Highly efficient one-pot synthesis of α-aminophosphonates catalyzed by ytterbium triflate in water

Article abstract of DOI:10.1080/00397911.2013.806669

A facile one-pot, three-component synthesis of α-aminophosphonates catalyzed by ytterbium triflate [Yb(OTf)₃] in water using polyoxyethanyl α-tocopheryl sebacate (PTS) as amphiphile has been developed. The catalytic system could be readily recycled and reused several times without significant loss in its activity.

Full text of DOI:10.1080/00397911.2013.806669

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Highly Efficient One-Pot Synthesis of
α-Aminophosphonates Catalyzed by
Ytterbium Triflate in Water
MingGui Shen a b , ShiBin Shang a b , ZhanQian Song a b , Dan Wang a b
, XiaoPing Rao a b , Hong Gao a b & Juan Wang a b
a Institute of Chemical Industry of Forest Products, National
Engineering Laboratory for Biomass Chemical Utilization, Key and
Open Laboratory on Forest Chemical Engineering, Key Laboratory of
Biomass Energy and Material, Jiangsu Province , Nanjing , China
b Institute of New Technology of Forestry , Beijing , China
Published online: 20 Nov 2013.
To cite this article: MingGui Shen , ShiBin Shang , ZhanQian Song , Dan Wang , XiaoPing Rao , Hong
Gao & Juan Wang (2014) Highly Efficient One-Pot Synthesis of α-Aminophosphonates Catalyzed
by Ytterbium Triflate in Water, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 44:3, 361-367, DOI: 10.1080/00397911.2013.806669
To link to this article: http://dx.doi.org/10.1080/00397911.2013.806669
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Synthetic Communications1, 44: 361–367, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.806669
HIGHLY EFFICIENT ONE-POT SYNTHESIS OF
a-AMINOPHOSPHONATES CATALYZED BY
YTTERBIUM TRIFLATE IN WATER
MingGui Shen,1,2 ShiBin Shang,1,2 ZhanQian Song,1,2
Dan Wang,1,2 XiaoPing Rao,1,2 Hong Gao,1,2 and
Juan Wang1,2
1Institute of Chemical Industry of Forest Products, National Engineering
Laboratory for Biomass Chemical Utilization, Key and Open Laboratory on
Forest Chemical Engineering, Key Laboratory of Biomass Energy and
Material, Jiangsu Province, Nanjing, China
2Institute of New Technology of Forestry, Beijing, China
GRAPHICAL ABSTRACT
Abstract A facile one-pot, three-component synthesis of a -aminophosphonates catalyzed by
ytterbium triflate [Yb(OTf)3] in water using polyoxyethanyl a -tocopheryl sebacate
(PTS) as amphiphile has been developed. The catalytic system could be readily recycled
and reused several times without significant loss in its activity.
Keywords a-Aminophosphonates; micellar catalysis; one-pot; ytterbium triflate
INTRODUCTION
a-Aminophosphonates and their derivatives are attractive synthetic targets
because of their considerable potential application in medicinal and bioorganic
chemistry. They have been widely reported as enzyme inhibitors, antibiotics, peptide
mimics, herbicides, and pharmacological agents, and many other applications have
also been well documented.[1–5]
Recently, various synthetic methods for preparation of a-aminophosphonates
have been reported. Among them, three-component condensation of an amine, alde-
hyde, and diethylphosphite or triethylphosphite is the most common and convenient
Received March 7, 2013.
Address correspondence to ShiBin Shang, Institute of New Technology of Forestry, CAF, Beijing
100091, China. E-mail: shenminggui@sina.com; shangsb@163.com
361

362
M.-G. SHEN ET AL.
Scheme 1. Yb(OTf)3 catalyzes the one-pot synthesis of a-aminophosphonates in water.
way to construct such a significant scaffold. Various catalysts including bases and
Lewis acids have been reported to catalyze the reaction successfully.[6–15] In addition,
reactions under neat conditions[16–21] or in water[22–24] also smoothly provide the
target compounds in good yields. While acknowledging the pioneering work in this
field, some drawbacks remain. For example, some Lewis acids such as AlCl3,[25]
SnCl4,[26] BF3 ꢀ OEt2,[27] etc. were sensitive to the water generated during the forma-
tion of imines, leading to deactivation of the catalysts. Other procedures also suffered
from drawbacks of the use of organic solvents, long reaction times, difficulties in
workup procedures, and relatively poor yields. Thus, simple and convenient methods
for the preparation of a-aminophosphonates under mild conditions in environmen-
tally benign solvents are highly desirable.
Because its high reactivity, easy handling, and inertness toward air and water,
Yb(OTf)3 has been widely employed as an efficient Lewis acid catalyst in organic trans-
formations.[14,28,29] Qian et al. also realized the one-pot synthesis of a-aminophospho-
nates using Yb(OTf)3 as catalyst, however, in dichloromethane.[30] Recently, reactions
in aqueous media or ‘‘on water’’[31] have gained wide interest because water is inexpen-
sive, nontoxic, and safe with respect to handling. However, reactions ‘‘in water’’ have
been extremely limited because of the insolubility of organic substrates. Just recently,
polyoxyethanyl a-tocopheryl sebacate (PTS, Scheme 1), a nonionic amphiphile, has
been introduced by Lipshutz’s group and proved to be a versatile ‘‘solubilizer’’ for
organic molecules in water, leading to a series of reactions at room temperature.[32–36]
Importantly, there is no need for a cosolvent to enhance the solubility of water-insoluble
substrates in these reactions. Herein, in continuation of our interest in green synthetic
methods, we report a facile, one-pot synthesis of a-aminophosphonates catalyzed by
Yb(OTf)3 in water at room temperature (Scheme 1).
RESULTS AND DISCUSSION
The three-component reaction of benzaldehyde 1a, aniline 2a, and diethyl phos-
phite 3 was selected as a model reaction to optimize the reaction conditions. Initially,
the influence of various solvents on the reaction was investigated, and the results are
summarized in Table 1. The reaction proceeded in ethanol and acetonitrile smoothly
to give the corresponding product 4a in 72 and 70% yield, respectively. Other solvents
such as toluene, ethyl acetate, tetrahydrofuran, and dichloromethane were less

a-AMINOPHOSPHONATES IN WATER
363
Table 1. Influence of the solvent on synthesis of a -aminophosphonate 4aa
Entry
Solvent
Ethanol
Additive
Yield (%)b
1
2
—
—
72
70
38
40
52
50
32
95
95
78
70
63
84
Acetonitrile
Toluene
3
—
—
4
Ethyl acetate
Tetrahydrofuran
Dichloromethane
Water
5
—
—
6
7
—
PTS
PTSc
8
Water
Water
9
10
11
12
13
Water
Water
Triton X-100d
SDSd
TBABd
—
Water
Solvent-free
aReaction conditions: benzaldehyde (1 mmol), aniline (1 mmol), diethyl phosphite (1.2 mmol), Yb(OTf)3
(1 mol%), solvent (2 mL), additive (2 wt%), room temperature, 1 h.
bIsolated yields.
c5 wt% of PTS was used.
dTriton X-100 is polyethylene glycol octylphenol ether; SDS is sodium dodecyl sulfate; TBAB is
tetrabutylammonium bromide.
efficient and relatively lower yields were obtained (Table 1, entries 3–6). In addition,
the reaction ‘‘on water’’ gave the lowest level of conversion (Table 1, entry 7). It was
worth noting that addition of PTS in water could effectively promote the reaction and
2 wt% of PTS was sufficient (Table 1, entries 8 and 9). Other surfactants including
Triton X-100, sodium dodecyl sulfate (SDS), and tetrabutylammonium bronide
(TBAB) were also examined; however, they were not as effective as PTS. The reaction
under solvent-free condition was also examined and 84% yield of product was
obtained (Table 1, entry 13).
Next, various catalysts were evaluated (Table 2). Trace product was found in the
absence of any catalyst. To our delight, 10 mol% of Yb(OTf)3 provided the product 4a
in 98% yield within 1 h. The yield was not obviously changed when the amount of
Yb(OTf)3 was reduced to 1 mol% (Table 2, entry 4). Other rare-earth metal salts as
well as metal triflates gave the desired product in moderate to good yields (Table 2,
entries 5–11).
To establish the generality, the reaction of various aldehydes and amines with
diethyl phosphite in the presence of 1 mol% of Yb(OTf)3 in PTS=H2O were investi-
gated. The results are shown in Table 3. It was found that both electron-donating
and electron-withdrawing substitutions of aromatic amines provided excellent
yields, showing negligible influences on the reactions. Meanwhile, different aromatic
aldehydes also provided products in good to excellent yields, whereas aliphatic

364
M.-G. SHEN ET AL.
Table 2. Effect of catalyst on the synthesis of a -aminophosphonate 4aa
Entry
Catalyst
Amount of catalyst (mol%)
Yield (%)b
1
2
—
—
10
5
trace
98
95
95
56
90
83
70
72
76
65
Yb(OTf)3
Yb(OTf)3
Yb(OTf)3
YbCl3
3
4
1
5
1
6
Yb(PFO)3
Sc(OTf)3
Hf(OTf)4
Sn(OTf)4
Zn(OTf)2
Cu(OTf)2
1
7
1
8
1
9
1
10
11
1
1
aReaction conditions: benzaldehyde (1 mmol), aniline (1 mmol), diethyl
phosphite (1.2 mmol), 2% PTS=H2O (2 mL), room temperature, 1 h.
bIsolated yields.
aldehydes afforded phosphonates in moderate yield (56%), even with a prolonged
reaction time (Table 3, entry 15). The heterocyclic aldehyde such as furfuraldehyde
also survived the reaction conditions, affording the product in 83% yield (Table 3,
entry 14).
Table 3. Synthesis of 4a–o in the presence of 1 mol% of Yb(OTf)3 in watera
Entry
R1
R2
Product
Yield (%)b
1
2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
95
94
92
84
86
85
89
83
96
90
91
86
92
83
56c
4-CH3C6H4
4-OCH3C6H4
4-NO2C6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
Ph
3
4
5
6
7
4g
4h
4i
8
9
4-NO2C6H4
2-NO2C6H4
4-ClC6H4
10
11
12
13
14
15
Ph
Ph
4j
4k
4l
4-OCH3C6H4
4-CH3C6H4
Furfuryl
Ph
Ph
4m
4n
4o
Ph
Ph
(CH3)2CH-
aReaction conditions: aldehyde (1 mmol), primary amine (1 mmol), diethyl phosphite (1.2 mmol),
Yb(OTf)3 (1 mol%), 2% PTS=H2O (2 mL), room temperature, 1 h.
bIsolated yields.
c5 mol% catalyst was used.

a-AMINOPHOSPHONATES IN WATER
365
Figure 1. Recycling of the catalytic system. (Figure is provided in color online.)
Another advantage of this protocol is the recyclability of the aqueous phase as
a result of the preferred solubility of PTS in water, as opposed to common organic
solvents (e.g., hydrocarbons, Et2O, and EtOAc). The reaction of benzaldehyde,
aniline, and diethyl phosphite was carried out under the optimized conditions for
1 h, followed by extraction with minimal amounts of EtOAc several times. After that,
the catalyst stayed in the aqueous phase, and fresh substrates were introduced into the
aqueous phase again. As illustrated in Fig. 1, almost the same yield could be realized
within five runs. However, a decreased yield was found in the sixth run. This is may be
due to the loss of catalyst in the aqueous micelles during the workup in each run.
CONCLUSION
In summary, a highly efficient protocol for one-pot reaction of aldehydes,
amines, and diethyl phosphite to afford a -aminophosphonates in good to excellent
yields with only 1 mol% of Yb(OTf)3 in water has been developed. The procedure
has many advantages such as short reaction time, small amount of catalyst, and
environmentally benign and recyclable reaction medium, which provide a green
and efficient method for synthesis of a-aminophosphonates.
EXPERIMENTAL
All reagents were obtained from local commercial suppliers and used without
further purification. Melting points were determined with a WRS-1B apparatus and
were uncorrected. 1H and13C NMR spectra were recorded on a Bruker Advance 400
analyzer. All the products are known compounds and were identified by comparing
of their physical and spectra data with those reported in the literature.
General Procedure for Synthesis of a-Aminophosphonates
A mixture of aldehyde (1 mmol), amine (1 mmol), diethyl phosphite (1.2 mmol),
and ytterbium triflate (1 mol%) in degassed PTS solution (2 mL, 2 wt%) was stirred
under air. After completion of the reaction as monitored by TLC, ethyl acetate
(5 ml) was then added to the reaction mixture and stirred for 30 s. The reaction
mixture was then allowed to separate and the ethyl acetate layer was removed by

366
M.-G. SHEN ET AL.
pipet. The aqueous layer was successively washed with ethyl acetate (3 ꢁ 5 mL). The
combined ethyl acetate extracts layers were dried over anhydrous Na2SO4, filtered,
concentrated by rotary evaporation, and purified by silica-gel chromatography. All
the products were characterized by spectral methods as well as by comparison of their
spectral data with those reported earlier.[12,13,30]
Diethyl (Phenyl)(phenylamino)methylphosphonate (4a)
White solid; mp: 91–93 ꢂC [.30] 1H NMR (400 MHz, CDCl3) d 1.13 (t, J ¼ 6.8 Hz,
3H), 1.30 (t, J ¼ 6.8 Hz, 3H), 3.66–3.75 (m, 1H), 3.91–4.00 (m, 1H), 4.06–4.21 (m, 2H),
4.80 (d, J ¼ 24.4 Hz, 1H), 4.87 (br, s, 1H), 6.62 (d, J ¼ 8.4 Hz, 2H), 6.70 (t, J ¼ 6.8 Hz,
1H), 7.11 (t, J ¼ 7.6 Hz, 2H), 7.27–7.36 (m, 3H), 7.50 (d, J ¼ 7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 146.39, 146.25, 135.92, 129.17, 128.61, 128.58, 127.94, 127.88,
118.40, 113.86, 63.32, 63.29, 63.26, 63.22, 56.83, 55.33, 16.46, 16.40, 16.21, 16.16.
Recycling of the Catalyst
After completion of the reaction, the mixture was extracted by ethyl acetate
(3 ꢁ 5 mL). The organic layer was separated from the aqueous layer by pipet. The
remaining ethyl acetate in the micellar solution was removed in vacuo. For the second
run, fresh starting materials were added to the aqueous solution, and the reaction was
conducted as described for the initial run.
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