Fluorous bis(oxazolines) ligand: Synthesis and application in Kabachnik-Fields reaction

Article abstract of DOI:10.1016/j.jfluchem.2014.09.024

A novel fluorous bis(oxazolines) ligand was synthesized with 70% overall yield in 5 steps starting from 5-aminoisophthalic acid. The ligand was applied in the one-pot synthesis of α-aminophosphonates via copper-catalyzed Kabachnik-Fields reaction, giving the corresponding products in moderate to excellent yields under mild conditions. Furthermore, the fluorous ligand could be easily recovered and reused for four times without significant loss of activity.

Full text of DOI:10.1016/j.jfluchem.2014.09.024

Journal of Fluorine Chemistry 168 (2014) 144–150
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Fluorous bis(oxazolines) ligand: Synthesis and application in
Kabachnik-Fields reaction
*
Hongjun Wang, Tao Deng, Chun Cai
School of Chemical Engineering, Nanjing University of Science and Technology, 200 Xiao Ling Wei Street, Nanjing, Jiangsu, People’s Republic of China
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel fluorous bis(oxazolines) ligand was synthesized with 70% overall yield in 5 steps starting from
Received 20 August 2014
5-aminoisophthalic acid. The ligand was applied in the one-pot synthesis of
a-aminophosphonates via
Received in revised form 12 September 2014
Accepted 22 September 2014
Available online 30 September 2014
copper-catalyzed Kabachnik-Fields reaction, giving the corresponding products in moderate to excellent
yields under mild conditions. Furthermore, the fluorous ligand could be easily recovered and reused for
four times without significant loss of activity.
ß 2014 Elsevier B.V. All rights reserved.
Keywords:
Fluorous bis(oxazolines)
Kabachnik-Fields reaction
a
-Aminophosphonates
1. Introduction
numbers and permit low catalyst loadings. Moreover, it needs to
be amenable to rational design, giving the possibility for fine-
Organophosphorus compounds have been widely used in
organic synthesis, biological, pharmaceutical, and materials
sciences as valuable building blocks [1,2]. As an important class
tuning the catalytic properties of the metal center. These issues
can usually be solved by an appropriate choice of ligands [13]. In
2007, Muraki and co-workers reported the synthesis of
of organophosphorus compounds,
attracted considerable attention because they are considered to be
structural analogs of the corresponding -amino acids and
transition-satate mimics of peptide hydrolysis [3]. -Aminopho-
a
-aminophosphonates have
a
-aminophosphonates employing a novel copper-2,20-bipyri-
dine derivative complex [14]. In 2012, the gold-2,20-bipyridine
complex was successfully synthesized and applied in the
formation of a-aminophosphonates by Zhang et al. [15]. In
a
a
sphonates display a broad spectrum of biological activities that
include peptide mimetics [4], enzyme inhibitors [5], antibiotics [6],
herbicides [7], catalytic antibodies [8], anti HIV [9], anti cancer [10]
and thrombotic agents [11].
the same year, Zhu et al. carried out the reaction in the presence
of lanthanide amido complexes [16].
As an important nitrogen based ligands, a large number of
bis(oxazolines) have been reported because of their ready
accessibility, modular nature and applicability in a wide range
of metal catalyzed transformations [17,18]. However, most of the
bis(oxazolines) ligands are difficult to be recovered and reused.
Fluorous technology provides the possibility to design recyclable
and subsequently reusable versions of ligands. Fluorous synthesis
has been widely utilized in organic synthesis since the pioneering
Considering the wide range of biological property of
phosphonates, a large number of methods for the preparation of
-aminophosphonates have been published. In recent years, a
a-amino-
a
three-component synthesis that starts from aldehydes, amines, and
diethyl phosphite has been reported by using metalcatalysts such as
Mg(ClO4)2, ZrOCl2ꢀ8H2O, FeCl3, LiClO4, ZrCl4 [12]. However, the
harsh reaction conditions, expensive reagents, long reaction times,
complicated workup procedures, relatively low yields and large
amount of catalysts limit the use of these methods. Therefore, it is
necessary to find an effective metal catalyst for the synthesis of
´
works of Horvath in 1994 [19]. In 1997, Curran’s group further
substantiated this concept by introducing a perfluoroalkyl chain as
fluorous tag [20]. Fluorous-tagged molecules are easily separated
from non-fluorous molecules by a fluorous liquid–liquid extraction
(F-LLE) using fluorous solvents or a fluorous solid phase extraction
(F-SPE) using perfluorinated silica gel [21].
a-aminophosphonates. An effective metal catalyst has to be stable
and highly selective, but also highly active to ensure high turnover
However, there were few reports describing the recyclability of
fluorous bis(oxazolines) [22]. As a follow up to our previous work
[23], a novel fluorous bis(oxazolines) ligand was synthesized and
*
Corresponding author. Tel.: +86 25 84315514; fax: +86 25 84315030.
applied in copper-catalyzed asymmetric a-hydrophosphonylation
E-mail address: c.cai@njust.edu.cn (C. Cai).
http://dx.doi.org/10.1016/j.jfluchem.2014.09.024
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

H. Wang et al. / Journal of Fluorine Chemistry 168 (2014) 144–150
145
The fluorous bis(oxazolines) (L2) was applied in copper-
catalyzed Kabachnik-Fields reaction. The reaction of benzalde-
hyde, aniline, and diethyl phosphite was selected as a model for the
synthesis of a-aminophosphonate. Table 1 summarizes the results
of the reaction. Initially, different metal catalysts were investigated
in the reaction (Table 1, entries 2–10). The product was obtained in
28% yield without any catalyst, but no significant promoting effects
were obtained in the presence of metal catalysts (Table 1, entries
2–8) because the water was generated during the course of the
reaction which can deactivate or decompose the catalysts
[26]. However, the product was obtained in 62% yield when using
zinc(II) triflate and 66% yield in the presence of copper(II) triflate
(Table 1, entries 9 and 10). Probably due to their high reactivity and
inertness toward water. As a result, copper(II) triflate was selected
as catalyst for this reaction.
In order to probe the influence of the ligand, two different
bis(oxazolines) ligand (Fig. 1) were then examined in the reaction.
It was found that the yields were obviously increased by the
addition of bis(oxazolines) ligands (Table 1, entries 13 and 14).
Compared to the non-fluorous bis(oxazolines) ligand (L1) [27], the
similar result was obtained when using the fluorous bis(oxazo-
lines) ligand (L2). After that, we studied the reaction time and the
best result was obtained when reacted for 6 h (Table 1, entries 14–
17). On the other hand, the amount of catalyst was also
investigated. The yield was not obviously changed when the
amount of catalyst was reduced to 5 mol% (Table 1, entries 14 and
19). Finally, different solvents were tested in the reaction (Table 1,
entries 18 and 20–28). The results showed that dichloromethane
was the best solvent for this reaction.
Fig. 1. Bis(oxazolines) ligands.
[24]. In this literature, the racemic fluorous bis(oxazolines) (Fig. 1
L2) was investigated in the synthesis of a-aminophosphonates via
copper-catalyzed Kabachnik-Fields reaction. Compared to the
silica supported or polymer supported bis(oxazolines) [25], the
modified bis(oxazolines) with long perfluoroalkyl groups are
soluble in organic solvents, yet they could be easily separated
and recovered from the reaction mixture by F-SPE.
2. Results and discussion
The fluorous bis(oxazolines) ligand (Fig. 1 L2) was successfully
synthesized in 5 steps starting from 5-aminoisophthalic acid
(Scheme 1). The 5-iodoisophthalic acid (2) was synthesized
through diazotization and halogenation from commercially
available 5-aminoisophthalic acid (1). Compound 2 was refluxed
in thionyl chloride with catalytic amount of N,N-dimethylforma-
mide to give 5-iodoisophthaloyl dichloride (3). Treatment of 3 with
phenylglycinol in the presence of triethylamine gave compound
4. A solution of compound 4, p-toluenesulfonyl chloride and
triethylamine was refluxed in dichloromethane to give bis(ox-
azolines) 5. The introduction of perfluoroalkyl chain was per-
formed by a copper-catalyzed coupling reaction. The desired
fluorous bis(oxazolines) ligand (L2) was obtained in 70% overall
yield.
To demonstrate the generality of this method, we next
investigated the scope of this reaction, and the results were
summarized in Table 2. The reactions of various aldehydes, amines
and diethyl phosphite under the optimized conditions giving the
corresponding
a-aminophosphonates in moderate to excellent
yields (68–95%). The aromatic aldehydes containing electron-
donating and electron-withdrawing substituent reacted with
aniline and diethyl phosphite provide good to excellent yields
Scheme 1. Synthesis of fluorous bis(oxazolines).

146
H. Wang et al. / Journal of Fluorine Chemistry 168 (2014) 144–150
Table 1
Table 2
Scope of substrates.a
Optimization of reaction conditions including catalyst, solvent and ligand.a
Entry
R1
R2
Product
Yieldb (%)
Entry
Catalyst
Amount
of cat.
Ligand
Solvent
Time
(h)
Yieldb
(%)
1
2
C6H5-
H
6a
6b
6c
6d
6e
6f
94
92
93
92
90
91
85
92
90
87
90
91
73
85
87
91
Trace
68
92
95
90
86
4-CH3-C6H4-
4-Cl-C6H4-
4-F-C6H4-
4-OCH3-C6H4-
4-NO2-C6H4-
4-NMe2-C6H4-
4-CF3-C6H4-
3-CF3-C6H4-
3-NO2-C6H4-
3-Cl-C6H4-
3-Br-C6H4-
2-CF3-C6H4-
2-NO2-C6H4-
2-Br-C6H4-
1-Naphthyl
2-Furyl
H
(mol%)
3
H
1
2
None
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2
10
5
5
5
5
5
5
5
5
5
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
6
6
6
6
6
6
6
6
6
6
6
6
6
6
3
9
12
6
6
6
6
6
6
6
6
6
6
6
28
35
34
55
43
43
52
23
62
66
85
82
93
94
88
92
91
89
94
91
90
89
86
87
85
62
65
38
4
H
Cu(OAc)2
CuSO4
–
5
H
3
–
6
H
4
CuCl2
–
7
H
6g
6h
6i
5
CuCl
–
8
H
6
AlCl3
–
9
H
7
FeCl3
–
10
11
12
13
14
15
16
17
18
19
20
21
22
H
6j
8
Zn(OAc)2
Zn(OTf)2
Cu(OTf)2
CuCl2
–
H
6k
6l
9
–
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
–
H
6m
6n
6o
6p
6q
6r
6s
6t
L1
L1
L1
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
L2
H
FeCl3
H
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
H
H
2-Thienyl
C6H5-
H
Cl
CH3
OCH3
NO2
C6H5-
C6H5-
6u
6v
C6H5-
a
Reaction conditions: 1 mmol aldehyde, 1 mmol amine, 1.5 mmol diethyl
PhCH3
Dioxane
CH3CN
MeOH
EtOH
phosphite, 5 mol% Cu(OTf)2, 5 mol% L2, 1 mL CH2Cl2, room temperature, 6 h.
b
Isolated yields.
DMF
DMSO
H2O
(Table 2, entries 1–8). The similar results were obtained when
using aromatic amines containing electron-donating and electron-
withdrawing substituent reacted with benzaldehyde and diethyl
phosphite (Table 2, entries 19–22). The steric effect showed slight
influences on the reactions (Table 2, entries 6, 10 and 14). 2-
a
Rcaction conditions: 1 mmol benzaldehyde, 1 mmol aniline, 1.5 mmol diethyl
phosphite, metal catalyst, ligand (same scale of metal catalyst), 1 mL solvent, room
temperature.
b
Isolated yields.
Thenaldehyde afforded a-aminophosphonate in 68% yield while 2-
furaldehyde gave no product which are probably due to the
instability of the intermediate (Table 2, entries 17 and 18).
Table 3
Recycling and reuse of the fluorous liganda
Run
Recovery of ligandb (%)
Yieldc (%)
–
1
2
3
4
–
94
95
92
93
94
93
91
92
90
a
Rcaction conditions: 1 mmol benzaldehyde, 1 mmol aniline, 1.5 mmol diethyl phosphite, 5 mol% Cu(OTf)2, 5 mol% L2,
1 mL CH2Cl2, room temperature, 6 h.
b
Recovered by F-SPE.
c
Isolated yields.

H. Wang et al. / Journal of Fluorine Chemistry 168 (2014) 144–150
147
The recyclability of the fluorous bis(oxazolines) ligand was
studied by choosing the reaction of benzaldehyde, aniline and
diethyl phosphite as a model. After the reaction was finished, the
ligand was recovered by FluoroFlash silica gel. The non-fluorous
component was eluted by the mixture of methanol and water, then
fluorous bis(oxazolines) was eluted by pure methanol. The
recovered ligand could be used directly for the next run. As listed
in Table 3, the fluorous bis(oxazolines) ligand could be reused for
four times without significant loss of activity.
7.38 (d, J = 7.4 Hz, 4H), 7.32 (t, J = 7.6 Hz, 4H), 7.23 (t, J = 7.3 Hz, 2H),
5.07–5.02 (m, 2H), 4.98 (t, J = 5.9 Hz, 2H), 3.72–3.67 (m, 2H), 3.65–3.60
(m, 2H); 13C NMR (125 MHz, DMSO-d6)
d: 163.83, 140.50, 137.55,
136.08, 127.62, 126.47, 126.38, 125.90, 93.82, 63.86, 55.78.
4.4. 1,3-Bis(4,4-diphenyl-2-oxazolin-2-yl)-5-iodobenzene (5)
p-Toluenesulfonyl chloride (15 mmol) was added to the
solution of 5-iodo-N,N0-bis(1-hydroxy-3-phen-2-yl)benzene-1,3-
dicarbonamide 4 (6 mmol) and Et3N (2.3 mL) in CH2Cl2 (30 mL).
The reaction mixture was allowed to reflux for 24 h. Saturated
NH4Cl solution was then poured into the reaction mixture. The
organic layer was separated and the aqueous layer extracted with
CH2Cl2 (3ꢁ 15 mL). The combined extracts were washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The
crude product was purified by column chromatography (ethyl
acetate/petroleum ether, 1:8). Yellow oil, Yield: 88%. 1H NMR
3. Conclusion
In summary, a novel fluorous bis(oxazolines) ligand was
synthesized and used in copper-catalyzed Kabachnik-Fields
reaction to give the corresponding
a-aminophosphonates. The
reactions proceeded smoothly to provide products in moderate to
excellent yields (68–95%). This facile and efficient method was
applicable for a wide range of substrates. Furthermore, the fluorous
bis(oxazolines) ligand could be easily recovered by F-SPE and
reused for four times without significant loss of activity.
(500 MHz, CDCl3) d: 8.63 (s, 1H), 8.55 (d, J = 1.0 Hz, 2H), 7.41–7.34
(m, 4H), 7.31 (t, J = 3.1 Hz, 4H), 7.29 (s, 2H), 5.44–5.37 (m, 2H), 4.82
(dd, J = 10.0, 8.7 Hz, 2H), 4.31 (t, J = 8.4 Hz, 2H); 13C NMR (125 MHz,
CDCl3) d: 161.73, 140.86, 138.99, 128.64, 127.87, 126.83, 126.64,
125.74, 92.52, 74.15, 69.27.
4. Experimental
All reagents were purchased from commercial sources and
without further purification, unless otherwise indicated. The
products were purified by column chromatography over silica
gel. 1H and 13C NMR were recorded on a Bruker Avance III
(500 MHz) spectrometer and tetramethylsilane (TMS) was used as
a reference. Melting points were determined in open capillary
tubes. Elemental analysis was performed on a Vario EL III recorder.
4.5. 1,3-Bis(4,4-diphenyl-2-oxazolin-2-yl)-5-perfluorooctyl benzene
(L2)
A mixture of 5 (5.0 mmol), C8F17I (5.0 mmol) and Cu powder
(1.6 g, 25.0 mmol) in DMSO (10 ml) was stirred for 22 h at 120 8C.
The mixture was filtered by Celite and washed with Et2O and
water. The aqueous layer was extracted with Et2O (3ꢁ 15 ml). The
organic layer was washed with brine, dried over anhydrous Na2SO4
and concentrated in vacuo. The crude product was purified by
short-path silica gel column chromatography (ethyl acetate/
petroleum ether, 1:6). White solid, Yield: 91%. Mp: 112–114 8C.
4.1. 5-Iodoisophthalic acid (2)
5-Aminoisophthalic acid (1.75 g, 9.6 mmol) was suspended in
water (5 ml) at 0–5 8C. Dilute HCl (10%, 30 mL, 30 mmol) and
NaNO2 (701 mg, 10.1 mmol) solutions were added successively,
and then the solution was stirred for 1 h to complete diazotization.
Then KI (6.37 g, 38.4 mmol) was slowly added, and the mixture
was stirred overnight at room temperature. After the reaction, the
precipitate was collected by filtration, washed with water several
times, and dried in vacuo. Yellow solid. Yield: 96%. Mp: 304–
1H NMR (500 MHz, CDCl3)
(m, 4H), 7.34–7.28 (m, 6H), 5.48–5.41 (m, 2H), 4.90–4.84 (m, 2H),
4.35 (t, J = 8.4 Hz, 2H); 13C NMR (125 MHz, CDCl3)
: 162.99,
141.85, 131.93, 130.16, 129.67, 129.20, 129.03, 128.02, 126.88,
75.42, 70.53; 19F NMR (470 MHz, CDCl3)
d: 8.91 (s, 1H), 8.41 (s, 2H), 7.42–7.35
d
d
: ꢂ80.72 (t, J = 9.8 Hz,
3F), ꢂ110.62 (dt, J = 64.3, 13.1 Hz, 2F), ꢂ121.00 to ꢂ121.27 (m, 4F),
ꢂ121.83 (s, 4F), ꢂ122.67 (s, 2F), ꢂ125.99 to ꢂ126.14 (m, 2F). Anal.
Calc. for C32H19F17N2O2: C, 48.85; H, 2.44; Found: C, 48.64; H, 2.53.
306 8C. 1H NMR (500 MHz, DMSO-d6)
d
: 8.40 (s, 3H); 13C NMR
(125 MHz, DMSO-d6) : 164.72, 140.90, 132.63, 128.59, 94.26.
d
4.6. General procedure for synthesis of
recovery of fluorous bis(oxazolines)
a-aminophosphonates and
4.2. 5-Iodoisophthaloyl dichloride (3)
5-Iodoisophthalic acid 2 (2.63 g, 9.0 mmol) was suspended in
thionyl chloride (20 mL). Two drops of DMF was added and the
mixture was heated to reflux for 3 h. The excess SOCl2 was
removed under reduced pressure to afford the 5-iodoisophthaloyl
dichloride 3 as a yellow solid which was used directly for the next
step.
5 mol% Cu(OTf)2 and 5 mol% ligand was stirred in CH2Cl2 at
room temperature for 30 min. Aldehyde (1 mmol), amine (1 mmol)
and diethyl phosphite (1.5 mmol) was added respectively and then
the mixture was stirred for 6 h at room temperature. After the
reaction was finished, the mixture was separated by FluoroFlash
silica gel. The non-fluorous component was eluted by the mixture
of methanol and water (methanol/water, 4:1), then fluorous
bis(oxazolines) was eluted by pure methanol. The elutant was
concentrated in vacuo and the recovered ligand could be used
directly for the next run. The non-fluorous mixture was
concentrated in vacuo and then purified by short-path silica gel
column chromatography (ethyl acetate/petroleum ether, 1:4).
4.3. 5-Iodo-N,N0-bis(1-hydroxy-3-phen-2-yl)benzene-1,3-
dicarbonamide (4)
The above 5-iodoisophthaloyl dichloride in CH2Cl2 (20 mL) was
added dropwise to a solution of phenylglycinol (22.5 mmol) and
Et3N (4.9 mL) in CH2Cl2 (20 mL) at 0 8C, then the mixture was
stirred overnight at room temperature. The reaction mixture was
successively washed with saturated NH4Cl (aq), HCl (1 M),
saturated NaHCO3 (aq) and brine. The organic layer was dried
over anhydrous Na2SO4 and concentrated in vacuo. The crude
product was purified by column chromatography (MeOH/CH2Cl2,
1:30). White solid, Yield: 91%. Mp: 129–131 8C. 1H NMR (500 MHz,
4.6.1. Diethyl (phenylamino)(phenyl)methylphosphonate (6a) [28]
White solid; Mp: 92–94 8C. 1H NMR (500 MHz, CDCl3)
d: 7.47 (d,
J = 7.3 Hz, 2H), 7.33 (t, J = 7.5 Hz, H), 7.26 (t, J = 7.2 Hz, 1H), 7.10 (t,
J = 7.8 Hz, 2H), 6.69 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 7.9 Hz, 2H), 4.79
(br, s, 1H), 4.74 (s, 1H), 4.19–4.04 (m, 2H), 3.98–3.90 (m, 1H), 3.73–
3.63 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR
DMSO-d6)
d:8.97 (d, J = 8.1 Hz, 2H), 8.39 (d, J = 1.1 Hz, 2H), 8.36 (s, 1H),
(125 MHz, CDCl3) d: 146.46 (d, J = 14.6 Hz), 136.04, 129.29, 128.71,

148
H. Wang et al. / Journal of Fluorine Chemistry 168 (2014) 144–150
128.00, 118.53, 114.00, 63.40, 56.83, 55.63, 16.55 (d, J = 3.3 Hz),
16.31 (d, J = 4.0 Hz).
128.71, 123.07, 118.25, 114.04, 112.67, 63.23 (dd, J = 13.5, 5.9 Hz),
56.09, 54.87, 40.61, 16.58, 16.45.
4.6.2. Diethyl (phenylamino)(4-methylphenyl)methylphosphonate
4.6.8. Diethyl (phenylamino)[4-
(6b) [28]
(trifluoromethyl)phenyl]methylphosphonate (6h) [31]
White solid; Mp: 64–65 8C. 1H NMR (500 MHz, CDCl3)
d
: 7.35
White solid; Mp: 121–123 8C. 1H NMR (500 MHz, CDCl3)
d:
(dd, J = 8.0, 2.0 Hz, 2H), 7.17–7.06 (m, 4H), 6.69 (t, J = 7.3 Hz, 1H),
6.59 (d, J = 7.9 Hz, 2H), 4.76 (br, s, 1H), 4.71 (s, 1H), 4.18–4.04 (m,
2H), 3.99–3.91 (m, 1H), 3.74–3.66 (m, 1H), 2.31 (d, J = 0.9 Hz, 3H),
1.29 (t, J = 7.1 Hz, 3H), 1.13 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
7.65–7.54 (m, 4H), 7.12 (t, J = 7.9 Hz, 2H), 6.73 (t, J = 7.3 Hz, 1H),
6.57 (d, J = 7.9 Hz, 2H), 4.86 (br, s, 1H), 4.81 (d, J = 6.1 Hz, 1H),
4.21–4.07 (m, 2H), 4.05–3.97 (m, 1H), 3.87–3.77 (m, 1H), 1.30 (t,
J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d:
CDCl3)
d
: 146.51 (d, J = 14.4 Hz), 137.70, 132.85, 129.43, 129.25,
146.02 (d, J = 14.0 Hz), 140.53, 129.36, 128.25, 125.59, 118.88,
113.88, 63.65 (d, J = 5.4 Hz), 63.44 (d, J = 5.4 Hz), 56.58, 55.39,
16.46, 16.26.
127.82, 118.44, 113.98, 63.33, 56.48, 55.28, 21.25, 16.55 (d,
J = 3.2 Hz), 16.34 (d, J = 3.2 Hz).
4.6.3. Diethyl (phenylamino)(4-chlorophenyl)methylphosphonate
4.6.9. Diethyl (phenylamino)[3-
(6c) [29]
(trifluoromethyl)phenyl]methylphosphonate (6i)
White solid; Mp: 58–59 8C. 1H NMR (500 MHz, CDCl3)
d
: 7.41
White solid; Mp: 108–110 8C. 1H NMR (500 MHz, CDCl3)
d: 7.82
(dd, J = 8.5, 2.1 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.11 (t, J = 7.8 Hz,
2H), 6.71 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 8.0 Hz, 2H), 4.75 (br, s, 1H),
4.70 (d, J = 6.8 Hz, 1H), 4.18–4.05 (m, 2H), 4.03–3.95 (m, 1H),
3.83–3.73 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H);
(d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H),
7.38 (t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.9 Hz, 2H), 6.75–6.60 (m, 3H),
5.26 (d, J = 23.7 Hz, 1H), 4.98 (br, s, 1H), 4.26–4.10 (m, 2H), 3.90–
3.82 (m, 1H), 3.56–3.48 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.97 (t,
13C NMR (125 MHz, CDCl3)
d
: 146.15 (d, J = 14.3 Hz), 134.74,
J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d: 144.63 (d,
133.84, 129.35, 129.28, 128.92, 118.80, 113.97, 63.99–62.95,
56.29, 55.09, 16.55 (d, J = 3.8 Hz), 16.37 (d, J = 3.5 Hz).
J = 12.4 Hz), 135.00, 131.34, 128.25, 128.01, 127.56, 127.00,
125.31, 117.68, 112.85, 62.43, 51.11, 49.90, 15.39 (d, J = 3.1 Hz),
14.92 (d, J = 3.2 Hz).
4.6.4. Diethyl (phenylamino)(4-fluorophenyl)methylphosphonate
(6d) [30]
4.6.10. Diethyl (phenylamino)(3-nitrophenyl)methylphosphonate
White solid; Mp: 83–84 8C. 1H NMR (500 MHz, CDCl3)
d
: 7.49–
(6j) [30]
7.42 (m, 2H), 7.11 (t, J = 7.9 Hz, 2H), 7.03 (t, J = 8.6 Hz, 2H), 6.71 (t,
J = 7.3 Hz, 1H), 6.58 (d, J = 8.1 Hz, 2H), 4.77 (br, s, 1H), 4.72 (s, 1H),
4.19–4.04 (m, 2H), 4.01–3.93 (m, 1H), 3.80–3.71 (m, 1H), 1.29 (t,
J = 7.1 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d:
163.50, 161.53, 146.19 (d, J = 14.3 Hz), 131.74, 129.62, 129.51,
129.28, 118.66, 115.72, 115.55, 113.92, 63.40, 56.05, 54.85, 16.49
(d, J = 3.0 Hz), 16.30 (d, J = 3.4 Hz).
Yellow solid; Mp: 96–98 8C. 1H NMR (500 MHz, CDCl3)
d: 8.35
(d, J = 1.6 Hz, 1H), 8.13 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H),
7.51 (t, J = 7.9 Hz, 1H), 7.11 (t, J = 7.9 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H),
6.57 (d, J = 7.9 Hz, 2H), 4.90 (s, 1H), 4.85 (s, 1H), 4.21–4.10 (m, 2H),
4.08–4.01 (m, 1H), 3.94–3.85 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.18
(t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d: 148.50, 145.75 (d,
J = 13.6 Hz), 138.95, 133.86, 129.61, 129.39, 122.93 (d, J = 16.6 Hz),
119.06, 113.86, 63.81 (d, J = 5.4 Hz), 63.48 (d, J = 5.3 Hz), 56.30,
55.11, 16.47 (d, J = 2.9 Hz), 16.29.
4.6.5. Diethyl (phenylamino)(4-methoxyphenyl)methylphosphonate
(6e) [28]
White solid; Mp: 101–103 8C. 1H NMR (500 MHz, CDCl3)
d
: 7.38
4.6.11. Diethyl (phenylamino)(3-chlorophenyl)methylphosphonate
(dd, J = 8.7, 2.1 Hz, 2H), 7.10 (t, J = 7.8 Hz, 2H), 6.86 (d, J = 8.6 Hz,
2H), 6.69 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.3 Hz, 2H), 4.73 (br, s, 1H),
4.69 (s, 1H), 4.17–4.04 (m, 2H), 3.98–3.91 (m, 1H), 3.77 (s, 3H),
3.74–3.65 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H);
d: 159.41, 146.47 (d, J = 14.0 Hz),
129.26, 129.05, 127.80, 118.46, 114.17, 114.00, 63.33, 56.09, 55.34,
(6k) [29]
White solid; Mp: 90–91 8C. 1H NMR (500 MHz, CDCl3)
d: 7.48 (s,
1H), 7.40–7.35 (m, 1H), 7.29–7.22 (m, 2H), 7.12 (t, J = 7.9 Hz, 2H),
6.72 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 7.9 Hz, 2H), 4.86 (s, 1H), 4.74 (dd,
J = 24.4, 5.5 Hz, 1H), 4.20–4.07 (m, 2H), 4.03–3.95 (m, 1H), 3.83–
3.74 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); 13C NMR
13C NMR (125 MHz, CDCl3)
54.89, 16.57 (d, J = 3.4 Hz), 16.40.
(125 MHz, CDCl3) d: 146.08 (d, J = 14.1 Hz), 138.42, 134.55, 129.87,
129.28, 128.16, 127.98, 126.02, 118.69, 113.83, 63.47, 56.36, 55.17,
4.6.6. Diethyl (phenylamino)(4-nitrophenyl)methylphosphonate (6f)
16.44 (d, J = 2.9 Hz), 16.22 (d, J = 3.3 Hz).
[28]
Yellow solid; Mp: 124–125 8C. 1H NMR (500 MHz, CDCl3)
d
:
4.6.12. Diethyl (phenylamino)(3-bromophenyl)methylphosphonate
8.20 (d, J = 8.6 Hz, 2H), 7.66 (dd, J = 8.7, 2.1 Hz, 2H), 7.11 (t,
J = 7.8 Hz, 2H), 6.74 (t, J = 7.3 Hz, 1H), 6.53 (d, J = 8.1 Hz, 2H), 4.88 (s,
1H), 4.83(s, 1H), 4.20–4.09(m, 2H), 4.07–3.99 (m, 1H), 3.92–3.84(m,
1H), 1.30 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d: 146.65, 144.66 (d, J = 13.9 Hz), 143.09, 128.38,
127.67, 122.78, 118.14, 112.83, 62.75 (d, J = 5.8 Hz), 62.50 (d,
J = 5.8 Hz), 55.66, 54.49, 15.43 (d, J = 3.3 Hz), 15.28.
(6l) [32]
White solid; Mp: 96–98 8C. 1H NMR (500 MHz, CDCl3)
d: 7.63 (d,
J = 1.2 Hz, 1H), 7.41 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 7.8 Hz, 1H), 7.12 (t,
J = 7.8 Hz, 2H), 6.72 (t, J = 7.3 Hz, 1H), 6.58 (d, J = 8.0 Hz, 2H), 4.82
(s, 1H), 4.72 (dd, J = 24.5, 4.5 Hz, 1H), 4.19–4.06 (m, 2H), 4.03–3.95
(m, 1H), 3.82–3.74 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3)
d: 146.07 (d, J = 13.9 Hz), 138.69,
131.11, 130.89, 130.19, 129.31, 126.45, 122.75, 118.74, 113.85,
4.6.7. Diethyl (phenylamino)[4-
63.51, 56.34, 55.15, 16.47 (d, J = 3.0 Hz), 16.25 (d, J = 3.3 Hz).
(dimethylamino)phenyl]methylphosphonate (6g) [30]
Yellow solid; Mp: 109–111 8C. 1H NMR (500 MHz, CDCl3)
d
:
4.6.13. Diethyl (phenylamino)[2-
7.31 (dd, J = 8.7, 2.0 Hz, 2H), 7.09 (t, J = 7.8 Hz, 2H), 6.67 (t,
J = 7.6 Hz, 3H), 6.61 (d, J = 8.1 Hz, 2H), 4.69 (br, s, 1H), 4.65 (d,
J = 4.5 Hz, 1H), 4.17–4.04 (m, 2H), 3.98–3.90 (m, 1H), 3.73–3.63 (m,
(trifluoromethyl)phenyl]methylphosphonate (6m) [31]
White solid; Mp: 123–125 8C. 1H NMR (500 MHz, CDCl3)
d: 7.82
(d, J = 7.6 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.38
(t, J = 7.6 Hz, 1H), 7.11 (t, J = 7.9 Hz, 2H), 6.76–6.61 (m, 3H), 5.26
(d, J = 23.7 Hz, 1H), 4.99 (br, s, 1H), 4.24–4.12 (m, 2H), 3.90–3.82
1H), 2.92 (s, 6H), 1.28 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H); 13
NMR (125 MHz, CDCl3)
C
d
: 150.35, 146.73 (d, J = 14.3 Hz), 129.21,

H. Wang et al. / Journal of Fluorine Chemistry 168 (2014) 144–150
149
(m, 1H), 3.56–3.48 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz,
3H); 13C NMR (125 MHz, CDCl3)
145.73 (d, J = 12.4 Hz), 136.10,
132.44, 129.35, 129.11, 128.66, 128.10, 126.41, 118.78, 113.95,
1H), 6.91 (d, J = 8.2 Hz, 2H), 6.52 (d, J = 8.3 Hz, 2H), 4.77 (s, 1H), 4.72
(s, 1H), 4.17–4.07 (m, 2H), 3.98–3.91 (m, 1H), 3.74–3.64 (m, 1H),
2.18 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR
d
63.53, 52.21, 51.00, 16.49 (d, J = 3.1 Hz), 16.02 (d, J = 3.2 Hz).
(125 MHz, CDCl3) d: 144.06 (d, J = 15.3 Hz), 136.10, 129.75, 128.64,
127.94, 127.70, 114.09, 63.36, 57.03, 55.83(s), 20.43, 16.51 (d,
4.6.14. Diethyl (phenylamino)(2-nitrophenyl)methylphosphonate
J = 3.0 Hz), 16.27 (d, J = 2.9 Hz).
(6n) [30]
Yellow solid; Mp: 155–157 8C. 1H NMR (500 MHz, CDCl3)
d
8.00
4.6.20. Diethyl (4-
(d, J = 8.1 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H),
7.41 (t, J = 7.7 Hz, 1H), 7.13 (t, J = 7.7 Hz, 2H), 6.73 (t, J = 7.3 Hz, 1H),
6.68 (d, J = 8.0 Hz, 2H), 6.18 (d, J = 26.2 Hz, 1H), 5.07 (s, 1H),
4.23–4.10 (m, 2H), 4.00–3.89 (m, 1H), 3.86–3.76 (m, 1H), 1.30 (t,
methoxyphenylamino)(phenyl)methylphosphonate (6u) [34]
Gray solid; Mp: 70–72 8C. 1H NMR (500 MHz, CDCl3)
d: 7.46 (d,
J = 7.2 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 7.28–7.20 (m, 1H), 6.68 (d,
J = 8.8 Hz, 2H), 6.55 (d, J = 8.8 Hz, 2H), 4.69 (d, J = 24.0 Hz, 1H),
4.17–4.06 (m, 2H), 3.97–3.90 (m, 1H), 3.73–3.64 (m, 4H), 1.28 (t,
J = 7.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d:
152.71, 140.41 (d, J = 15.6 Hz), 136.09, 128.61, 127.93, 115.29,
114.79, 63.30, 57.63, 56.43, 55.68, 16.48 (d, J = 3.0 Hz), 16.24 (d,
J = 3.1 Hz).
J = 7.1 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d
149.52, 145.48 (d, J = 14.0 Hz), 133.57, 132.01, 129.48, 128.89,
128.61, 125.30, 118.87, 113.64, 63.95 (d, J = 5.2 Hz), 63.44 (d,
J = 5.9 Hz), 50.58, 49.38, 16.42 (d, J = 2.8 Hz), 16.01 (d, J = 2.9 Hz).
4.6.15. Diethyl (phenylamino)(2-bromophenyl)methylphosphonate
(6o) [31]
4.6.21. Diethyl (4-nitrophenylamino)(phenyl)methylphosphonate
White solid; Mp: 120–121 8C. 1H NMR (500 MHz, CDCl3)
d
: 7.58
(6v) [31]
(t, J = 8.3 Hz, 2H), 7.26 (dd, J = 8.9, 6.1 Hz, 1H), 7.11 (t, J = 7.9 Hz, 3H),
6.69(t,J = 7.3 Hz,1H), 6.60(d, J = 7.9 Hz, 2H), 5.36(d,J = 24.6 Hz,1H),
5.07 (br, s, 1H), 4.28–4.17 (m, 2H), 3.94–3.86 (m, 1H), 3.67–3.57 (m,
1H), 1.34 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d: 145.79 (d, J = 14.4 Hz), 135.78, 132.82, 129.47,
129.27 (d, J = 9.7 Hz), 128.03, 124.83 (d, J = 6.2 Hz), 118.53, 113.68,
63.54, 54.92, 53.70, 16.50 (d, J = 3.2 Hz), 16.16 (d, J = 3.2 Hz).
Yellow solid; Mp: 145–147 8C. 1H NMR (500 MHz, CDCl3)
d:
7.99 (d, J = 9.1 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.35 (t, J = 7.4 Hz,
2H), 7.30 (dd, J = 8.0, 6.4 Hz, 1H), 6.59 (d, J = 9.2 Hz, 2H), 6.09 (t,
J = 8.6 Hz, 1H), 4.82 (dd, J = 24.0, 7.8 Hz, 1H), 4.22–4.07 (m, 2H),
3.95–3.87 (m, 1H), 3.67–3.56 (m, 1H), 1.96 (s, 1H), 1.30 (t,
J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d:
152.14 (d, J = 13.5 Hz), 138.96, 134.71, 129.15, 128.96, 128.57,
127.89, 126.13, 112.47, 63.99, 63.70 (dd, J = 63.6, 5.3 Hz), 56.18,
54.98, 16.50 (d, J = 2.7 Hz), 16.24 (d, J = 2.3 Hz).
4.6.16. Diethyl (phenylamino)(1-naphthalenyl)methylphosphonate
(6p) [33]
White solid; Mp: 123–125 8C. 1H NMR (500 MHz, CDCl3)
d: 8.27
References
(d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 7.6, 2.8 Hz,
2H), 7.62 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz,
1H), 7.05 (t, J = 7.9 Hz, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.56 (d, J = 8.1 Hz,
2H), 5.66 (d, J = 24.1 Hz, 1H), 5.13 (br, s, 1H), 4.25–4.12 (m, 1H),
3.80–3.67 (m, 1H), 3.27–3.17 (m, 1H), 1.33 (t, J = 7.1 Hz, 3H), 0.74
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126.37, 125.75, 125.50, 125.05, 123.04, 118.37, 113.68, 63.39
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4.6.17. Diethyl (phenylamino)(2-thienyl)methylphosphonate (6r)
[14]
Brown solid; Mp: 59–61 8C. 1H NMR (500 MHz, CDCl3)
d: 7.22 (d,
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J = 4.9 Hz, 1H), 7.19–7.10 (m, 3H), 7.01–6.93 (m, 1H), 6.75 (t, J = 7.3 Hz,
1H), 6.68 (d, J = 8.0 Hz, 2H), 5.05 (d, J = 23.7 Hz, 1H), 4.65 (br, s, 1H),
4.23–4.01 (m, 3H), 3.93–3.81 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.20 (t,
J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d: 146.20 (d, J = 12.9 Hz),
139.93, 129.31, 127.16, 126.24 (d, J = 5.7 Hz), 125.36, 119.03, 114.07,
63.63 (dd, J = 22.5, 5.4 Hz), 52.78, 51.52, 16.50, 16.35 (d, J = 3.1 Hz).
4.6.18. Diethyl (4-chlorophenylamino)(phenyl)methylphosphonate
(6s) [31]
White solid; Mp: 112–114 8C. 1H NMR (500 MHz, CDCl3)
d: 7.44
(d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.27 (dd, J = 6.7, 5.2 Hz,
1H), 7.03 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 4.89 (br, s, 1H),
4.70 (d, J = 24.1 Hz, 1H), 4.18–4.04 (m, 2H), 3.96–3.88 (m, 1H),
3.70–3.61 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H);
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d: 145.00 (d, J = 14.2 Hz), 135.53,
129.10, 128.76, 128.18, 127.90, 123.14, 115.09, 63.45 (dd, J = 16.3,
5.6 Hz), 56.85, 55.65, 16.51 (d, J = 2.4 Hz), 16.26 (d, J = 3.2 Hz).
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4.6.19. Diethyl (4-methylphenylamino)(phenyl)methylphosphonate
(6t) [31]
White solid; Mp: 117–119 8C. 1H NMR (500 MHz, CDCl3)
d
: 7.47
(d, J = 7.4 Hz, 2H), 7.33 (t, J = 7.5 Hz, 2H), 7.26 (dd, J = 8.0, 6.1 Hz,
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