A Simple and Green Procedure for the One-Pot Synthesis of α-Aminophosphonates with Quaternary Ammonium Salts as Efficient and Recyclable Reaction Media

Article abstract of DOI:10.1055/s-0034-1380523

A simple and highly efficient approach has been developed for a multicomponent one-pot reaction of aldehydes or ketones with amines and diethyl or triethyl phosphite to give the corresponding α-aminophosphonates. In the presence of quaternary ammonium salts, which are environmental friendly, inexpensive, and recyclable, α-aminophosphonates were obtained in excellent yields at room temperature within short times.

Full text of DOI:10.1055/s-0034-1380523

SYNTHESIS
0
0
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7
8
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1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1869–1876
paper
1869
Y.-Q. Yu, D.-Z. Xu
Paper
Synthesis
A Simple and Green Procedure for the One-Pot Synthesis of
α-Aminophosphonates with Quaternary Ammonium Salts as
Efficient and Recyclable Reaction Media
Ya-Qin Yua
Da-Zhen Xu*b
OEt
OEt
O
P
P
OEt
EtO
OEt
NH2
R1
R2
a Key Laboratory for Water Environment and Resources, Tianjin Normal
University, Tianjin 300387, P. R. of China
b National Pesticide Engineering Research Center (Tianjin), Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), Nankai
University, Tianjin 300071, P. R. of China
O
QASs
r.t.
NH
or
+
+
R1
R2
R
OEt
R
H
P
xudazhen@nankai.edu.cn
OEt
Received: 29.01.2015
Accepted after revision: 12.03.2015
Published online: 09.04.2015
sult, the development of a simple, efficient, and green pro-
cedure for one-pot synthesis of α-aminophosphonate in ex-
cellent yields from a broad range of carbonyl compounds
remains a major challenge in synthetic organic chemistry.
Multicomponent reactions (MCRs) are highly important
reactions that are widely used in pharmaceutical chemistry
for the production of structural scaffolds or combinatorial
libraries for drug discovery.16 MCRs provide powerful meth-
ods for obtaining complex structures from simple precur-
sors by one-pot procedures.17 Ionic liquids (ILs), acting as
homogeneous catalysts, can be easily separated from reac-
tion mixtures for reuse, and have consequently attracted
significant attention as environmentally benign media for
organic synthesis and catalytic reactions.18 There have been
many reports of the successful use of functionalized ILs as
catalysts in various reactions, such as Michael reactions,19
aldol reactions,20 Mannich reactions,21 Friedel–Crafts reac-
tions,22 or Henry reactions.23
We have designed a series of IL catalysts based on the
1,4-diazabicyclo[2.2.2]octane (DABCO) skeleton, and have
shown them to be very effective catalysts for Michael addi-
tion reactions24 and for Knoevenagel condensations.25 Re-
cently, other types of functionalized ILs based on DABCO
have been designed and used in various reactions.26 As part
of our continuing interest in IL-mediated organic reactions,
we report on our study of the use of quaternary ammonium
salts base on DABCO as media for a multicomponent
Kabachnik–Fields reaction of various aldehydes or ketones
with amines and diethyl or triethyl phosphite to give the
corresponding α-aminophosphonates.
DOI: 10.1055/s-0034-1380523; Art ID: ss-2015-h0067-op
Abstract A simple and highly efficient approach has been developed
for a multicomponent one-pot reaction of aldehydes or ketones with
amines and diethyl or triethyl phosphite to give the corresponding α-
aminophosphonates. In the presence of quaternary ammonium salts,
which are environmental friendly, inexpensive, and recyclable, α-ami-
nophosphonates were obtained in excellent yields at room temperature
within short times.
Key words aminophosphonates, multicomponent reactions, quater-
nary ammonium salts, green chemistry, phosphorylations
α-Aminophosphonates, an important class of organo-
phosphorus compounds, have attracted considerable atten-
tion because of their wide range of applications in biologi-
cal and medicinal chemistry.1–8 Various synthetic methods
have been developed for the preparation of α-aminophos-
phonates.9 Of these methods, the multicomponent Kabachnik–
Fields reaction, which uses an aldehyde, an amine, and a di-
alkyl or trialkyl phosphite as substrates, is one of the most
efficient for the synthesis of α-aminophosphonates.10 The
transformations can be catalyzed by various acids, hetero-
geneous catalysts, or nanocatalysts.11–13 Although some sig-
nificant advances have been made, the reaction retains
some drawbacks, such as inconvenient synthetic proce-
dures, long reaction times, elevated temperatures, and ex-
pensive and moisture-sensitive catalysts. Typically, when
Lewis acid catalysts such as zinc(II) chloride14 are used, it is
necessary to ensure the exclusion of water; furthermore,
these catalysts cannot be reused because of the water that
is formed by condensation of the amine with the carbonyl
compound. In most cases, the range of carbonyl compounds
is limited to aldehydes, and few examples have used ke-
tones at room temperature with excellent yields.15 As a re-
The quaternary ammonium salts 1,4-diazabicyc-
lo[2.2.2]octane hydroacetate ([H-DABCO][AcO]), hydro-
tetrafluoroborate ([H-DABCO][BF4]), and hydrochloride ([H-
DABCO]Cl) and 1-butyl-1,4-diazabicyclo[2.2.2]octanylium
bromide ([C4-DABCO]Br) (Figure 1) were synthesized by the
reported methods.25
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1870
Y.-Q. Yu, D.-Z. Xu
Paper
Synthesis
3a was obtained in 97% when two equivalents of methanol
were added (entry 7). Other DABCO-based quaternary am-
monium salts were also tested in the reaction under the
same conditions (entries 8–10). We were pleased to ob-
serve that 3a was obtained in near-quantitative yield in the
presence of [H-DABCO]Cl within 30 minutes (entry 9). To
confirm the efficient of [H-DABCO]Cl, other ILs and quater-
nary ammonium salts, such as 1-butyl-3-methylimidazoli-
um tetrafluoroborate, hexadecyl(trimethyl)ammonium
chloride, and triethylamine hydrochloride, were also inves-
tigated; however, only low to moderate yields were ob-
tained (entries 11–13).
Having optimized the conditions, we next explored the
generality of this method by studying the reactions of aro-
matic aldehydes 1, aromatic amines 2, and triethyl phos-
phite in the presence of the quaternary ammonium salt [H-
DABCO]Cl as a reaction medium at room temperature. The
results are summarized in Table 2. Both aromatic aldehydes
and amines with electron-withdrawing groups or electron-
R
X
N
N
[H-DABCO][AcO], X = AcO, R = H
[H-DABCO][BF4], X = BF4, R = H
[H-DABCO]Cl, X = Cl, R = H
[C4-DABCO]Br, X = Br, R = n-Bu
Figure 1 Structures of the DABCO-based quaternary ammonium salts.
With the quaternary ammonium salts in hand, we set
out to optimize the conditions for the multicomponent re-
action of benzaldehyde (1.0 mmol), 4-methoxyaniline (1.0
mmol), and trimethyl phosphite (2 mmol) at room tem-
perature (Table 1). The yields of the α-aminophosphonate
3a differed significantly when the quaternary ammonium
salt [H-DABCO][AcO] was used with various solvents. When
organic solvents such as tetrahydrofuran, dichloromethane,
toluene, or acetonitrile were used, 3a was obtained in poor
to moderate yields (Table 1, entries 1–4). The strongly polar
solvents ethanol and methanol gave fairly good yields in
shorter times (entries 5 and 6); the α-aminophosphonate
Table 2 Scope of the Multicomponent Condensation Reactions of
Aromatic Aldehydes, Aromatic Amines, and Triethyl Phosphitea
Table 1 Optimization of the Conditions for the Condensation of Benz-
OEt
O
aldehyde, 4-Methoxyaniline, and Triethyl Phosphitea
P
OEt
NH2
OEt
O
[H-DABCO]Cl
OEt
P
Ar
NH
+
+
Ar CHO
P
OEt
NH2
R
MeOH
(2 equiv)
r.t.
EtO
OEt
1
CHO
OEt
P
R
catalyst
NH
+
+
2
co-solvent
OEt
EtO
3
1a
OMe
Entry
Ar
R
Product Time (min) Yieldb (%)
2a
OMe
1
2
Ph
Ph
Ph
Ph
Ph
Ph
4-MeO
H
3a
3b
3c
3d
3e
3f
30
10
10
100
3
98
96
97
93
98
98
95
95
98
95
91
90
98
97
96
91
98
3a
Entry Catalyst
Solvent
Time (h)
Yieldb (%)
3
4-F
1
2
[H-DABCO][AcO]
[H-DABCO][AcO]
[H-DABCO][AcO]
[H-DABCO][AcO]
[H-DABCO][AcO]
[H-DABCO][AcO]
[H-DABCO][AcO]
[H-DABCO][BF4]
[H-DABCO]Cl
THF
48
48
48
48
24
12
7
17
40
35
53
85
94
97
98
98
10
53
15
44
4
4-Cl
4-Br
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Cl
H
CH2Cl2
toluene
MeCN
EtOH
5
3
6
25
30
40
40
60
60
120
8
4
7
4-ClC6H4
3g
3h
3i
5
8
4-MeOC6H4
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-ClC6H4
6
MeOH
MeOHc
MeOHc
MeOHc
MeOHc
MeOHc
MeOHc
MeOHc
9
7
10
11
12
13
14
15
16
17
3j
8
8
3k
3l
9
0.5
10
11
12
13
[C4-DABCO]Br
24
24
24
24
3m
3n
3o
3p
3q
[Bmim][BF4]d
H
20
30
120
20
[Me(CH2)15N+Me3]Cl–
[Et3N+H]Cl–
4-MeOC6H4
2-thienyl
H
H
a Reaction conditions: aldehyde (1 mmol), amine (1 mmol), P(OEt)3 (2
mmol), solvent (1 mL), catalyst (1 mmol), r.t.
b Isolated yield.
2-furyl
H
a Reaction conditions: aldehyde (1 mmol), amine (1 mmol), P(OEt)3 (2
mmol), [H-DABCO]Cl (1 mmol), r.t.
c MeOH (2 equiv) was used.
b Isolated yield.
d 1-Butyl-3-methylimidazolium tetrafluoroborate.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1869–1876

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Y.-Q. Yu, D.-Z. Xu
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Synthesis
donating groups were converted into the corresponding α-
aminophosphonates in good to excellent yields (90–98%)
within three minutes to two hours. The α-aminophospho-
nate products were obtained in higher yields when benzal-
dehyde was used as a substrate in the reaction than when
substituted aromatic aldehydes were used (Table 2, entries
4 and 6–12). In reactions with the same aromatic amine,
para-substituted aromatic aldehydes needed shorter reac-
tion times and gave higher yields of the corresponding α-
aminophosphonates than did substrates with ortho- or
meta-substituents (entries 9–11). Hetaromatic aldehydes,
such as thiophene-2-carbaldehyde or furan-2-carbalde-
hyde were also effective substrates for the Kabachnik–
Fields reactions in [H-DABCO]Cl (entries 16 and 17).
Other carbonyl compounds, such as aliphatic aldehydes
and cyclic/acyclic ketones were also found to be compatible
with [H-DABCO]Cl and gave the corresponding α-amino-
phosphonates under the optimized conditions (Table 3).
These carbonyl compounds smoothly gave the expected α-
aminophosphonates in acceptable yields (Table 3, entries
1–4); however, little product was obtained in the case of an
aromatic ketone (entry 5).
OEt
O
NH2
P
OEt
CHO
O
P
[H-DABCO]Cl
OEt
OEt
NH
+
R +
H
MeOH
(2 equiv)
r.t.
1a
2
R
3
OEt
OEt
OEt
OEt
P OEt
O
O
P
O
P
OEt
NH
NH
NH
OMe
F
Me
3a 90%
3c 91%
3f 93%
Scheme 1 Synthesis of α-aminophosphonates from diethyl phosphite
adds to the C=N bond of the imine to give a phosphonium
intermediate that reacts with water to give the correspond-
ing α-aminophosphonates 3a and ethanol.
Table 3 Multicomponent Condensations of Various Carbonyl Com-
OMe
H
O
N
N
pounds, Aromatic Amines, and Triethyl Phosphitea
N
N
H
N
OEt
O
H2N
OMe
P
OEt
OEt
OEt
OEt
H
NH2
••
– H2O
O
R1
P
OEt
P
[H-DABCO]Cl
NH
+
+
R3
R2
R1
R2
MeOH
(2 equiv)
r.t.
EtO
OEt
1
H2O
R3
2
OMe
OMe
3
Entry R1
R2
R3
4-Cl
Product Time (h) Yieldb (%)
HN
HN
O
OH
1
2
3
4
5
i-Pr
H
3r
3s
3t
3u
3v
1
5
94
74
90
62
<5
P
O Et
P
OEt
EtO
EtOH
(CH2)8Me
(CH2)5
Et
H
H
EtO
OEt
4-Cl
H
3
Scheme 2 Proposed mechanism for the three-component reaction
Et
12
12
Ph
Me
H
The recyclability and reusability of the quaternary am-
monium salt [H-DABCO]Cl were examined for the reaction
of benzaldehyde, aniline, and triethyl phosphite under the
standard reaction conditions. When the reaction was com-
plete, the mixture was concentrated and the residue was
extracted three times with ethyl acetate. Removal of the
solvent and purification by column chromatography gave
the product 3a. The residual quaternary ammonium salt
[H-DABCO]Cl was treated with hydrochloric acid, more wa-
ter was evaporated from the salt under vacuum, and the
salt was reused in the same reaction with fresh reactants
under similar conditions. The salt [H-DABCO]Cl could be
used at least seven times without any significant change in
reactivity (Figure 2).
a Reaction conditions: carbonyl compound (1 mmol), amine (1 mmol),
P(OEt)3 (2 mmol), [H-DABCO]Cl (1 mmol), r.t.
b Isolated yield.
The α-aminophosphonates could be also prepared from
diethyl phosphite instead of triethyl phosphite, under the
same conditions. At room temperature, products 3a, 3c, and
3f were obtained in yields of 90%, 91%, and 93%, respective-
ly (Scheme 1).
A reasonable pathway for the reaction of an aldehyde
with an amine and triethyl phosphite conducted in the
presence of [H-DABCO]Cl is presented in Scheme 2. In the
first stage of this reaction, an activated imine is formed
from benzaldehyde and 4-methoxyaniline. Phosphite then
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1869–1876

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Y.-Q. Yu, D.-Z. Xu
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Synthesis
Diethyl {[(4-Methoxyphenyl)amino](phenyl)methyl}phosphonate
(3a)27
White solid; yield: 342 mg (98%); mp 79–80 °C.
1H NMR (400 MHz, CDCl3): δ = 1.08 (t, J = 7.2 Hz, 3 H), 1.25 (t, J = 7.2
Hz, 3 H), 3.62 (s, 3 H), 3.64–3.72 (m, 1 H), 3.87–3.96 (m, 1 H), 4.05–
4.15 (m, 2 H), 4.56 (br s, 1 H), 4.70 (d, J = 24.0 Hz, 1 H), 6.54 (d, J = 9.2
Hz, 2 H), 6.66 (d, J = 8.8 Hz, 2 H), 7.20–7.24 (m, 1 H), 7.29 (t, J = 7.6 Hz,
2 H), 7.46 (d, J = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 16.20 (d, 3JCP = 5.7 Hz), 16.44 (d, 3JCP
=
5.7 Hz), 56.54, 56.93 (d, JCP = 149.7 Hz), 63.18 (d, 2JCP = 7.4 Hz), 63.25
2
(d, JCP = 7.2 Hz), 114.69, 115.21, 127.90, 127.96, 128.53, 136.11,
140.47, 152.61.
31P NMR (162 MHz, CDCl3): δ = 22.90.
Diethyl [Anilino(phenyl)methyl]phosphonate (3b)27
White solid; yield: 306 mg (96%); mp 90–92 °C.
1H NMR(400 MHz, CDCl3): δ = 1.10 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2
Hz, 3 H), 3.61–3.71 (m, 1 H), 3.88–3.96 (m, 1 H), 4.05–4.16 (m, 2 H),
4.76 (d, J = 24.0 Hz, 1 H), 4.79 (br s, 1 H), 6.59 (d, J = 8.0 Hz, 2 H), 6.68
(t, J = 7.2 Hz, 1 H), 7.09 (t, J = 8.0 Hz, 2 H), 7.25–7.27 (m, 1 H), 7.32 (t,
J = 7.6 Hz, 2 H), 7.47 (d, J = 7.6 Hz, 2 H).
Figure 2 Recycling of the quaternary ammonium salt [H-DABCO]Cl in
the synthesis of 3a
In summary, we have shown that readily available and
cheap DABCO-based quaternary ammonium salts can be
use as reaction media for the multicomponent one-pot
Kabachnik–Fields reaction of a wide range of carbonyl com-
pounds (aromatic, heterocyclic, or aliphatic aldehydes and
cyclic or acyclic ketones). The procedure offers several ad-
vantages, including short reaction times, mild reaction con-
ditions, excellent yields, and easy workup procedures. The
quaternary ammonium salt [H-DABCO]Cl can be easily re-
covered and reused at least seven times without loss of ac-
tivity. In addition, either triethyl phosphite or diethyl phos-
phite can be used to carry out the condensation. We believe
that this method is a useful addition to the available meth-
ods for the syntheses of α-aminophosphonates.
13C NMR (100 MHz, CDCl3): δ = 16.41 (d, 3JCP = 5.5 Hz), 16.65 (d, 3JCP
=
5.5 Hz), 56.29 (d, JCP = 149.3 Hz), 63.49, 114.06, 118.60, 128.03,
128.09, 128.80, 129.38, 136.10, 146.44, 146.58.
31P NMR (162 MHz, CDCl3): δ = 23.79.
Diethyl {[(4-Fluorophenyl)amino](phenyl)methyl}phosphonate
(3c)27
White solid; yield: 327 mg (97%); mp 110–111 °C.
1H NMR (400 MHz, CDCl3): δ = 1.07 (t, J = 7.2 Hz, 3 H), 1.25 (t, J = 6.8
Hz, 3 H), 3.60–3.71 (m, 1 H), 3.86–3.96 (m, 1 H), 4.07–4.17 (m, 2 H),
4.72 (d, J = 24.0 Hz, 1 H), 5.02 (br s, 1 H), 6.53–6.56 (m, 2 H), 6.76 (t, J =
8.8 Hz, 2 H), 7.22 (t, J = 7.6 Hz, 1 H), 7.29 (t, J = 7.2 Hz, 2 H), 7.46–7.48
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 16.14 (d, 3JCP = 6.0 Hz), 16.39 (d, 3JCP
=
=
5.9 Hz), 56.58 (d, JCP = 150.0 Hz), 63.26 (d, 2JCP = 6.4 Hz), 63.32 (d, 2JCP
6.4 Hz), 114.84, 115.41, 115.63, 127.98, 128.56, 135.80, 142.72,
142.87, 156.13 (d, JCF = 234.5 Hz).
31P NMR (162 MHz, CDCl3): δ = 22.61.
All chemicals were purchased from commercial suppliers and were
used without further purification. Flash column chromatography was
performed on silica gel (200–300 mesh). Melting points were deter-
mined with an X-4 apparatus and are uncorrected. 1H, 13C, and 31P
NMR spectra were recorded on a Bruker AV-400 spectrometer with
CDCl3 as the solvent. Chemical shifts are reported relative to TMS as
internal standard.
Diethyl {[(4-Chlorophenyl)amino](phenyl)methyl}phosphonate
(3d)28
White solid; yield: 329 mg (93%); mp 118–120 °C.
1H NMR (400 MHz, CDCl3,): δ = 1.09 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2
Hz, 3 H), 3.59–3.68 (m, 1 H), 3.86–3.96 (m, 1 H), 4.05–4.16 (m, 2 H),
4.68 (d, J = 24.0 Hz, 1 H), 6.49 (d, J = 9.2 Hz, 2 H), 7.02 (d, J = 8.8 Hz, 2
H), 7.25–7.28 (m, 1 H), 7.32 (t, J = 7.2 Hz, 2 H), 7.42–7.44 (m, 3 H).
α-Phosphonomalonates 3a–u; General Procedure
A 5 mL round-bottomed flask was charged with the carbonyl com-
pound 1 (1.0 mmol), aromatic amine 2 (1 mmol), P(OEt)3 (2 mmol),
[H-DABCO]Cl (1 mmol), and MeOH (2.0 mmol), and the mixture was
stirred at r.t. When the reaction was complete (TLC), the mixture was
concentrated and the residue was extracted with EtOAc (3 × 2 mL).
The combined extracts were washed with brine (3 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was purified by col-
umn chromatography [silica gel, PE–EtOAc (1:1)].
13C NMR (100 MHz, CDCl3): δ = 16.40 (d, 3JCP = 5.7 Hz), 16.39 (d, 3JCP
=
=
5.6 Hz), 56.40 (d, JCP = 149.5 Hz), 63.47 (d, 2JCP = 6.4 Hz), 63.62 (d, 2JCP
6.8 Hz), 115.21, 123.27, 128.03, 128.28, 128.89, 129.22, 135.63,
145.01.
31P NMR (162 MHz, CDCl3,): δ = 23.43.
The residual quaternary ammonium salt [H-DABCO]Cl was treated
with 5 M HCl, more H2O was evaporated from the salt under vacuum,
and the salt was reused in the next recycling run. [H-DABCO]Cl could
be recovered and reused in this reaction at least seven times.
Diethyl {[(4-Bromophenyl)amino](phenyl)methyl}phosphonate
(3e)9l
White solid; yield: 390 mg (98%); mp 121–122 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1869–1876

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Y.-Q. Yu, D.-Z. Xu
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.06 (t, J = 7.2 Hz, 3 H), 1.24 (t, J = 7.2
Hz, 3 H), 3.58–3.68 (m, 1 H), 3.85–3.94 (m, 1 H), 4.07–4.19 (m, 2 H),
4.74 (d, J = 24.4 Hz, 1 H), 5.54 (br s, 1 H), 6.51 (d, J = 8.8 Hz, 2 H), 7.12
(d, J = 8.8 Hz, 2 H), 7.19–7.23 (m, 1 H), 7.27 (t, J = 7.2 Hz, 2 H), 7.47 (d,
J = 6.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 1.16 (t, J = 7.2 Hz, 3 H), 1.29 (t, J = 7.2
Hz, 3 H), 2.17 (s, 3 H), 3.82–3.92 (m, 1 H), 3.98–4.06 (m, 1 H), 4.10–
4.18 (m, 2 H), 4.58 (br, s, 1 H), 4.82 (d, J = 25.2 Hz, 1 H), 6.44 (d, J = 8.4
Hz, 2 H), 6.90 (d, J = 8.0 Hz, 2 H), 7.64 (d, J = 8.8 Hz, 2 H), 8.17 (d, J = 8.4
Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 16.24 (d, 3JCP = 5.9 Hz), 16.50 (d, 3JCP
=
=
13C NMR (100 MHz, CDCl3): δ = 16.47 (d, 3JCP = 5.4 Hz), 16.64 (d, 3JCP
5.4 Hz), 56.32 (d, JCP = 147.3 Hz), 63.62 (d, 2JCP = 7.0 Hz), 63.94 (d, 2JCP
6.7 Hz), 114.16, 123.95, 128.89, 130.05, 143.38, 144.42, 147.79.
=
=
5.5 Hz), 56.92 (d, JCP = 150.4 Hz), 63.30 (d, 2JCP = 7.4 Hz), 63.36 (d, 2JCP
8.0 Hz), 109.75, 115.50, 128.02, 128.62, 131.76, 135.65, 145.66,
145.81.
31P NMR (162 MHz, CDCl3): δ = 22.35
31P NMR (162 MHz, CDCl3): δ = 21.99.
Diethyl {(3-Nitrophenyl)[(4-tolyl)amino]methyl}phosphonate
(3j)9j
Diethyl {Phenyl[(4-tolyl)amino]methyl}phosphonate (3f)28
White solid; yield: 327 mg (98%); mp 119–120 °C.
Yellow solid; yield: 359 mg (95%); mp 102–103 °C.
1H NMR (400 MHz, CDCl3): δ = 1.10 (t, J = 7.2 Hz, 3 H), 1.27 (t, J = 7.2
Hz, 3 H), 2.17 (s, 3 H), 3.62–7.32 (m, 1 H), 3.88–3.98 (m, 1 H), 4.05–
4.16 (m, 2 H), 4.58 (br s, 1 H), 4.73 (d, J = 24.4 Hz, 1 H), 6.50 (d, J = 8.0
Hz, 2 H), 6.90 (d, J = 8.4 Hz, 2 H), 7.23–7.26 (m, 1 H), 7.31 (t, J = 7.6 Hz,
2 H), 7.46 (d, J = 7.2 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.2 Hz, 3 H), 1.29 (t, J = 7.2
Hz, 3 H), 2.18 (s, 3 H), 3.84–3.94 (m, 1 H), 3.99–4.06 (m, 1 H), 3.11–
4.18 (m, 2 H), 4.61 (br s, 1 H), 4.80 (d, J = 24.8 Hz, 1 H), 6.47 (d, J = 8.0
Hz, 2 H), 6.92 (d, J = 8.0 Hz, 2 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.81 (d, J = 7.2
Hz, 1 H), 8.11 (d, J = 8.4 Hz, 1 H), 8.32 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 16.42 (d, 3JCP = 5.6 Hz), 16.65 (d, 3JCP
=
13C NMR (100 MHz, CDCl3): δ = 16.43 (d, 3JCP = 5.6 Hz), 16.62 (d, 3JCP
=
=
5.7 Hz), 20.57, 56.55 (d, JCP = 149.4 Hz), 63.47 (d, 2JCP = 5.9 Hz), 63.48
5.3 Hz), 56.20 (d, JCP = 148.8 Hz), 63.56 (d, 2JCP = 7.0 Hz), 63.94 (d, 2JCP
2
(d, JCP = 6.0 Hz), 114.18, 127.81, 128.03, 128.07, 128.77, 129.87,
6.6 Hz), 114.16, 122.98, 123.08, 128.58, 129.72, 130.05, 134.00,
139.22, 143.43, 148.67.
136.22, 144.25.
31P NMR (162 MHz, CDCl3,): δ = 23.91.
31P NMR (162 MHz, CDCl3): δ = 22.17.
Diethyl {(4-Chlorophenyl)[(4-tolyl)amino]methyl}phosphonate
(3g)12h
Diethyl {(2-Nitrophenyl)[(4-tolyl)amino]methyl}phosphonate
(3k)9j
White solid; yield: 350 mg (95%); mp 111–113 °C.
Yellow solid; yield: 344 mg (91%); mp 160–162 °C.
1H NMR (400 MHz, CDCl3): δ = 1.15 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2
Hz, 3 H), 2.18 (s, 3 H), 3.72–3.82 (m, 1 H), 3.93–4.01 (m, 1 H), 4.08–
4.16 (m, 2 H), 4.66 (br s, 1 H), 4.69 (d, J = 25.6 Hz, 1 H), 6.46 (d, J = 8.4
Hz, 2 H), 6.91 (d, J = 8.4 Hz, 2 H), 7.28 (d, J = 8.4 Hz, 2 H), 7.38–7.41 (m,
2 H).
1H NMR (400 MHz, CDCl3): δ = 1.08 (t, J = 7.2 Hz, 3 H), 1.29 (t, J = 7.2
Hz, 3 H), 2.19 (s, 3 H), 3.75–3.85 (m, 1 H), 3.89–3.97 (m, 1 H), 4.11–
4.21 (m, 2 H), 4.86 (br s, 1 H), 6.13 (d, J = 26.4 Hz, 1 H), 6.58 (d, J = 8.4
Hz, 2 H), 6.94 (d, J = 8.4 Hz, 2 H), 7.40 (t, J = 8.0 Hz, 1 H), 7.53 (t, J = 7.6
Hz, 1 H), 7.71–7.73 (m, 1 H), 7.98 (d, J = 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 16.47 (d, 3JCP = 5.6 Hz), 16.65 (d, 3JCP
=
13C NMR (100 MHz, CDCl3): δ = 16.16 (d, 3JCP = 5.5 Hz), 16.58 (d, 3JCP
=
5.6 Hz), 20.56, 56.06 (d, JCP = 149.6 Hz), 63.46 (d, 2JCP = 6.8 Hz), 63.63
5.5 Hz), 20.57, 50.34 (d, JCP = 150.1 Hz), 63.50 (d, 2JCP = 7.2 Hz), 64.07
2
2
(d, JCP = 6.6 Hz), 114.19, 128.14, 128.96, 129.38, 129.93, 133.86,
(d, JCP = 7.1 Hz), 113.85, 125.43, 128.29, 128.68, 129.02, 130.14,
134.95, 143.96.
132.33, 133.71, 143.28, 149.71.
31P NMR (162 MHz, CDCl3): δ = 23.23.
31P NMR (162 MHz, CDCl3,): δ = 22.14.
Diethyl {(4-Methoxyphenyl)[(4-tolyl)amino]methyl}phosphonate
(3h)12h
Diethyl {[(4-Chlorophenyl)amino](4-nitrophenyl)methyl}phos-
phonate (3l)9j
White solid; yield: 345 mg (95%); mp 95–96 °C.
Yellow solid; yield: 359 mg (90%); mp 165–167 °C.
1H NMR (400 MHz, CDCl3): δ =1.13 (t, J = 7.2 Hz, 3 H), 1.27 (t, J = 7.2
Hz, 3 H), 2.17 (s, 3 H), 3.64–3.72 (m, 1 H), 3.76 (s, 3 H), 3.89–3.97 (m, 1
H), 4.04–4.15 (m, 2 H), 4.56 (br s, 1 H), 4.65 (d, J = 23.6 Hz, 1 H), 6.51
(d, J = 8.4 Hz, 2 H), 6.85 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.4 Hz, 2 H), 7.36
(d, J = 8.8 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 1.18 (t, J = 7.2 Hz, 3 H), 1.30 (t, J = 7.2
Hz, 3 H), 3.80–3.90 (m, 1 H), 3.99–4.05 (m, 1 H), 4.10–4.18 (m, 2 H),
4.59 (br s, 1 H), 4.76 (d, J = 25.2 Hz, 1 H), 6.44 (d, J = 8.8 Hz, 2 H), 7.02
(d, J = 8.8 Hz, 2 H), 7.61 (d, J = 7.6 Hz, 2 H), 8.17 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 16.46 (d, 3JCP = 5.6 Hz), 16.64 (d, 3JCP
=
=
13C NMR (100 MHz, CDCl3): δ = 16.48 (d, 3JCP = 5.8 Hz), 16.65 (d, 3JCP
=
5.0 Hz), 56.32 (d, JCP = 147.8 Hz), 63.79 (d, 2JCP = 6.9 Hz), 63.98 (d, 2JCP
5.7 Hz), 20.57, 55.41, 56.17 (d, JCP = 151.1 Hz), 63.36 (d, 2JCP = 5.3 Hz),
63.41 (d, 2JCP = 5.2 Hz), 114.23, 127.76, 128.00, 129.12, 129.84, 144.13,
144.28, 159.43.
7.1 Hz), 115.15, 124.02, 128.78, 129.43, 143.76, 144.36, 144.50,
147.87.
31P NMR (162 MHz, CDCl3): δ = 21.53.
31P NMR (162 MHz, CDCl3): δ = 24.11.
Diethyl [Anilino(4-nitrophenyl)methyl]phosphonate (3m)27
Diethyl {(4-Nitrophenyl)[(4-tolyl)amino]methyl}phosphonate
(3i)9j
Yellow solid; yield: 357 mg (98%); mp 142–144 °C.
Yellow solid; yield: 371 mg (98%); mp 159–161 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1869–1876

1874
Y.-Q. Yu, D.-Z. Xu
Paper
Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.17 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2
Hz, 3 H), 3.82–3.91 (m, 1 H), 3.98–4.06 (m, 1 H), 4.08–4.18 (m, 2 H),
4.58 (br s, 1 H), 4.85 (d, J =25.2 Hz, 1 H), 6.56 (d, J = 8.0 Hz, 2 H), 6.72
(t, J = 7.2 Hz, 1 H), 7.10 (t, J = 8.0 Hz, 2 H), 7.65 (d, J = 6.8 Hz, 2 H), 8.18
(d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 16.26 (d, 3JCP = 5.7 Hz), 16.39 (d, 3JCP
5.3 Hz), 50.12 (d, JCP = 158.7 Hz), 63.29 (d, 2JCP = 6.6 Hz), 63.32 (d, 2JCP
6.6 Hz), 108.76, 110.78, 113.91, 118.75, 129.14, 142.42, 146.28,
149.49.
=
=
31P NMR (162 MHz, CDCl3): δ = 20.30.
13C NMR (100 MHz, CDCl3): δ = 16.47 (d, 3JCP = 5.8 Hz), 16.64 (d, 3JCP
=
=
5.8 Hz), 56.24 (d, JCP = 147.2 Hz), 63.70 (d, 2JCP = 7.1 Hz), 63.97 (d, 2JCP
Diethyl {1-[(4-Chlorophenyl)amino]-2-methylpropyl}phospho-
nate (3r)9j
6.8 Hz), 114.04, 119.32, 123.96, 128.85, 129.56, 144.25, 145.88,
147.79.
31P NMR (162 MHz, CDCl3): δ = 21.85.
White solid; yield: 301 mg (94%); mp 88–89 °C.
1H NMR (400 MHz, CDCl3): δ = 1.03–1.35 (m, 12 H), 2.20–2.31 (m, 1
H), 3.50–3.70 (m, 1 H), 3.89–4.16 (m, 5 H), 6.57–6.63 (m, 2 H), 7.09–
7.16 (m, 2 H).
Diethyl [Anilino(4-chlorophenyl)methyl]phosphonate (3n)28
White solid; yield: 343 mg (97%); mp 72–74 °C.
13C NMR (100 MHz, CDCl3): δ = 16.40 (d, 3JCP = 7.8 Hz), 16.47 (d, 3JCP
6.9 Hz), 17.97 (d, JCP = 15.8 Hz), 20.67 (d, JCP = 16.2 Hz), 29.84 (d,
2JCP = 7.4 Hz), 56.49 (d, JCP = 201.4 Hz), 61.85 (d, 2JCP = 9.8 Hz), 62.59 (d,
2JCP = 9.6 Hz), 114.33, 122.33, 129.06, 146.44.
=
1H NMR (400 MHz, CDCl3): δ = 1.15 (t, J = 7.2 Hz, 3 H), 1.28 (t, J = 7.2
Hz, 3 H), 3.72–3.82 (m, 1 H), 3.93–4.01 (m, 1 H), 4.05–4.16 (m, 2 H),
4.07 (br s, 1 H), 4.76 (d, J = 24.4 Hz, 1 H), 6.56 (d, J = 8.0 Hz, 2 H), 6.71
(t, J = 7.2 Hz, 1 H), 7.10 (t, J = 7.6 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2 H), 7.41
(d, J = 8.4 Hz, 2 H).
3
3
31P NMR (162 MHz, CDCl3): δ = 25.18.
13C NMR (100 MHz, CDCl3): δ = 16.47 (d, 3JCP = 5.4 Hz), 16.65 (d, 3JCP
=
=
Diethyl (1-Anilinoundecyl)phosphonate (3s)9f
5.6 Hz), 55.83 (d, JCP = 149.4 Hz), 63.57 (d, 2JCP = 7.6 Hz), 63.64 (d, 2JCP
Colorless oil; yield: 273 mg (74%).
7.6 Hz), 109.99, 114.16, 118.97, 129.01, 129.43, 133.96, 134.75,
146.21.
31P NMR (162 MHz, CDCl3): δ = 23.04.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.18 (t, J = 7.2
Hz, 3 H), 1.24–1.31 (m, 16 H), 1.53–1.57 (m, 1 H), 1.63–1.71 (m, 1 H),
1.88–1.95 (m, 1 H), 3.66–3.76 (m, 2 H), 3.96–4.04 (m, 1 H), 4.08–4.13
(m, 3 H), 6.66 (d, J = 8.0 Hz, 2 H), 6.71 (t, J = 7.6 Hz, 1 H), 7.17 (t, J = 7.2
Hz, 2 H).
Diethyl [Anilino(4-methoxyphenyl)methyl]phosphonate (3o)27
White solid; yield: 336 mg (96%); mp 98–100 °C.
13C NMR (100 MHz, CDCl3): δ = 14.10, 16.36 (d, 3JCP = 5.6 Hz), 16.46 (d,
1H NMR (400 MHz, CDCl3): δ = 1.12 (t, J = 7.2 Hz, 3 H), 1.27 (t, J = 7.2
Hz, 3 H), 3.65–3.71 (m, 1 H), 3.75 (s, 3 H), 3.90–3.96 (m, 1 H), 4.06–
4.15 (m, 2 H), 4.70 (d, J = 23.6 Hz, 1 H), 4.73 (br s, 1 H), 6.58 (d, J = 8.0
Hz, 2 H), 6.67 (t, J = 7.2 Hz, 1 H), 6.85 (d, J = 6.8 Hz, 2 H), 7.09 (t, J = 7.6
Hz, 2 H), 7.37 (d, J = 8.8 Hz, 2 H).
3JCP = 4.0 Hz), 17.09, 20.44, 22.65, 26.05, 29.36, 30.73, 31.85, 35.94,
39.19, 50.87 (d, JCP = 155.3 Hz), 61.99 (d, 2JCP = 7.4 Hz), 63.01 (d, 2JCP
=
7.1 Hz), 113.24, 117.82, 129.21, 147.37.
31P NMR (162 MHz, CDCl3): δ = 26.51.
13C NMR (100 MHz, CDCl3): δ = 16.48 (d, 3JCP = 5.6 Hz), 16.66 (d, 3JCP
=
Diethyl {1-[(4-Chlorophenyl)amino]cyclohexyl}phosphonate
(3t)12h
5.6 Hz), 55.43, 55.58 (d, JCP = 151.3 Hz), 63.39 (d, 2JCP = 4.8 Hz), 63.97
2
(d, JCP = 4.2 Hz), 114.09, 114.26, 118.54, 127.89, 129.18, 129.35,
White solid; yield: 311 mg (90%); mp 133–135 °C.
146.63, 159.51.
31P NMR (162 MHz, CDCl3): δ = 24.02.
1H NMR (400 MHz, CDCl3): δ = 1.25 (t, J = 9.6 Hz, 6 H), 1.38–1.68 (m, 6
H), 1.79 (t, J = 16.8 Hz, 2 H), 2.14–2.19 (m, 2 H), 3.32 (br s, 1 H), 4.05
(q, J1 = 9.2 Hz, J2 = 18.8 Hz, 4 H), 6.98 (d, J = 11.6 Hz, 2 H), 7.10 (d, J =
11.6 Hz, 2 H).
Diethyl [Anilino(2-thienyl)methyl]phosphonate (3p)13b
Wax; yield: 296 mg (91%).
13C NMR (100 MHz, CDCl3): δ = 16.53, 16.65, 19.99, 20.14, 25.36,
1H NMR (400 MHz, CDCl3): δ = 1.18 (t, J = 6.8 Hz, 3 H), 1.26 (t, J = 6.8
Hz, 3 H), 3.80–3.90 (m, 1 H), 3.99–4.07 (m, 1 H), 4.10–4.20 (m, 2 H),
4.93 (br s, NH, 1 H), 5.05 (d, J = 24.0 Hz, 1 H), 6.68 (d, J = 8.0 Hz, 2 H),
6.72 (t, J = 7.2 Hz, 1 H), 6.94 (t, J = 4.8 Hz, 1 H), 7.10–7.16 (m, 3 H), 7.19
(dt, J = 1.2, 4.8 Hz, 1 H).
30.06, 56.12, 58.24, 62.25, 62.37, 119.55, 124.25, 128.59, 144.35.
31P NMR (162 MHz, CDCl3): δ = 27.44.
Diethyl (1-Anilino-2-ethylbutyl)phosphonate (3u)29
White solid; yield: 186 mg (62%); mp 116–117 °C.
13C NMR (100 MHz, CDCl3): δ = 16.28 (d, 3JCP = 6.0 Hz), 16.45 (d, 3JCP
=
=
1H NMR (400 MHz, CDCl3): δ = 0.99 (t, J = 7.2 Hz, 6 H), 1.24 (t, J = 6.8
Hz, 6 H), 1.91–2.01 (m, 4 H), 3.63–3.67 (m, 2 H), 4.02–4.10 (m, 3 H),
6.80 (t, J = 7.2 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 2 H), 7.12–7.17 (m, 2 H).
5.9 Hz), 56.58 (d, JCP = 157.4 Hz), 63.54 (d, 2JCP = 6.7 Hz), 63.76 (d, 2JCP
7.1 Hz), 113.99, 118.88, 125.29, 126.21, 127.11, 129.23, 139.79,
146.30.
31P NMR (162 MHz, CDCl3): δ = 20.89.
3
13C NMR (100 MHz, CDCl3): δ = 7.83, 16.41, 16.46 (d, JCP = 5.6 Hz),
26.46, 61.11 (d, JCP = 148.8 Hz), 62.04 (d, 2JCP = 7.6 Hz), 62.21 (d, 2JCP
=
8.0 Hz), 118.90, 119.64, 128.74, 145.69.
31P NMR (162 MHz, CDCl3): δ = 29.14.
Diethyl [Anilino(2-furyl)methyl]phosphonate (3q)27
Wax; yield: 303 mg (98%).
1H NMR (400 MHz, CDCl3): δ = 1.16 (t, J = 6.8 Hz, 3 H), 1.25 (t, J = 6.8
Hz, 3 H), 3.82–3.88 (m, 1 H), 4.00–4.07 (m, 1 H), 4.13–4.20 (m, 2 H),
4.91 (d, J = 24.0 Hz, 1 H), 5.11 (br s, 1 H), 6.27 (s, 1 H), 6.38 (t, J = 3.2
Hz, 1 H), 6.65–6.72 (m, 3 H), 7.11 (t, J = 8.0 Hz, 2 H), 7.34 (s, 1 H).
Acknowledgment
This work was financially supported by the National Natural Science
Foundation of China (NSFC) (Grant no. 21302101).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1869–1876

1875
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Synthesis
Supporting Information
C.; Ni, C. Heteroat. Chem. 2010, 21, 546. (p) Hou, J.-T.; Gao, J.-W.;
Zhang, Z.-H. Appl. Organomet. Chem. 2011, 25, 47. (q) Zhang, G.;
Zi, Y.; Xia, Y.; Fei, Y.; Wang, Y. Huaibei Shifan Daxue Xuebao,
Ziran Kexueban 2011, 32, 38.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380523.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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