One-pot, three-component synthesis of α-aminophosphonates catalyzed by acyclic acidic ionic liquids

Article abstract of DOI:10.1080/10426501003724905

Some acyclic acidic ionic liquids were prepared and used as the catalysts for the one-pot, three-component synthesis of α-aminophosphonates from aldehydes, amines, and trimethylphosphite at room temperature in water. The products could simply be separated from the system of catalyst/water, and the catalysts could be reused at least six times without noticeably decreasing the catalytic activity. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426501003724905

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Phosphorus, Sulfur, and Silicon and the
Related Elements
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One-Pot, Three-Component Synthesis
of α-Aminophosphonates Catalyzed by
Acyclic Acidic Ionic Liquids
Dong Fang a b , Changmei Jiao a & Baohua Ji b
a Jiangsu Provincial Key Laboratory of Coast Wetland Bioresources &
Environment Protection, Jiangsu, P. R. China
b School of Chemistry & Chemical Engineering, Yancheng Normal
University, Yancheng, P. R. China
Published online: 19 Nov 2010.
To cite this article: Dong Fang , Changmei Jiao & Baohua Ji (2010) One-Pot, Three-Component
Synthesis of α-Aminophosphonates Catalyzed by Acyclic Acidic Ionic Liquids, Phosphorus, Sulfur, and
Silicon and the Related Elements, 185:12, 2520-2526, DOI: 10.1080/10426501003724905
To link to this article: http://dx.doi.org/10.1080/10426501003724905
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Phosphorus, Sulfur, and Silicon, 185:2520–2526, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003724905
ONE-POT, THREE-COMPONENT SYNTHESIS
OF α-AMINOPHOSPHONATES CATALYZED
BY ACYCLIC ACIDIC IONIC LIQUIDS
Dong Fang,1,2 Changmei Jiao,1 and Baohua Ji2
1Jiangsu Provincial Key Laboratory of Coast Wetland Bioresources & Environment
Protection, Jiangsu, P. R. China
2School of Chemistry & Chemical Engineering, Yancheng Normal University,
Yancheng, P. R. China
Some acyclic acidic ionic liquids were prepared and used as the catalysts for the one-
pot, three-component synthesis of α-aminophosphonates from aldehydes, amines, and
trimethylphosphite at room temperature in water. The products could simply be separated
from the system of catalyst/water, and the catalysts could be reused at least six times without
noticeably decreasing the catalytic activity.
Keywords α-Aminophosphonates; aqueous media; homogeneous catalysis; ionic liquids
INTRODUCTION
α-Aminophosphonates are pharmacologically important compounds that exhibit
broad biological activities. These compounds have emerged as peptide mimics,1 enzyme in-
hibitors,2 antibiotics,3 and catalytic antibodies.4 Though substantial progress has been made
to develop efficient methods for the preparation of these compounds, they suffer from harsh
conditions, long reaction times, and frequently low yields, and the search for a milder and
more efficient procedure and efficient catalysts for the synthesis of α-aminophosphonates
continues to attract the attention of researchers.
Recently, nucleophilic addition of phosphite to imines has emerged as an important
alternative to hydrophosphonylation of imines for the synthesis of α-aminophosphonates
under the assistance of microwave or ultrasound irradiation,5 and catalyzed by Lewis acids,6
Brønsted acids,7 solid acid,8 and organocatalysts,9 and the search for new water-tolerant,
readily available, and green catalysts is still being actively pursued.
Received 14 January 2010; accepted 23 February 2010.
This work was financially supported by the Educational Commission of Jiangsu Provinces (2010 Qing
Lan, Project), Jiangsu Provincial Key Laboratory of Coastal Wetland Bioresources & Environmental Protection
(JLCBE 09023), and Professional Elite Foundation of Yancheng Normal University.
Address correspondence to D. Fang, Jiangsu Provincial Key Laboratory of Coast Wetland Bioresources
& Environment Protection, 50 Kai Fang Da Dao, Yancheng 224002, Jiangsu, P. R. China. E-mail: fang-njust@
hotmail.com
2520

ONE-POT SYNTHESIS OF α-AMINOPHOSPHONATES
2521
Currently, ionic liquids attract much interest as environmentally benign catalysts or
excellent alternatives to organic solvents, due to their favorable properties such as neg-
ligible volatility and high thermal stability. Brønsted acidic or basic functionalized ionic
liquids (TSILs) are designed to replace traditional acid or base catalysts in organic synthetic
procedures. In view of both the advantages and disadvantages of homogeneous and hetero-
geneous catalytic reactions, the use of TSILs as reaction medium/catalytic system may offer
a convenient solution to both the solvent emission and catalytic recycling problem. Yadav
et al. used [bmim]BF4/[bmim]PF6 to synthesize α-aminophosphonates.10 Very recently,
Akbari and Heydari reported a sulfonic acid functionalized ionic liquid as a recyclable
catalyst for the synthesis of α-aminophosphonates,11 and Sadaphal et al. used functional-
ized ionic liquid [bnmim][HSO4] to synthesize these compounds.12 However, TSILs with
imidazole as the cation are relatively expensive, which hinders their industrial applications.
Furthermore, typical ionic liquids consist of halogen-containing anions (such as [PF6]−,
[BF4]−, [CF3SO3]−, or [(CF3SO2)2N]−), which in some regard limit their “greenness.”13
Therefore, it is necessary to synthesize novel, efficient, inexpensive, and halogen-free
TSILs. In continuation of our work in studying ionic liquid–catalyzed multicomponent
reactions (MCRs) in aqueous media,14 we synthesized some SO3H-functional Brønsted-
acidic TSILs that bear an alkane sulfonic acid group in an acyclic tri-alkanyl-ammonium
cation (Scheme 1), and their uses as novel catalysts for the one-pot, three-component
synthesis of α-aminophosphonates (Scheme 2) were also explored.
Et
N
Me
N
SO3H
Et
SO3H
Me
HSO4
HSO4
Et
Me
[TMPSA][HSO4]
[TEPSA][HSO4]
n-Bu
Me
HSO4
N
Me
SO3H
n-Bu
N
HSO4
SO3H
Me
n-Bu
[TMBSA][HSO4]
[TBPSA][HSO4]
Et
N
Et
HSO4
SO3H
Et
[TEBSA][HSO4]
Scheme 1 TSIL a: [TMPSA][HSO4]; TSIL b: [TEPSA][HSO4]; TSIL c: [TBPSA][HSO4]; TSIL d:
[TMBSA][HSO4]; TSIL e: [TEBSA][HSO4].

2522
D. FANG ET AL.
O
R3
NH
O
R1
R2
H3CO
OCH3
P
P
TSILs (5 mol%)
H2O, r.t.
OCH3
OCH3
R1
R2
1
+
OCH3
3
4
R3NH2
2
Scheme 2
RESULTS AND DISCUSSION
The preparation of the catalyst TSILs were made up of a two-step atom economic
reaction, and the fresh, new catalysts are somewhat viscous colorless or pale yellow liquids
at room temperature. All produced catalysts are entirely miscible with water and are soluble
or partly soluble in organic solvents. Indeed, all TSILs could act as water-tolerant catalysts.
In the initial catalytic activity experiments, benzaldehyde, aniline, and trimethylphos-
phite were employed as the model reactants at room temperature in TSILs for a length of
time to compare the catalytic performance of the TSILs (Table I).
It was shown that no desirable product could be detected when a mixture of ben-
zaldehyde, aniline, and trimethylphosphite was heated at r.t. for 60 min in the absence
of TSILs (Table I, entry 1), which indicates that the catalysts were absolutely necessary
for this three-component reaction. All the TSILs proved to be very active. It is clear that
the yield was increased with adding TSILs, and the optimal amount of the TSILs was
0.5 mmol (Table I, entries 4, 7–10), amounting to 5 mol% of reactant 1. A higher amount
of the catalysts did not improve the yield. Additionally, ionic liquids containing the shorter
Table I Effect of different catalysts on the synthesis of α-aminophosphonates
Entry
Catalyst (mmol)
Isolated yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
0
0
TSILs a (0.1)
TSILs a (0.3)
TSILs a (0.4)
TSILs a (0.5)
TSILs a (0.6)
TSILs a (0.7)
TSILs a (0.8)
TSILs a (0.9)
TSILs b (0.5)
TSILs c (0.5)
TSILs d (0.5)
TSILs e (0.5)
61
86
90
95
95
95
95
95
95
94
95
93
Reaction conditions: 10 mmol benzaldehyde, 10 mmol aniline, 12 mmol trimethyl phosphite,
H2O 5 mL, r.t., 10 min.

ONE-POT SYNTHESIS OF α-AMINOPHOSPHONATES
2523
Figure 1 Recycle performance of the catalyst.
length of alkyl chain are relatively cheaper. Further, the better immiscibility of the resulting
α-aminophosphonates with the ionic liquid containing shorter length of alkyl chain should
facilitate the separation in workup procedure. Hence, [TMPSA][HSO4] should be the best
catalyst for this procedure among these acyclic TSILs, and the optimized reaction condi-
tions are presented in Table I (entry 4). As a clean and cheap solvent, it is important to carry
out this reaction in water for environmental and economic reasons.
The recycling performance of [TMPSA][HSO4] was also investigated using the above
same model reaction. After completion of the reaction, the products were isolated from the
catalytic system by filtration; the catalyst was reused in the next run after the extraction
with CH2Cl2. As shown in Figure 1, the catalyst can be reused at least six times without
appreciable decrease in yield and reaction rate. Compared with the traditional solvents and
catalysts, the easy recycling performance is also an attractive property of the TSILs for
environmental protection and economic reasons.
Table II Synthesis of α-aminophosphonates catalyzed by [TMPSA][HSO4]
Entry
R1
R2
R3
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
3-NO2C6H4
4-FC6H4
C6H5CH2
2-Pyridyl
C6H5
Time (min)
Yield (%)a
Reference
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
4-CH3OC6H4
2,5-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
4-CH3C6H4
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
10
30
30
10
10
10
60
15
60
60
15
15
15
90
60
95
88
86
90
95
95
85
91
85
85
90
90
90
82
90
[6f]
[6h]
[6f]
[9b]
[6f]
[6f]
[6h]
[5a]
[6h]
[6f]
[6f]
[9b]
[6f]
[6f]
[6f]
4-ClC6H4
2,6-Cl2C6H3
4-NO2C6H4
2-Thiazolyl
2-Furyl
4-CH3OC6H4
4-CH3C6H4
C6H5
4-CH3OC6H4
4-CH3OC6H4
Reaction conditions: 10 mmol benzaldehyde, 10 mmol aniline, 12 mmol trimethyl phosphite, 0.5 mol
[TMPSA][HSO4], H2O 5 mL, r.t.
aIsolated yield.

2524
D. FANG ET AL.
Then, this condensation reaction with various aldehydes/ketone, amines, and
trimethylphosphites in the presence of [TMPSA][HSO4] as the catalyst was explored
under the optimized reaction conditions described above, and the results are presented in
Table II.
It can easily be seen that this one-pot, three-component condensation completed
within 10–90 min, and the products were isolated in good yields by filtration. Aromatic
aldehydes carrying either electron-donating or electron-withdrawing substituents could
afford good yields of α-aminophosphonates (Table II, entries 1–8). In the case of anilines,
it is noteworthy that both the weak electron-donating and electron-withdrawing substituents
(Table II, entries 11, 12) were advantageous to this reaction. In addition, besides the aromatic
aldehydes, aromatic ketones could also be employed to give good yield (Table II, entries
15).
CONCLUSION
In summary, an efficient procedure for the synthesis of α-aminophosphonates via
a one-pot, three-component reaction catalyzed by acyclic ionic liquids was developed.
The methodology gives the advantages of short reaction time, free of organic solvent,
recyclability of catalysts, and easy workup in isolation of the products in good yield with
high purity.
EXPERIMENTAL
Materials and Methods
Melting points were determined by using an X6-Data microscope apparatus. The IR
spectra were run on a Bruker Vectter 22 spectrometer and are expressed in cm−1 (KBr).
1H NMR spectra were recorded on a Bruker DRX300 (300 MHz) spectrometer. Elemental
analyses were recorded on a Perkin Elmer C spectrometer. Mass spectra were obtained
with an automated Finnigan TSQ Quantum Ultra AM (Thermal) LC-MS spectrometer. All
chemicals (AR grade) were commercially available and used without further purification.
Synthesis of SO3H-Functional, Halogen-Free Acidic Ionic Liquids
(TSILs)
All of the acyclic SO3H-functionalized, halogen-free acidic ionic liquids used were
synthesized according to our previous methods.12 The TSILs were analyzed by 1H NMR,
13C NMR, and MS spectroscopes, and the spectral data agreed with their structures
(Scheme 1).
N,N,N-Trimethyl-N-propanesulfonic acid ammonium hydrogen sulfate
1
[TMPSA][HSO4]. H NMR (300 Mz, D2O): δ = 3.22 (t, J = 7.2Hz, 2H, N CH2 ),
2.90 (s, 9H, CH3), 2.73 (t, J = 7.8Hz, 2H, CH2 SO3), 1.98–2.00 (m, 2H, CH2 ).
13C NMR (D2O,): δ = 65.0, 52.5, 47.9, 18.9. Anal. Calcd. For C6H17NO7S2: C,25.80;
H,6.13; N,5.01; Found: C,25.53; H,6.14; N,4.96.
N,N,N-Triethyl-N-propanesulfonic acid ammonium hydrogen sulfate
1
[TEPSA][HSO4]. H NMR (300 Mz, D2O): δ = 3.22–3.05 (m, 8H, (6H+2H),
N
CH2 CH3, N CH2 C2H4 ), 2.85 (t, J = 7.2Hz 2H, CH2 SO3), 1.96–1.98 (m,
2H, CH2 ), 1.12 (m, 9H, CH3). 13C NMR (75.5Mz, D2O): δ = 56.0, 53.0, 48.3, 18.93,

ONE-POT SYNTHESIS OF α-AMINOPHOSPHONATES
2525
8.0. Anal. Calcd. For C9H23NO7S2: C,33.63; H,7.21; N,4.36; Found: C,33.45; H,7.24;
N,4.21.
N,N,N-Tributyl-N-propanesulfonic acid ammonium hydrogen sulfate
1
[TBPSA][HSO4]. H NMR (500 Mz, D2O): δ = 3.28(t, 2H, J = 4.0 Hz, N CH2 ),
3.13 (t, 6H, J = 8.5 Hz, N CH2 ), 2.85 (t, 2H, J = 7.0Hz, CH2 SO3), 2.03 (m,
2H, CH2 CH2 CH2), 1.56 (m, 6H, CH2 CH2CH3), 1.25–1.28 (m, 6H, CH2 CH3),
0.84 (t, 9H, J = 7.5Hz, CH3). 13CNMR (300Mz, D2O): δ = 58.5, 50.7, 48.4, 24.0, 20.4,
19.2, 14.5. Anal. Calcd. For C15H35NO7S2: C,44.42; H,8.70; N,3.45; Found: C,44.27;
H,8.71; N,3.28.
N,N,N-Trimethyl-N-butanesulfonic acid ammonium hydrogen sulfate
1
[TMBSA][HSO4]. H NMR (300 Mz, D2O): δ = 3.24 (t, J = 8.4 Hz, 2H, N CH2 ),
2.99 (s, 9H, CH3), 2.85 (t, J = 7.5 Hz, 2H, CH2 SO3), 1.82 (m, 2H, CH2 ),
1.69–1.71 (m, 2H, CH2 ). 13C NMR (D2O,): δ = 66.2, 53.2, 50.3, 21.5, 19.9. Anal.
Calcd. For C7H19NO7S2: C, 28.66; H, 6.53; N, 4.77; Found: C, 28.40; H, 6.51; N, 4.92.
N,N,N-Triethyl-N-butanesulfonic acid ammonium hydrogen sul-
1
fate [TEBSA][HSO4]. H NMR (300 Mz, D2O): δ = 3.15 (q, J = 7.2 Hz, 6H,
N CH2 CH3), 3.07 (t, J = 8.4 Hz, 2H, N CH2 C3H6SO3), 2.82 (t, J = 7.2 Hz,
2H, CH2 SO3), 1.67–1.69 (m, 4H, C2H4 CH2SO3), 1.10–1.12 (m, 9H, CH3). 13
C
NMR (D2O,): δ = 56.2, 52.9, 50.3, 21.5, 20.2, 6.9. Anal. Calcd. For C10H25NO7S2: C,
35.78; H, 7.51; N, 4.18; Found: C, 35.82; H, 7.53; N, 4.36.
General Procedure for the Synthesis of α-Aminophosphonates
In a typical experiment, to a round-bottomed flask charged with aldehyde (10 mmol)
and aniline (10 mmol) in water (5 mL), TSILs (0.5 mmol) were added under stirring.
The mixture was stirred at room temperature for 5 min, and then trimethyl phosphite (12
mmol) was added. Upon completion (monitored by TLC), the products were separated by
filtration and dried under vacuum. The TSILs could be separated from the reaction mixture
by extraction with water. The products were identified by 1H NMR and physical data (mp)
and compared with authentic characterized samples as given in Table II.
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