NbCl5: An efficient catalyst for one-pot synthesis of α-aminophosphonates under solvent-free conditions

Article abstract of DOI:10.1002/aoc.1687

NbCl₅ has been found to be a very effective catalyst for the synthesis of a variety of α-aminophosphonates through the Kabachnik-Fields reaction of carbonyl compound, amine and diethyl phosphite under solvent-free conditions. Copyright

Full text of DOI:10.1002/aoc.1687

Full Paper
Received: 8 April 2010
Revised: 25 April 2010
Accepted: 5 May 2010
Published online in Wiley Online Library: 27 July 2010
(wileyonlinelibrary.com) DOI 10.1002/aoc.1687
NbCl5: an efficient catalyst for one-pot
synthesis of α-aminophosphonates under
solvent-free conditions
Jun-Tao Hou, Jian-Wu Gao and Zhan-Hui Zhang∗
NbCl5 has been found to be a very effective catalyst for the synthesis of a variety of α-aminophosphonates through the
c
Kabachnik–Fields reaction of carbonyl compound, amine and diethyl phosphite under solvent-free conditions. Copyright ꢀ
2010 John Wiley & Sons, Ltd.
Keywords: NbCl5; α-aminophosphonates; Kabachnik–Fields reaction; solvent-free
R2
Introduction
O
OEt
O
R1
C P
NbCl5 (5 mol%)
R3NH2
HOP(OEt)2
+
+
R1
R2
OEt
NH
R3
solvent-free, 60 °C
The great importance of α-aminophosphonates is based on
their presence in a number of biologically active compounds,
as well as on their application as substitutes for the correspond-
ing α-amino acids[1] and versatile intermediates and catalysts
in organic synthesis.[2] The activity of α-aminophosphonates as
peptidomimetics, pharmacogenic agents, antitumor agents, en-
zyme inhibitors, inhibitors of UDP-galactopyranose mutase and
plant glutamine synthetase has been demonstrated.[3] Conse-
quently, different methods have been developed for the synthesis
of α-aminophosphonates.[4] Among them, the Kabachnik–Fields
reaction appears to be still one of the simplest and most di-
rect approaches.[5] The reaction proceeds via the imine formed
upon reaction of carbonyl compounds and amines, where an
imine is converted to the corresponding aminophosphonates
by reaction with phosphite. This one-pot reaction can be pro-
moted by acid or base catalysts, microwave irradiation or by
heating.[6] Several acid catalysts, such as Lewis acids [recent
examples are Al(H2PO4)3,[7] InCl3,[8] BiCl3,[9] FeCl3,[3a] YbCl3,[10]
In(OTf)3,[11] Ce(OTf)4,[12] Al(OTf)3,[13] Sn(OTf)2,[14] Mg(ClO4)2,[15]
1
2
3
4
Scheme 1. The synthesis of α-aminophosphonates catalyzed by NbCl5.
industrial and synthetic points of view, introduction of an efficient
method for the preparation of these compounds is still in demand.
In recent years, the use of niobium catalysts for organic syn-
thesis has been an ever-growing research area, and a variety
of reactions have been developed, such as cyanosilylation of
ketones,[43] regioselective dealkylation of alkyl aryl ethers,[44]
alkoxide rearrangements,[45] conversion of aldehydes and ke-
tones to allylic halides,[46] conversion of carboxylic acids to
carboxamides[47], deprotection of methoxy methyl ether[48] and
synthesis of pyranoquinoline derivatives,[49] α-aminonitriles,[50]
1,1-diacetates,[51] β-hydroxyethers[52] and hydrazide.[53] However,
to the best of our knowledge, there is no report on the synthe-
sis of α-aminophosphonates using niobium pentachloride as a
reagent. As part of our continuing interest in the development of
new synthetic methodologies,[54] we report herein an efficient and
convenient procedure for the synthesis of α-aminophosphonates
by one-pot three-component reaction of carbonyl compound,
amine and diethyl phosphite catalyzed by NbCl5 under solvent-
free conditions (Scheme 1).
LiClO4,[16] ZrOCl2 · 5H2O,[17] CAN,[18] Yb(PFO)3,[19] SmI2,[20] TaCl5-
[21]
SiO2
and SbCl3/Al2O[22])] Brønsted acids (recent examples are
hypophosphorus acid,[23] sulfamic acid[24] and oxalic acid[25]), het-
eropoly acids,[26] solid acids (montmorillonite KSF,[27] silica sulfuric
acid,[28] Amberlyst-15[29] and Amberlite-IR 120[30]), base catalysts
[31]
such as CaCl2
and PPh3,[32] as well as other catalysts such
as ZnO,[33] TiO2,[34] tosyl chloride,[35] phenyltrimethylammonium
chloride,[36] (bromodimethyl)sulfonium bromide,[37] tetramethyl-
tetra-3,4-pyridinoporphyrazinato copper (II) methyl sulfate
[Cu(3,4-tmtppa)(MeSO4)4],[38] tetra-tert-butylphthalocyanine,[39]
β-cyclodextrine (β-CD),[40] NBS[41] and mesoporous aluminosil-
icate nanocage,[42] have been used to promote this reaction.
Although these procedures worked nicely in many cases, some-
times some of these procedures were associated with one or more
shortcomings such as long reaction time, low yield, lack of general-
ity, requirement of excess of reagents, the use of expensive or less
easily available catalysts and vigorous reaction conditions. Owing
to the importance of α-aminophosphonates from pharmaceutical,
Experimental
Melting points were determined using an X-4 apparatus and are
uncorrected. IR spectra were recorded with a Shimadzu FTIR-8900
∗
Correspondence to: Zhan-Hui Zhang, Hebei Normal University, The College of
Chemistry and Material Science, Hebei Normal University, Shjazhuang, Hebei
050016, China. E-mail: zhanhui@126.com
The College of Chemistry and Material Science, Hebei Normal University,
Shijiazhuang 050016, China
c
Appl. Organometal. Chem. 2011, 25, 47–53
Copyright ꢀ 2010 John Wiley & Sons, Ltd.

J.-T. Hou, J.-W. Gao, Z.-H. Zhang
1
spectrometer. NMR spectra were taken with a Bruker DRX-500
spectrometer at 500 (1H), 125 (13C) and 201 MHz (31P) using CDCl3
as the solvent. Elemental analyses were carried out on a Vario EL
III CHNOS elemental analyzer.
690 cm−1; H NMR δH 1.28 (t, J = 7.0 Hz, 3H, -OCH2Me), 1.30 (t,
J = 7.0 Hz, 3H, -OCH2Me), 1.38 (t, J = 7.0 Hz, 3H, ArOCH2Me),
3.98 (q, J = 7.0 Hz, 2H, ArOCH2Me), 4.02–4.19 (m, 4H, -OCH2Me),
4.97 (dd, J = 26.0, 7.0 Hz, 1H, CHP), 6.46 (d, J = 9.0 Hz, 1H, ArH),
7.00 (dd, J = 9.0, 3.0 Hz, 1H, ArH), 7.65 (dd, J = 9.0, 2.0 Hz, 2H,
ArH), 7.67 (d, J = 3.0 Hz, 1H, ArH); 8.23 (d, J = 9.0 Hz, 2H, ArH);
8.76 (dd, J = 11.5, 7.0 Hz, 1H, ArH); 13C NMR δC 14.6, 16.3 (d,
General Procedure for the Preparation of
α-Aminophosphonates
3JPC = 5.3 Hz), 16.4 (d, JPC = 5.3 Hz), 55.6 (d, JPC = 148.1 Hz),
63.7 (d, 2JPC = 6.6 Hz), 64.0 (d, 2JPC = 7.1 Hz), 64.3, 108.9, 115.5,
123.3 (d, JPC = 2.8 Hz), 126.7, 128.4 (d, JPC = 4.5 Hz), 133.1, 138.4
(d, JPC = 13.6 Hz), 142.8 (d, JPC = 3.5 Hz), 147.8, 150.2; 31P NMR δP
28.5. Anal. calcd for C19H24N3O8P: C, 50.33; H, 5.34; N, 9.27. Found:
C, 50.21; H, 5.50; N, 9.07.
3
1
A mixture of an aldehyde (1 mmol), aniline (1 mmol), diethyl
phosphate (1.1 mmol) and NbCl5 (0.05 mmol) was heated in an
oil bath at 60 ◦C for an appropriate time. The progress of the
reaction was monitored by TLC using hexane and ethyl acetate as
eluent. After completion, the reaction mixture was cooled to room
temperature and treated with water (10 ml). The resulting mixture
was extracted with ethyl acetate (3 × 5 ml). Drying (Na2SO4)
and evaporation of the solvent under reduced pressure gave
a residue that was purified by chromatography on silica gel
(hexane/ethyl acetate). All the physical and spectroscopic data of
the known compounds were in agreement with those reported in
the literature.
[(4-Ethoxy-2-nitrophenylamino)-(3-nitrophenyl)-methyl]-
phosphonic acid diethyl ester (4v)
Yellow solid; IR (KBr): 3350, 2983, 1635, 1573, 1521, 1481, 1415,
1350, 1259, 1225, 1137, 1101, 1047, 979, 817, 682 cm−1; 1H NMR
δH 1.29 (t, J = 7.0 Hz, 6H, -OCH2Me), 1.35 (t, J = 7.0 Hz, 3H,
ArOCH2Me), 3.99 (q, J = 7.0 Hz, 2H, ArOCH2Me), 4.06–4.19 (m,
4H, -OCH2Me), 4.97 (dd, J = 26.0, 7.0 Hz, 1H, CHP), 6.50 (d,
J = 9.0 Hz, 1H, ArH), 7.01 (dd, J = 9.0, 3.0 Hz, 1H, ArH), 7.57
(t, J = 9.0 Hz, 1H, ArH), 7.68 (d, J = 3.0 Hz, 1H, ArH); 7.83 (d,
J = 8.0 Hz, 1H, ArH); 8.19 (d, J = 8.0 Hz, 1H, ArH); 8.32 (s, 1H,
ArH), 8.76 (dd, J = 11.5, 7.0 Hz, 1H, ArH); 13C NMR δC 14.6, 16.2 (d,
Spectral and Analytical Data for New Compounds
[Benzo[1,3]dioxol-5-yl-(4-nitrophenylamino)-methyl]-phosphonic
acid diethyl ester (4o)
Yellow solid; IR (KBr): 3265, 1596, 1504, 1481, 1413, 1286, 1230,
1110, 1049, 1022, 962, 837, 752 cm−1;1HNMRδH 1.17(t, J = 7.0 Hz,
3H, -OCH2Me), 1.32 (t, J = 7.0 Hz, 3H, -OCH2Me), 3.68–3.76 (m,
1H, -OCH2Me), 3.94–4.02 (m, 1H, -OCH2Me), 4.08–4.19 (m, 2H,
-OCH2Me), 4.70 (dd, J = 24.0, 7.5 Hz, 1H, CHP), 5.57 (dd, J = 10.0,
7.5 Hz, 1H, NH), 5.96 and 5.98 (AB system, J = 2.0 Hz, 2H, -
OCH2O-), 6.57 (d, J = 9.0 Hz, 2H, ArH), 6.78 (d, J = 7.5 Hz, 1H,
ArH), 6.89–6.92 (m, 2H, ArH), 8.03 (d, J = 9.0 Hz, 2H, ArH); 13C
3JPC = 5.3 Hz), 16.4 (d, JPC = 5.3 Hz), 54.8 (d, JPC = 148.1 Hz),
63.7 (d, 2JPC = 7.0 Hz), 64.0 (d, 2JPC = 7.1 Hz), 64.3, 108.9, 115.5,
112.6 (d, JPC = 4.8 Hz), 123.3 (d, JPC = 2.8 Hz), 126.7, 129.9,
133.0, 133.4 (d, JPC = 4.5 Hz), 137.8 (d, JPC = 3.5 Hz), 138.4 (d,
JPC = 13.6 Hz), 148.4 (d, JPC = 3.0 Hz), 150.2; 31P NMR δP 18.7.
Anal. calcd for C19H24N3O8P: C, 50.33; H, 5.34; N, 9.27; Found: C,
50.18; H, 5.53; N, 9.10.
3
1
3
3
NMR δC 16.2 (d, JPC = 5.7 Hz), 16.4 (d, JPC = 5.7 Hz), 55.2 (d,
2
2
[(4-Nitrophenylamino)-thiophen-2-yl-methyl]-phosphonic acid
diethyl ester (4aa)
1JPC = 152.5 Hz), 63.3 (d, JPC = 7.2 Hz), 63.8 (d, JPC = 7.2 Hz),
101.3, 107.8 (d, JPC = 4.6 Hz), 108.5 (d, JPC = 2.6 Hz), 112.4, 121.3
(d, JPC = 6.4 Hz), 126.0, 128.2 (d, JPC = 3.2 Hz), 139.0, 147.7,
148.2, 151.8 (d, JPC = 13.8 Hz); 31P NMR δP 21.2. Anal. calcd for
C18H21N2O7P: C, 52.94; H, 5.18; N, 6.86. Found: C, 53.06; H, 4.99; N,
7.03.
Yellow solid; IR (KBr): 3255, 3197, 1598, 1502, 1481, 1315, 1230,
1114, 1051, 1014, 839, 754, 646 cm−1;1HNMRδH 1.22(t, J = 7.0 Hz,
3H, -OCH2Me), 1.29 (t, J = 7.0 Hz, 3H, -OCH2Me), 3.84–3.91(m,
1H, -OCH2Me), 4.05–4.10(m, 1H, -OCH2Me), 4.13–4.23 (m, 2H, -
OCH2Me), 5.16 (d, J = 24.0 Hz, 1H, CHP), 6.56 (br s, 1H, NH), 6.73 (d,
J = 8.5 Hz, 2H, ArH), 6.98 (s, 1H, ArH), 7.23–7.29 (m, 2H, ArH), 8.03
(d, J = 8.5 Hz, 2H, ArH); 13C NMR δC 16.3 (d, 3JPC = 5.7 Hz), 16.4 (d,
[(4-Bromophenylamino)-(4-nitrophenyl)-methyl]-phosphonic
acid diethyl ester (4r)
3JPC = 5.7 Hz), 51.2 (d, JPC = 158.4 Hz), 63.7 (d, JPC = 7.1 Hz),
64.0 (d, 2JPC = 7.1 Hz), 112.3, 125.8 (d, JPC = 3.5 Hz), 126.0, 126.9
(d, JPC = 6.8 Hz), 127.3 (d, JPC = 2.6 Hz), 137.9, 139.0, 152.1 (d,
JPC = 12.0 Hz); 31P NMR δP 19.4. Anal. calcd for C15H19N2O5PS: C,
48.64; H, 5.17; N, 7.56; Found: C, 48.81; H, 5.01; N, 7.75.
1
2
Yellow solid; IR (KBr): 3294, 2985, 2902, 1593, 1487, 1390, 1344,
1209, 1163, 958, 904, 815, 696 cm−1; 1H NMR δH 1.19 (t, J = 7.5 Hz,
3H, -OCH2Me), 1.31 (t, J = 7.5 Hz, 3H, -OCH2Me), 3.83–3.91 (m,
1H, -OCH2Me), 3.99–4.06 (m, 1H, -OCH2Me), 4.09–4.19 (m, 2H, -
OCH2Me), 4.80 (d, J = 26.0 Hz, 1H, CHP), 4.86 (br s, 1H, NH), 6.41 (d,
J = 9.0 Hz, 2H, ArH), 7.20 (d, J = 9.0 Hz, 2H, ArH), 7.63 (dd, J = 8.5,
2.5 Hz, 2H, ArH), 8.21 (d, J = 8.5 Hz, 2H, ArH); 13C NMR δC 16.2 (d,
[1-(4-Nitrophenylamino)-1-phenyl-ethyl]-phosphonicaciddiethyles-
ter (4af)
3
1
3JPC = 6.9 Hz), 16.4 (d, JPC = 6.9 Hz), 55.4 (d, JPC = 148.0 Hz),
63.5 (d, 2JPC = 7.0 Hz), 63.7 (d, 2JPC = 6.8 Hz), 110.8, 115.3, 123.7,
129.5 (d, JPC = 5.1 Hz), 132.0, 143.5, 144.6 (d, JPC = 14.4 Hz), 147.6;
31P NMR δP 20.4. Anal. calcd for C17H20BrN2O5P: C, 46.07; H, 4.55;
N, 6.32. Found: C, 46.25; H, 4.72; N, 6.18.
Yellow solid; IR (KBr): 3240, 1635, 1618, 1600, 1487, 1325, 1276,
;
1222, 1113, 1051, 1024, 875, 617 cm−1 1H NMR δH 1.24 (t,
J = 7.0 Hz, 6H, -OCH2Me), 2.04 (d, J = 16.0 Hz, 3H, COMe),
3.84–4.03(m, 4H, OCH2Me), 5.64 (br s, 1H, NH), 6.36 (d, J = 8.0 Hz,
2H, ArH), 7.32 (t, J = 7.0 Hz, 1H, ArH), 7.37 (t, J = 7.0 Hz, 2H, ArH),
7.52 (d, J = 7.0 Hz, 2H, ArH), 7.90 (d, J = 8.0 Hz, 2H, ArH); 13C
[(4-Ethoxy-2-nitrophenylamino)-(4-nitrophenyl)-methyl]-
phosphonic acid diethyl ester (4u)
3
3
NMR δC 16.3 (d, JPC = 5.4 Hz), 20.6 (d, JPC = 3.0 Hz), 59.7 (d,
1JPC = 148.4 Hz), 63.8 (d, JPC = 7.1 Hz), 64.0 (d, JPC = 7.1 Hz),
114.7, 125.4, 127.7 (d, JPC = 4.8 Hz), 127.9 (d, JPC = 3.1 Hz), 128.6,
136.6 (d, JPC = 7.8 Hz), 138.7, 150.7 (d, JPC = 14.6 Hz); 31P NMR δP
2
2
Reddish brown solid; IR (KBr): 3369, 2979, 2903, 1635, 1608, 1573,
1525, 1469, 1419, 1299, 1215, 1149, 1110, 1097, 1014, 862, 783,
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 47–53

Synthesis of α-aminophosphonates
Table 1. Investigation of the amounts of catalyst and temperature effects on the reaction of piperonal, p-choroaniline and diethyl phosphite
O
O
Cl
NH2
+
CHO
+
O
O
NbCl5
O
P
HOP(OEt)2
O
N
H
Cl
O
Entry
Catalyst loading (mol%)
Temperature (◦C)
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
No
3
60
60
60
60
60
40
50
70
120
35
30
84
95
96
96
75
92
96
5
35
7
35
10
5
35
120
45
5
5
35
a Isolated yields
24.0. Anal. calcd for C18H23N2O5P: C, 57.14; H, 6.13; N, 7.40; Found:
C, 57.32; H, 5.98; N, 7.59.
Under the optimized conditions, the substrate scope of the
Kabachnik–Fields reaction was investigated, and a range of α-
aminophosphonates were prepared (Table 2). Various aromatic
aldehydes containing electron-withdrawing groups and electron-
donating groups gave the corresponding α-aminophosphonates
in high to excellent yields (Table 2, entries 1–23). In general, the
electronic properties of the substituents of aromatic aldehydes did
notaffecttheyields.However,α,β-unsaturatedaldehyde(entry24)
and heterocyclic aromatic aldehydes (entries 25–28) were found
to be less reactive in this reaction and gave slightly lower yields
of the desired products; incomplete conversion of the starting
materials to the product was observed by GC or TLC. Moreover,
it was noteworthy that the methodology worked well for cyclic
ketone (entry 31). However, poor yield was obtained when the
reactionwasappliedtounactivatedketonessuchasacetophenone
(entry 32). On the other hand, various amines were examined as
substrates for this three-component reaction. The nature of the
substituents on the aromatic ring of aniline had a delicate effect on
this conversion. The presence of an electron-withdrawing group
on the benzene ring decreased the reactivity and required longer
reactiontimes. Furthermore, bis(α-aminophosphonates)werealso
obtained successfully under similar conditions (entries 33–35).
These compounds are multidentate ligands which may be used
fortheextractionofmetalsandcanbeemployedasthemonomers
for the preparation of macrocyclic or polymeric compounds
carrying phosphonate and amine moieties.[3a] No competitive side
reactions such as aromatic nucleophilic substitution of halogen
atom, nucleophilic cleavage of the O-Me group or decomposition
of acid sensitive substrates were observed.
{1,4-Phenylenebis[(4-nitrophenylamino)methylene]}bis-
(phosphonic acid tetraethyl ester) (4ag)
Yellow solid; IR (KBr): 3276, 3070, 1597, 1541, 1485, 1442, 1296,
1
1280, 1228, 1110, 1020, 979, 837, 754 cm−1; H NMR δH 1.06 (t,
J = 7.0 Hz, 6H, -OCH2Me), 1.29 (t, J = 7.0 Hz, 6H, -OCH2Me),
3.62–3.67 (m, 2H, -OCH2Me), 3.88–3.95 (m, 2H, -OCH2Me),
4.14–4.23 (m, 4H, -OCH2Me), 4.87 (dd, J = 23.5, 8.5 Hz, 2H, CHP),
6.63(d, J = 9.0 Hz, 4H, ArH), 7.51(s, 4H, ArH), 7.97(d, J = 9.0 Hz, 4H,
ArH);13CNMRδC 16.2(d,3JPC = 2.6 Hz),16.3(d,3JPC = 2.6 Hz),16.4
(d, 3JPC = 2.5 Hz), 16.5 (d, 3JPC = 2.5 Hz), 54.9 (d, 1JPC = 153.8 Hz),
63.4 (d, J = 3.5 Hz), 63.5 (d, 2JPC = 3.5 Hz), 63.4 (d, 2JPC = 3.5 Hz),
63.6 (d, 2JPC = 3.5 Hz), 63.7 (d, 2JPC = 3.5 Hz), 112.0, 126.0, 128.4,
135.2, 138.6, 152.4 (d, JPC = 7.1 Hz); 31P NMR δP 20.7. Anal. calcd
for C28H36N4O10P2: C, 51.69; H, 5.58; N, 8.61; Found: C, 51.82; H,
5.76; N, 8.43.
Results and Discussion
In the initial experiment, the one-pot, three-component reaction
of p-choroaniline, piperonal and diethyl phosphite was chosen as
the model reaction to optimize the reaction conditions. We were
pleased to find that the reaction occurred efficiently to afford
the corresponding α-aminophosphonates in 95% yield when
5 mol% NbCl5 was used at 60 ◦C under solvent-free conditions
(Table 1, entry 3). Moreover, we observed that the yields were
obviouslyaffectedbytheamountofNbCl5 loadedandthereaction
temperature. Lowering the amount of the catalyst or the reaction
temperature led to the formation of the product in lower yields.
Importantly, only 30% yield of the product was obtained in the
absence of NbCl5. The above results showed that NbCl5 was
essential to the reaction, and the best results were obtained
when the reaction was carried out with 5 mol% of NbCl5 under
solvent-free conditions at 60 ◦C.
Finally, the efficacy of NbCl5 was compared with that of other
catalysts reported earlier the synthesis of 4a was considered as a
representative example (Table 3). As demonstrated in Table 3,
NbCl5 is an equally or more efficient catalyst for this three-
component reaction in terms of yield and reaction rate.
Conclusion
In conclusion, we have developed a simple, mild and practical
protocol for the synthesis of α-aminophosphonates through
c
Appl. Organometal. Chem. 2011, 25, 47–53
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
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J.-T. Hou, J.-W. Gao, Z.-H. Zhang
Table 2. Scope for NbCl5-catalyzed synthesis of α-aminophosphonates
Melting point (◦C)
Entry
1
Aldehyde/ketone
Amine
NH2
Product
Time (min)
30
Yield (%)a
95
Found
90–91
Reported
89–90[4c]
4a
CHO
2
3
4
5
6
4b
4c
4d
4e
4f
35
30
40
45
50
92
95
92
93
92
71–72
70–73[4c]
117–118[26b]
112–113[26b]
121–123[32]
128–130[32]
MeO
Me
NH2
CHO
CHO
CHO
CHO
CHO
116–117
113–114
121–122
129–130
NH2
NH2
NH2
Cl
Br
O2N
NH2
NH2
7
8
4g
4h
4i
50
50
50
60
90
87
90
89
146–147
64–65
145–147[32]
63–65[6b]
CHO
O2N
CHO
NH2
Me
9
102–103
109–110
102–103[6b]
107–109[32]
NH2
NH2
MeO
CHO
CHO
CHO
10
4j
MeO
MeO
MeO
11
12
4k
4l
25
28
92
93
58–59
88–89
57[34]
88[34]
NH2
NH2
Cl
Cl
CHO
13
14
15
4m
4n
4o
35
30
30
95
92
95
115–116
102–103
150–151
114–115[6a]
102–104[55]
CHO
CHO
CHO
NH2
Cl
O
O
O
O
O
NH2
NH2
Me
O2N
O
16
17
18
19
4p
4q
4r
30
30
30
40
90
96
94
92
178–179
150–151
181–183
107–108
117–118[6a]
149–150[26b]
CHO
CHO
CHO
CHO
Cl
NH2
NH2
NH2
NH2
Cl
Cl
Br
Br
O2N
O2N
MeO
4s
106–108[6a]
c
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Copyright ꢀ 2010 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2011, 25, 47–53

Synthesis of α-aminophosphonates
Table 2. (Continued)
Melting point (◦C)
Entry
20
Aldehyde/ketone
Amine
Product
Time (min)
45
Yield (%)a
90
Found
Reported
115[11]
4t
115–116
MeO
O2N
CHO
O2N
EtO
NH2
NH2
21
22
23
4u
4v
35
50
50
95
86
80
111–112
CHO
NO2
NH2
NO2
146–148
144–145
O2N
EtO
CHO
4 w
143–145[56]
CHO
NO2
NH2
N
24
4x
30
85
105–106
104[34]
CHO
NH2
NH2
25
26
27
28
4y
4z
60
50
60
60
86
90
83
89
51–52
Oil
50–52[6b]
O
CHO
CHO
Oil[41]
NH2
MeO
O2N
O
4aa
4ab
146–147
89–90
NH2
S
CHO
CHO
90[8]
N
NH2
29
30
31
32
4ac
4ad
4ae
4af
30
30
60
60
90
92
90
45
Oil
Oil[6c]
Oil[18]
CH2NH2
NH2
CHO
CHO
Oil
109–110
140–141
108–109[6c]
O
O
NH2
O2N
NH2
33b
34b
35c
4ag
4 ah
4ai
80
90
50
90
89
91
185–186
264–266
200–201
184–185[57]
CHO
NH2
OHC
OHC
CHO
O2N
H2N
NH2
199–200[57]
NH2
CHO
a Isolated yields. b Two equivalents of amines were used. c Two equivalents of benzaldehyde were used.
the three-component reaction of carbonyl compound, amine
and diethyl phosphite catalyzed by NbCl5 under solvent-free
conditions. The methods allow the preparation of a wide variety
of α-aminophosphonates in good to excellent yields in short
time.
Acknowledgments
We are grateful for financial support from the Na-
tional Natural Science Foundation of China (20872025 and
20772022), the Natural Science Foundation of Hebei Province
c
Appl. Organometal. Chem. 2011, 25, 47–53
Copyright ꢀ 2010 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

J.-T. Hou, J.-W. Gao, Z.-H. Zhang
Table 3. Comparison of our results with previously reported data for synthesis of 4a
Entry
Catalyst
Reaction conditions
Time
Yield (%)
Reference
[7]
1
2
Al(H2PO4)3
Solvent-free/100 ◦C
THF/r.t.
90 min
11 h
6 h
93
92
92
92
93
79
94
99
96
92
98
90
99
87
86
96
61
90
87
95
[8]
InCl3
[9]
3
BiCl3
CH3CN/reflux
THF/60 ◦C
[3a]
[10]
[11]
[12]
[15]
[18]
[21]
[34]
[33]
[41]
[28]
[42]
[38]
[40]
[31]
[32]
4
FeCl3
0.75 h
24 h
21 h
20 min
5 h
5
YbCl3
CH3CN/r.t.
6
In(OTf)3
THF/reflux
7
Ce(OTf)4
Solvent-free/50 ◦C
Solvent-free/80 ◦C
Solvent-free/reflux
CH2Cl2/r.t.
8
Mg(ClO4)2
9
CAN
30 min
22 h
3.5 h
9 h
10
11
12
13
14
15
16
17
18
19
20
TaCl5-SiO2
TiO2
Solvent-free/50 ◦C
Solvent-free/r.t.
Solvent-free/50 ◦C
CH3CN/r.t.
CH3CN/80 ◦C
H2O/80 ◦C
ZnO
NBS
3 h
Silica sulfuric acid
5 h
3D mesoporous aluminosilicate nanocage
4 h
Cu(3,4-tmtppa)(MeSO4)4
0.5 h
24 h
3 h
β-CD
CaCl2
PPh3
H2O/reflux
Solvent-free/60 ◦C
Solvent-free/60 ◦C
Solvent-free/50 ◦C
1 h
NbCl5
30 min
This work
(B2008000149) and Science Foundation of Hebei Normal Univer-
sity (L20061314).
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