a wide range of aliphatic and ar-
omatic aldehydes carrying either electron-donating or
electron-withdrawing substituents in the ortho, meta and
para positions. The presence of electron-donating groups
on the aldehydes lowered the yields and made the reaction
sluggish. In contrast, aldehydes possessing electron-with-
drawing groups afforded the corresponding a-amino
phosphonates with shorter reaction times and in higher
yields. Nevertheless, amines possessing electron-donat-
ing groups gave the corresponding products in good
yields. Acid-sensitive aldehydes such as furfuraldehyde
worked well without the formation of any side products
and gave the a-amino phosphonate derivative in 84%
yield (Table 1, entry 11). In all cases, the three-component
couplings proceeded smoothly and the corresponding a-
amino phosphonates were isolated in good to high yields.
All products were characterized on the basis of their spec-
troscopic data such as 1H NMR and 13C NMR spectra.
3
4
5
6
7
neat
no catalyst
8
neat
bulk ZnO (20)
bulk ZnO (20)
ZnO NPs (5)
ZnO NPs (10)
ZnO NPs (20)
ZnO NPs (20)
ZnO NPs (30)
9
neat
10
11
12
13
14
neat
neat
neat
9
neat
5
In comparison to the same reaction catalyzed by the com-
mercially available ZnO bulk, using ZnO NPs reduced the
reaction time by more than half, and increased the product
yield to almost 100% (Table 2, entries 8 and 12). The use
of just 20 mol% of ZnO NPs is sufficient to push the reac-
tion forward. Higher amounts of the catalyst (30 mol%)
did not improve the result to a great extent (Table 2, entry
14).
neat
9
a Isolated yield.
A comparison of the efficiency of catalytic activity of the
ZnO NPs with several pervious methods is presented
(Table 3). The results show that this method is superior to
some of the earlier methods in terms of thermal condi-
tions, yields and reaction times.
To investigate the effects of reaction media, we carried
out the condensation of benzaldehyde, aniline and dime-
thyl phosphite in various organic solvents by using 20
mol% of ZnO NPs as the catalyst (Table 2). The use of
solvents such as CH2Cl2, MeCN, THF, EtOH and H2O de-
creased the product yields (Table 2, entries 1–5).
Table 3 Comparison of Catalytic Activity of ZnO NPs with Several
Known Catalysts
Entry Conditions
Yield (%) Ref.
1
2
3
4
5
6
7
8
TaCl5–SiO2, CH2Cl2, r.t., 20 h
90
84
88
91
90
61
98
90
28
30
26
38
39
40
25
–
To evaluate the effect of reaction temperature, reaction of
benzaldehyde, aniline and dimethyl phosphite in the pres-
ence of ZnO NPs (20 mol%) was carried out at different
temperatures under similar experimental conditions. Evi-
dently, increasing the temperature shortened the reaction
time while having no measurable effects on the yield.
PhNMe3Cl, CH2Cl2, r.t., 3 h
Sc(O3SOC12H25)3, H2O, 30 °C, 0.3 h
Na2CaP2O7, solvent-free, r.t., 12 h
Amberlite-IR 120, MW, 2 min
b-cyclodextrin, H2O, reflux, 24 h
TiO2, solvent-free, 50 °C, 3.5 h
ZnO NPs, solvent-free, r.t., 9 h
A plausible mechanism for the formation of the product
would be as follows: the ZnO NPs facilitate the imine for-
mation through Lewis acid sites (Zn2+) which are coordi-
nated to the oxygen of the aldehyde and activate it for
nucleophilic attack of amine. On the other hand, ZnO NPs
can activate P–O–H groups so that deprotonation occurs
in the presence of Lewis basic sites (O2–). As a result the
formation of a-amino phosphonate proceeds through acti-
vating reactants with both Lewis acidic and basic sites of
ZnO NPs.
The recycling potential of ZnO NPs catalyst was studied
by coupling aniline, benzaldehyde and dimethyl phos-
phite in five consecutive cycles. The ZnO NPs could be
recycled and reused by separating them from the reaction
mixture through centrifugation at 2000–3000 rpm at 10
°C for three to five minutes and frequent washing with ab-
Synlett 2009, No. 8, 1326–1330 © Thieme Stuttgart · New York

LETTER
ZnO Nanoparticles as Efficient Catalyst for the Synthesis of a-Amino Phosphonates
1329
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Figure 4 Recycling of ZnO nanoparticles
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solute ethanol. The results show that the yield of product
after five runs was only slightly reduced (Figure 4).
In conclusion, ZnO nanoparticles are found to catalyze the
three-component, one-pot reaction of aldehydes, amines,
and dialkyl phosphites efficiently, affording a-amino
phosphonates in good to high yields. Based on what this
manuscript has already demonstrated, ZnO NPs are sug-
gested to become engaged in many other organic reac-
tions. Their great advantages include high yields, eco-
friendliness, easy reaction workup procedures, mild and
solvent-free conditions, and avoiding the use of hazardous
acids or expensive/toxic Lewis acids as well as harsh
reaction conditions.
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(b) Undersolid-state reaction conditions, Zn(MeCOO)2·2H2O
(0.01 mol, 2.19 g) was ground for 5 min and then mixed with
NaOH (0.04 mol, 1.60 g). After the mixture was ground for
30 min, the product was washed with deionized H2O (3 ×)
and EtOH to remove the by-products. The final product was
first dried at 80 °C for 1 h and then was calcined in air at 600
°C for 2 h to decompose Zn(OH)2 into ZnO and H2O.
(36) Cullity, B. D.; Stock, S. R. Elements of X-ray Diffraction,
3rd ed.; Prentice-Hall: Englewood Cliffs NJ, 2001.
(37) General Procedure for the Synthesis of a-Amino
Phosphonate Derivatives: ZnO nanoparticles (20% mol)
were added to a mixture of aldehyde (1 mmol), amine (1
mmol) and dialkyl phosphite (1 mmol), at r.t., followed
by 8–18 h of stirring. The progress of the reaction was
monitored by TLC (eluent: EtOAc–n-hexane, 30:70). After
the reaction completion, CH2Cl2 (10 mL) was added to the
reaction mixture and the mixture was centrifuged at 2000–
3000 rpm, at 10 °C for 5 min to remove the catalyst.
Evaporation of the reaction solvent, followed by column
chromatography, afforded the pure a-amino phosphonates.
Spectral data for selected products, 4b: white solid; mp 89–
90 °C. 1H NMR (500 MHz, CDCl3): d = 1.14 (t, 3J = 7.0 Hz,
3 H), 1.29 (t, 3J = 7.1 Hz, 3 H), 3.66–3.68 (m, 1 H), 3.90–
3.93 (m, 1 H), 4.11–4.12 (m, 2 H), 4.79 (d, 2JHP = 24.3 Hz, 1
H), 4.81 (br, 1 H), 6.58–6.67 (m, 3 H), 7.07–7.08 (m, 2 H),
7.29–7.31 (m, 3 H), 7.45–7.46 (m, 2 H). 13C NMR (125
MHz, CDCl3): d = 16.12 (d, 3JPC = 5.6 Hz, Me), 16.26 (d,
3JPC = 5.7 Hz, Me), 56.71 (d, 1JPC = 151.3 Hz, CH), 63.21 (d,
2JPC = 7.0 Hz, OCH2), 63.97 (d, 2JPC = 6.9 Hz, OCH2), 114.28
(CH), 117.27 (CH), 127.34 (d, 3JPC = 5.6 Hz, CH), 128.51 (d,
4JPC = 2.9 Hz, CH), 128.84 (CH), 130.04 (CH), 134.11 (C),
146.73 (d, 3JPC = 14.3 Hz, C). 4d: white solid; mp 59–60 °C.
1H NMR (500 MHz, CDCl3): d = 1.15 (t, 3J = 6.9 Hz, 3 H),
1.28 (t, 3J = 7.0 Hz, 3 H), 3.71–3.74 (m, 1 H), 3.79–3.83 (m,
1 H), 4.06–4.10 (m, 2 H), 4.79 (d, 2JHP = 24.3 Hz, 1 H), 4.88
(br, 1 H), 6.49 (d, 3J = 7.6 Hz, 2 H), 6.73 (t, 3J = 7.2 Hz, 1
H), 7.07 (t, 3J = 7.4 Hz, 2 H), 7.33 (dd, 3J = 2.3, 8.0 Hz, 2 H),
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Synlett 2009, No. 8, 1326–1330 © Thieme Stuttgart · New York

1330
M. Z. Kassaee et al.
LETTER
7.43 (d, 3J = 8.0 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d =
16.44 (d, 3JPC = 5.5 Hz, Me), 16.61 (d, 3JPC = 5.6 Hz, Me),
63.05 (d, 2JPC = 7.1 Hz, OCH2), 63.27 (d, 2JPC = 6.9 Hz,
OCH2), 63.65 (d, 1JPC = 151.1 Hz, CH), 116.09 (CH), 116.89
(CH), 128.27 (d, 4JPC = 2.6 Hz, CH), 128.46 (CH), 130.63
(C), 131.03 (d, 3JPC = 5.9 Hz, CH), 135.43 (C), 147.29 (d,
3JPC = 14.3 Hz, C). 4h: white solid; mp 60 °C. 1H NMR (500
MHz, CDCl3): d = 1.13 (t, 3J = 7.0 Hz, 3 H), 1.28 (t, 3J = 7.0
Hz, 3 H), 2.30 (s, 3 H), 3.68–3.70 (m, 1 H), 3.92–3.94 (m, 1
H), 4.08–4.13 (m, 2 H), 4.73 (d, 2JHP = 24.1 Hz, 1 H), 4.96
(br, 1 H), 6.69 (d, 3J = 7.5 Hz, 2 H), 6.65–6.69 (m, 1 H),
7.07–7.13 (m, 4 H), 7.31–7.34 (m, 2 H). 13C NMR (125
MHz, CDCl3): d = 16.45 (d, 3JPC = 5.5 Hz, Me), 16.63 (d,
3JPC = 5.6 Hz, Me), 20.79 (Me), 58.65 (d, 1JPC = 151.7 Hz,
CH), 63.43 (d, 2JPC = 7.0 Hz, OCH2), 63.97 (d, 2JPC = 6.9 Hz,
OCH2), 115.08 (CH), 118.19 (CH), 128.04 (d, 4JPC = 2.9 Hz,
CH), 128.93 (d, 3JPC = 5.7 Hz, CH), 128.84 (CH), 132.52
(C), 137.36 (C), 146.73 (d, 3JPC = 14.1 Hz, C). 4q: white
solid; mp 117–119 °C. 1H NMR (500 MHz, CDCl3): d = 1.11
(t, J = 7.0 Hz, 3 H), 1.25 (t, J = 7.0 Hz, 3 H), 3.41 (s, 3 H),
3.43 (s, 3 H), 3.59–3.64 (m, 1 H), 3.81–3.85 (m, 1 H), 4.00–
4.08 (m, 2 H), 4.61 (d, 2JHP = 24.4 Hz, 1 H), 4.78 (br, 1 H),
6.50 (d, 3J = 7.6 Hz, 2 H), 6.63 (d, 3J = 7.2 Hz, 2 H), 6.91 (d,
3J = 8.4 Hz, 2 H), 7.23 (d, 3J = 8.5 Hz, 2 H). 4r: white solid;
mp 106–108 °C. 1H NMR (500 MHz, CDCl3): d = 1.12 (t,
J = 7.1 Hz, 3 H), 1.21 (t, J = 7.1 Hz, 3 H), 3.53 (s, 3 H), 3.52–
3.54 (m, 1 H), 3.58–3.69 (m, 1 H), 3.88–3.93 (m, 2 H), 4.45
(d, 2JHP = 23.9 Hz, 1 H), 4.65 (br, 1 H), 6.26 (d, 3J = 8.4 Hz,
2 H), 6.64 (d, 3J = 8.3 Hz, 2 H), 6.91 (d, 3J = 8.6 Hz, 2 H),
7.11 (d, 3J = 8.6 Hz, 2 H).
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2008, 49, 2598.
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9015.
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