A Simple and Green Tandem Knoevenagel-Phospha-Michael Reaction for One-Pot Synthesis of 2-Oxindol-3-ylphosphonates Catalyzed by a DABCO-Based Ionic Liquid

Article abstract of DOI:10.1055/s-0036-1588357

A simple, clean, and efficient approach for the one-pot synthesis of 2-oxindol-3-ylphosphonates has been successfully developed. With 7 mol% loading of the 1,4-diazabicyclo[2.2.2]octane-based ionic liquid catalyst, 2-oxindol-3-ylphosphonates form in good to excellent yields within short times. This tandem reaction involves a phospha-Michael- addition to the activated alkenes, which form in situ by Knoevenagel- condensation. The corresponding products are easily separated and purified by simple crystallization. The catalyst can be recycled five times without significant activity loss. This approach is readily amenable to large-scale synthesis.

Full text of DOI:10.1055/s-0036-1588357

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–G
paper
A
L.-L. Song et al.
Paper
Synthesis
A Simple and Green Tandem Knoevenagel–Phospha-Michael
Reaction for One-Pot Synthesis of 2-Oxindol-3-ylphosphonates
Catalyzed by a DABCO-Based Ionic Liquid
Lan-Lan Songa
O
O
O
Cheng Yanga
Ya-Qin Yu*b
Da-Zhen Xu*a
R2
O
N
R1
CN
X
O
P
OR3
OR3
a National Pesticide Engineering Research Center (Tianjin), State
Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University, Tianjin 300071, P. R.
of China
+
H
[DABCO-H]AcO
(5–7 mol%)
CN
NC
CN
P
O
P
OR3
OR3
X
O
xudazhen@nankai.edu.cn
O
THF, r.t.
b Key Laboratory for Water Environment and Resources, Tianjin
Normal University, Tianjin, 300387, P. R. of China
yuyaqin@mail.tjnu.edu.cn
OEt
R2
O
X = CN, CO2Et
OEt
N
R1
14 examples
(78–100% yield)
40 min, 95% yield
Received: 23.09.2016
Accepted after revision: 01.11.2016
Published online: 06.12.2016
C3-functionalized oxindoles often appear as the heterocy-
clic nucleus in natural products and medicinally relevant
compounds.4 Organophosphorus compounds are major
components of the living body of both people and animals.
Natural products containing phosphorus often show inter-
esting biological activities.5 Of the various organophospho-
rus compounds, much attention has been paid to phospho-
nates and their derivatives due to their usefulness in indus-
trial, agricultural, and medicinal chemistry.6–11
2-Oxindol-3-ylphosphonate compounds contain two
major components, 3,3-disubstituted oxindoles and β-
phosphonomalonates. Many synthetic protocols have been
developed for the synthesis of β-phosphonomalonates.12
However, reports for the synthesis of 2-oxindol-3-ylphos-
phonates are rare.13 In addition, these methods are often as-
sociated with limitations such as moderate yields, limited
substrates, and elevated temperatures. In particular, two-
pot procedures are often needed, in which the α,β-unsatu-
rated malonate intermediates are prepared in a separate
step, followed by the phosphorus–carbon bond formation
in the next separate step.13a As a result, the development of
a simple, clean, and efficient method for the one-pot syn-
thesis of 2-oxindol-3-ylphosphonates in excellent yields
tolerating a broad range of substrates is still considered a
significant challenge.
DOI: 10.1055/s-0036-1588357; Art ID: ss-2016-h0663-op
Abstract A simple, clean, and efficient approach for the one-pot syn-
thesis of 2-oxindol-3-ylphosphonates has been successfully developed.
With 7 mol% loading of the 1,4-diazabicyclo[2.2.2]octane-based ionic
liquid catalyst, 2-oxindol-3-ylphosphonates form in good to excellent
yields within short times. This tandem reaction involves a phospha-
Michael addition to the activated alkenes, which form in situ by
Knoevenagel condensation. The corresponding products are easily sep-
arated and purified by simple crystallization. The catalyst can be recy-
cled five times without significant activity loss. This approach is readily
amenable to large-scale synthesis.
Keywords phosphonates, oxindoles, ionic liquid, Knoevenagel con-
densation, phospha-Michael addition, tandem reaction
Multicomponent reactions (MCRs) are some of the most
important reactions, and are widely used in organic synthe-
sis for the construction of bioactive heterocyclic com-
pounds.1 MCRs offer an efficient way for the construction of
highly complex molecules from simple starting materials
via one-pot procedures without complicated purification
steps. These reactions also comply with the principles of
green chemistry, such as saving solvents, time, and re-
agents.
Indoles and their derivatives are widespread in natural
compounds. They have been identified as one of the most
intriguing heterocyclic compounds.2 Compounds contain-
ing the indole framework often display a wide variety of
pharmacological and biological activities.3 Oxindoles are
key compounds among the indole derivatives. In particular,
Ionic liquids (ILs) as environmentally friendly solvents
have been employed in many important transformations.14
In recent years, many IL catalysts have been prepared and
have shown notable performances in various reactions.15–19
Recently, we synthesized several kinds of highly efficient IL
catalysts and applied them in many important carbon–
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

B
L.-L. Song et al.
Paper
Synthesis
CN
O
CN
N
X
O
X
CN
O
O
HP(OR3)2
P(OR3)2
X
2
3
R1
O
R1
O
R1
N
N
R2
R2
R2
in situ
X = CN, CO2Et
1
4
Scheme 1 Tandem reaction for the one-pot synthesis of 2-oxindol-3-ylphosphonates 4
carbon and phosphorus–carbon bond-formation reac-
Table 1 The Effect of the DABCO-Based Ionic Liquid Catalysts on the
Tandem Reaction for the Synthesis of 2-Oxindol-3-ylphosphonate 4aa
tions.20–24 As part of our ongoing investigations on IL-cata-
lyzed organic reactions, we report here the results of using
ILs based on 1,4-diazabicyclo[2.2.2]octane (DABCO) as cata-
lysts for the preparation of 2-oxindol-3-ylphosphonates via
a one-pot tandem Knoevenagel–phospha-Michael reaction.
In this procedure, firstly, activated alkenes are formed in
situ from isatins and active methylenes via Knoevenagel
condensation. Then a phospha-Michael addition takes
place, affording the desired products in excellent yields
(Scheme 1).
O
O
CN
N
O
P
H
OEt
OEt
O
NC
1a
cat. (10 mol%)
O
P
CN
+
OEt
OEt
MeCN (1 mL)
r.t.
H
N
CN
H
4a
3a
2a
Yield (%)b
Eight kinds of DABCO-based IL catalysts were synthe-
sized, and they are shown in Figure 1.21 We initiated our in-
vestigations by screening for the best DABCO-based IL cata-
lyst for the model reaction between isatin (1a), malononi-
trile (2a), and diethyl phosphite (3a) in MeCN at room
temperature. The results are summarized in Table 1. All
tested DABCO-based IL catalysts could promote the reac-
tion, and afforded the corresponding product 4a in moder-
ate to good yields. When the reactions were carried out in
the presence of IL catalysts containing strong acids or alkyl
substituents, the reactions required longer reaction times
and afforded 4a in moderate yields. The IL catalysts with
longer carbon chain substituents gave the product 4a in
higher yield than that obtained with short carbon chain
substituents (entries 5 vs 6, 7 vs 8). Among the different
DABCO-based catalysts, [DABCO-H][AcO] gave 4a in an ex-
cellent yield of 95% within only one hour at room tempera-
ture (entry 1).
Entry
Cat. (10 mol%)
Time (h)
1
2
3
4
5
6
7
8
[DABCO-H][AcO]
[DABCO-H][HSO4]
[DABCO-H]Cl
1
24
24
24
24
24
24
24
95
74
87
90
32
54
26
67
[DABCO-H][BF4]
[DABCO-C4]Cl
[DABCO-C8]Cl
[DABCO-C2OH]Cl
[DABCO-C3OH]Cl
a Reaction conditions: isatin (1a, 1 mmol), malononitrile (2a, 1 mmol), di-
ethyl phosphite (3a, 1 mmol), DABCO-based IL catalyst (0.1 mmol), MeCN
(1 mL).
b Isolated yield.
When the reaction was performed in the classic organic
solvents MeCN, EtOH, 1,2-dichloroethane (DCE), and THF,
the target product was formed in good to excellent yield
(entries 1–4). Especially in THF, all the substrates dissolve
very well, and a near quantitative yield is obtained in only
20 minutes at room temperature (entry 4). When water
was used as the solvent, product 4a was obtained in a very
low yield (entry 5), because of poor dissolution. We next
tried to decrease the catalyst loading and the amount of sol-
vent. When the reaction was performed in 0.3 mL THF, cat-
alyst loadings of 10 mol%, 7 mol%, and 5 mol% could all re-
sult in quantitative yield, but the reaction time had to be in-
creased when reducing the catalyst loading (entries 6–8).
When the loading of the catalyst [DABCO-H][AcO] was re-
duced to 3 mol%, product 4a was obtained in only 15% yield
(entry 9). Importantly, in the absence of the [DABCO-
H][AcO] IL, no 4a was produced, even after one day (entry
10).
Next, different solvents were screened in the presence
of the catalyst [DABCO-H][AcO]. As shown in Table 2, the
yield of 4a differed significantly for different solvents.
R
N
N
X
[DABCO-H][AcO], X = AcO, R = H
[DABCO-H][HSO4], X = HSO4, R = H
[DABCO-H]Cl, X = Cl, R = H
[DABCO-H][BF4], X = BF4, R = H
[DABCO-C4]Cl, X = Cl, R = n-butyl
[DABCO-C8]Cl, X = Cl, R = n-octyl
[DABCO-C2OH]Cl, X = Cl, R = 2-hydroxyethyl
[DABCO-C3OH]Cl, X = Cl, R = 3-hydroxypropyl
Figure 1 Structures of the DABCO-based ionic liquid catalysts
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

C
L.-L. Song et al.
Paper
Synthesis
Table 2 Optimization of the Reaction Conditionsa
Table 3 Synthesis of 2-Oxindol-3-ylphosphonates 4 by Using [DABCO-
H][AcO] at Room Temperaturea
O
O
O
R2
N
H
1a
CN
O
O
P
N
R1
OEt
OEt
O
NC
[DABCO-H]AcO
(x mol%)
CN
N
O
P
OR3
OR3
1
+
O
P
NC
[DABCO-H]AcO
(7 mol%)
CN
OEt
OEt
solvent (1 mL)
r.t.
O
P
CN
+
H
N
H
OR3
OR3
R2
CN
H
O
CN
THF (0.3 mL), r.t.
4a
2a
3a
R1
2a
3
4
Entry
x (mol%)
Solvent
Time (min)
Yield (%)b
Entry Isatin 1
R3 Product 4
Time Yield
(min) (%)b
1
2
10
10
10
10
10
10
7
MeCN
EtOH
DCE
THF
H2O
THF
THF
THF
THF
THF
60
120
180
20
95
82
CN
O
P
O
OEt
NC
3
95
OEt
O
O
4
98
1
Et
Et
Et
Et
Et
Et
Et
17 100
N
N
H
5
120
12
<5
H
1a
4a
6c
7c
8c
9c
10c
100
100
100
15
CN
17
O
P
O
OEt
OEt
NC
F
5
40
F
O
2
3
4
5
6
7
60
40
97
97
O
3
120
24 h
N
N
H
H
0
–
1b
4b
a Reaction conditions: isatin (1a, 1 mmol), malononitrile (2a, 1 mmol), di-
ethyl phosphite (3a, 1 mmol), [DABCO-H][AcO] (0.1 mmol), solvent (1 mL).
b Isolated yield.
CN
O
P
O
OEt
OEt
O
NC
c THF (0.3 mL) used.
Cl
Cl
O
N
N
H
H
With the established optimal reaction conditions in
hand, a variety of isatins 1 with malononitrile (2a), and di-
alkyl or diphenyl phosphites 3 were next examined in the
reaction catalyzed by [DABCO-H][AcO] (7 mol%) in THF at
room temperature. As shown in Table 3, all isatins contain-
ing electron-withdrawing or -donating groups could react
well with malononitrile and diethyl phosphite, and con-
verted into the corresponding 2-oxindol-3-ylphosphonates
in good to excellent yields (87–100%) within 5–300 minutes
(entries 1–9). To show the generality and scope of this new
protocol, dimethyl phosphite (3b) and diphenyl phosphite
(3c) were also studied in this one-pot, three-component
tandem Knoevenagel–phospha-Michael reaction (entries
10 and 11). They also worked well under the optimal reac-
tion conditions. Notably, even diphenyl phosphite, which
contains sterically hindered phenyl groups, could also be
converted into the desired product 4k in a good yield of
90%.
1c
4c
CN
O
P
O
OEt
OEt
O
NC
Br
Br
O
20 100
N
N
H
H
1d
4d
CN
O
O
OEt
OEt
NC
MeO
P
MeO
O
5
120
300
100
O
N
N
H
H
1e
4e
CN
O
O
OEt
OEt
O
NC
O2N
P
O2N
O
91
N
N
H
H
1f
4f
Compared to malononitrile (2a), ethyl cyanoacetate (2b)
is a less reactive substrate, because the electron-withdraw-
ing ability of the carboxylate group is weaker than that of
the CN group. Therefore, the reaction of ethyl cyanoacetate
(2b) with isatin (1a) and diethyl phosphite (3a) was carried
out under heating, and afforded the corresponding product
4l in a yield of 78% after a longer reaction time (Scheme 2).
CN
NC
Br
O
P
O
Br
OEt
OEt
O
O
87
N
N
H
H
1g
4g
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

D
L.-L. Song et al.
Paper
Synthesis
Table 3 (continued)
NC
CN
O
O
O
O
R3 Product 4
Time Yield
(min) (%)b
[DABCO-H]AcO
(7 mol%)
Entry Isatin 1
P
OEt
O
P
CN
OEt
OEt
+
+
H
OEt
CN
THF (0.3 mL), r.t.
40 min
CN
O
O
2a
3a
OEt
OEt
O
NC
P
5
O
95% yield
8
Et
15
98
N
N
Scheme 3 Reaction of acenaphthenequinone with malononitrile and
Me
Me
1h
diethyl phosphite
4h
CN
O
O
OEt
OEt
O
NC
technique was needed. In this procedure, the ionic liquid
catalysts dissolved in water, which could be easily recov-
ered and directly reused in the same reaction. It was ob-
served that the DABCO-based catalyst can be recovered and
reused for five times at least. The results are presented in
Figure 2.
P
O
9
Et
15 100
N
N
Bn
Bn
1i
4i
CN
O
OMe
OMe
O
NC
P
10
11
1a
1a
Me
20
94
90
N
H
4j
CN
O
P
OPh
NC
OPh
O
Ph
100
N
H
4k
a Reaction conditions: isatin 1 (1 mmol), malononitrile (2a, 1 mmol), phos-
phite 3 (1 mmol), [DABCO-H][AcO] (0.07 mmol), THF (0.3 mL), r.t.
b Isolated yield.
O
Figure 2 Recycling of the catalyst [DABCO-H][AcO] for the synthesis of
4a. Reagents and conditions: isatin (1a, 5 mmol), malononitrile (2a, 5
mmol), diethyl phosphite (3a, 5 mmol), catalyst (7 mol%) THF (2 mL),
r.t.
O
CN
N
O
P
H
OEt
OEt
O
EtO2C
[DABCO-H]AcO
(7 mol%)
1a
O
P
CN
+
OEt
OEt
THF (0.3 mL)
50 °C, 4 h
H
To display the potential applicability of this methodolo-
gy, we tried out this one-pot three-component tandem re-
action on a 40-mmol scale in the presence of only 5 mol% of
the catalyst, and obtained 13.3 grams of 4a in >99% yield
(Scheme 4).
N
CO2Et
H
4l
78% yield
2b
3a
Scheme 2 Reaction of isatin with ethyl cyanoacetate and diethyl phos-
phite
CN
O
O
OEt
OEt
O
NC
[DABCO-H]AcO
(5 mol%)
P
O
P
Isatins were replaced by acenaphthenequinone in the
reaction with malononitrile (2a) and diethyl phosphite (3a)
under the optimized conditions. As expected, the reaction
proceeded very cleanly and afforded the corresponding
product 5 in an excellent yield of 95% (Scheme 3). No unde-
sirable side reactions were observed under the mild condi-
tions.
CN
CN
OEt
OEt
O
+
+
H
THF, r.t.
N
N
H
H
1a
2
3a
4a
13.3 g, yield >99%
Scheme 4 Synthesis of 2-oxindol-3-ylphosphonate 4a on 40-mmol
scale
The recyclability and reusability of the catalyst was ex-
amined for the synthesis of 4a. When the reaction was
complete, the crude products were filtered and washed
with cold water. The 2-oxindol-3-ylphosphonates could be
purified simply by crystallization, and no chromatographic
A plausible mechanism is proposed and shown in
Scheme 5. The tandem reaction involves a double activa-
tion. First, both of the carbonyl groups of the isatin, as well
as the malononitrile, are activated by the catalyst [DABCO-
H][AcO], to afford the key intermediate alkene I. Then, an-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

E
L.-L. Song et al.
Paper
Synthesis
other double activation of the cyano group and diethyl
phosphite occurred. The catalyst removes a proton from di-
ethyl phosphite and transfers a proton, attaching to itself to
the cyano group. Finally, tautomerization via a [1,3] hydro-
gen shift takes place to produce the desired product 4a.
2-Oxindol-3-ylphosphonates 4; General Procedure
Isatin 1 (1 mmol), active methylene 2 (1 mmol), phosphite 3 (1
mmol), and [DABCO-H][AcO] (17.2 mg, 0.1 mmol) were added to THF
(0.3 mL). Then the reaction mixture was vigorously stirred at r.t. The
progress of the reaction was monitored by TLC (n-hexane–EtOAc,
4:1). After completion of the reaction, cold H2O (2 mL) was added. The
IL catalyst dissolved in the H2O and the insoluble crude products were
isolated by simple filtration. The crude products were recrystallized
from EtOH to afford pure final products. After removal of the H2O un-
der reduced pressure, the catalyst [DABCO-H][AcO] could be directly
reused for the next run under similar reaction conditions.
N
N
H
O
AcO
H
H
CN
CN
O
O
–H2O
NC
O
N
Diethyl [3-(Dicyanomethyl)-2-oxindol-3-yl]phosphonate (4a)13c
H
N
H
CN
CN
Yield: 333 mg (100%); white solid; mp 174–176 °C.
+
O
1H NMR (400 MHz, CDCl3): δ = 1.28 (t, J = 6.8 Hz, 3 H, CH3), 1.35 (t, 3 H,
J = 6.8 Hz, CH3), 4.14–4.19 (m, 4 H, OCH2), 4.87 (d, J = 6.8 Hz, 1 H, CH),
7.00 (d, J = 7.2 Hz, 1 H, ArH), 7.14 (t, J = 7.6 Hz, 1 H, ArH), 7.37 (t, J = 6.8
Hz, 1 H, ArH), 7.69 (d, J = 6.8 Hz, 1 H, ArH), 10.83 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3): δ = 15.76, 26.94, 53.06 (d, 1JCP = 139 Hz, C-
P), 64.36, 65.02, 109.74, 110.25, 110.70, 120.58, 122.50, 125.67,
130.61, 142.77, 170.42.
CN
O
P
H
EtO
OEt
H
N
N
N
H
AcO
I
OEt
EtO
O
H
P
N
N
CN
CN
31P NMR (161 MHz, CDCl3): δ = 17.05.
O
OEt
OEt
O
NC
P
H
N
HN
AcO
Diethyl [3-(Dicyanomethyl)-5-fluoro-2-oxindol-3-yl]phosphonate
(4b)25
O
N
H
4a
Yield: 340 mg (97%); pale solid; mp 195–197 °C.
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 6.8 Hz, 3 H, CH3), 1.36 (t, J =
6.8 Hz, 3 H, CH3), 4.17–4.24 (m, 4 H, OCH2), 5.11 (d, J = 6.8 Hz, 1 H,
CH), 6.97 (dd, J = 4.4, 4.4 Hz, 1 H, ArH), 7.11 (t, J = 8.8 Hz, 1 H, ArH),
7.42 (d, J = 8.0 Hz, 1 H, ArH), 11.09 (s, 1 H, NH).
Scheme 5 Proposed mechanism
In conclusion, we have introduced a clean, efficient, and
atom-economical method for the preparation of 2-oxindol-
3-ylphosphonates from readily available starting materials
via a one-pot three-component tandem reaction. The reac-
tion involves a phospha-Michael addition of a phosphite to
an activated alkene, which formed in situ from an isatin and
an active methylene by Knoevenagel condensation. This
unique tandem Knoevenagel–phospha-Michael reaction al-
lows the preparation of 2-oxindol-3-ylphosphonates in just
one step. The DABCO-based ionic liquid catalyst, which is
inexpensive and recyclable, drives the reaction to afford the
desired products in high yields within short times. This
procedure also offers other significant advantages including
a green workup, ease of separation and recyclability of the
catalyst, scaling up to multigram quantities, and no byprod-
uct formation. A plausible reaction mechanism was pro-
posed. We believe that this method will find useful applica-
tions in organic synthesis.
13C NMR (100 MHz, CDCl3–DMSO-d6): δ = 16.11, 27.21, 53.73 (d, 1JCP
=
138.6 Hz, C-P), 64.85, 65.57, 109.82, 110.43, 111.85, 113.95, 117.65,
122.40, 139.27, 158.74, 170.68.
31P NMR (162 MHz, CDCl3): δ = 16.54.
Diethyl [5-Chloro-3-(dicyanomethyl)-2-oxindol-3-yl]phosphonate
(4c)13c
Yield: 356 mg (97%); white solid; mp 193–195 °C.
1H NMR (400 MHz, CDCl3–DMSO-d6): δ = 1.31 (t, J = 6.8 Hz, 3 H, CH3),
1.36 (t, J = 6.8 Hz, 3 H, CH3), 4.10–4.29 (m, 4 H, OCH2), 5.09 (d, J = 6.8
Hz, 1 H, CH), 6.96 (d, J = 8.4 Hz, 1 H, ArH), 7.36 (d, J = 8.0 Hz, 1 H, ArH),
7.63 (s, 1 H, ArH), 11.14 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3–DMSO-d6): δ = 16.07, 27.09, 53.46 (d, 1JCP
=
138.5 Hz), 64.84, 65.57, 109.78, 110.29, 112.11, 122.59, 126.16,
127.88, 130.94, 141.72, 170.38.
31P NMR (162 MHz, CDCl3–DMSO-d6): δ = 11.56.
Diethyl [5-Bromo-3-(dicyanomethyl)-2-oxindol-3-yl]phosphonate
(4d)13c
Yield: 411 mg (100%); white solid; mp 186–188 °C.
All chemicals were purchased from commercial suppliers and were
used without further purification. Melting points were determined
with an X-4 apparatus and are uncorrected. 1H NMR and 13C NMR
spectra were recorded on a Bruker AV-400 spectrometer with DMSO-
d6 or CDCl3 as the solvent. Chemical shifts are reported relative to
TMS as internal standard.
1H NMR (400 MHz, CDCl3): δ = 1.28–1.35 (m, 6 H, CH3), 4.20 (t, J = 6.4
Hz, 4 H, OCH2), 4.81 (d, J = 4.4 Hz, 1 H, CH), 6.86 (d, J = 8.0 Hz, 1 H,
ArH), 7.48 (s, 1 H, ArH), 7.75 (d, J = 5.2 Hz, 1 H, ArH), 10.93 (s, 1 H,
NH).
13C NMR (100 MHz, CDCl3–DMSO-d6): δ = 15.78, 26.80, 53.07 (d, 1JCP
=
137.7 Hz, C-P), 64.54, 65.28, 110.09, 112.26, 114.72, 122.77, 128.59,
133.49, 142.01, 169.98.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

F
L.-L. Song et al.
Paper
Synthesis
1
31P NMR (162 MHz, CDCl3–DMSO-d6): δ = 11.60.
13C NMR (100 MHz, CDCl3): δ = 16.25, 27.44, 44.71, 53.34 (d, JCP
=
138.9 Hz), 64.98, 65.95, 109.61, 110.50, 120.22, 123.91, 126.23,
127.22, 128.02, 128.93, 131.23, 134.34, 143.72, 169.45.
31P NMR (162 MHz, CDCl3): δ = 7.57.
Diethyl [3-(Dicyanomethyl)-5-methoxy-2-oxindol-3-yl]phospho-
nate (4e)25
Yield: 363 mg (100%); pale solid; mp 179–181 °C.
Dimethyl [3-(Dicyanomethyl)-2-oxindol-3-yl]phosphonate (4j)13c
1H NMR (400 MHz, CDCl3–DMSO-d6): δ = 1.25–1.37 (m, 6 H, CH3),
3.76–3.81 (m, 3 H, OCH3), 4.18–4.2 (m, 4 H, OCH2), 4.96 (d, J = 6 Hz, 1
H, CH), 6.87–6.92 (m, 2 H, ArH), 7.28 (s, 1 H, ArH), 10.77 (s, 1 H, NH).
13C NMR (100 MHz, CDCl3–DMSO-d6): δ = 16.55, 27.78, 54.19 (d, 1JCP
141 Hz, C-P), 56.11, 65.12, 65.86, 110.17, 110.93, 112.01, 113.10,
116.42, 122.33, 136.69, 156.18, 171.01.
Yield: 287 mg (94%); white solid; mp 175–177 °C.
1H NMR (400 MHz, CDCl3): δ = 3.67 (d, J = 10.8 Hz, 3 H, CH3), 3.75 (d,
J = 10.8 Hz, 3 H, CH3), 5.98 (br s, 1 H, CH), 7.00 (d, J = 8.0 Hz, 1 H, ArH),
7.16 (t, J = 7.6 Hz, 1 H, ArH), 7.41 (t, J = 7.2 Hz, 1 H, ArH), 7.52 (d, J = 7.2
Hz, 1 H, ArH), 11.37 (s, 1 H, NH).
=
1
31P NMR (162 MHz, CDCl3–DMSO-d6): δ = 12.42.
13C NMR (100 MHz, CDCl3): δ = 26.92, 52.75 (d, JCP = 139 Hz, C-P),
2
55.03 (d, JCP = 78 Hz, C-P), 110.76, 121.32, 122.71, 125.69, 131.06,
142.94, 170.41.
31P NMR (161 MHz, CDCl3): δ = 14.99.
Diethyl [3-(Dicyanomethyl)-5-nitro-2-oxindol-3-yl]phosphonate
(4f)13c
Yield: 344 mg (91%); brown solid; mp 186–188 °C.
Diphenyl [3-(Dicyanomethyl)-2-oxindol-3-yl]phosphonate (4k)13c
1H NMR (400 MHz, DMSO-d6): δ = 1.18 (t, J = 6.8 Hz, 3 H, CH3), 1.28 (t,
J = 6.8 Hz, 3 H, CH3), 4.06–4.20 (m, 4 H, OCH2), 6.2 (s, 1 H, CH), 7.26 (d,
J = 8.4 Hz, 1 H, ArH), 8.40 (d, J = 7.6 Hz, 2 H, ArH), 12.13 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 16.06, 26.53, 52.56 (d, 1JCP = 136.4
Hz, C-P), 65.05, 65.70, 111.31, 121.59, 122.78, 128.18, 142.73, 149.27,
171.14.
Yield: 386 mg (90%); white solid; mp 170–172 °C.
1H NMR (400 MHz, DMSO-d6): δ = 6.44 (br s, 1 H, CH), 6.83 (d, J = 8.0
Hz, 2 H, ArH), 7.10 (d, J = 8.0 Hz, 1 H, ArH), 7.15–7.24 (m, 4 H, ArH),
7.27–7.32 (m, 3 H, ArH), 7.42–7.54 (m, 3 H, ArH), 7.69 (d, J = 7.6 Hz, 1
H, ArH), 11.64 (s, 1 H, NH).
31P NMR (162 MHz, DMSO-d6): δ = 11.16.
13C NMR (100 MHz, DMSO-d6): δ = 26.99, 52.40 (d, 1JCP = 145.3 Hz, C-
P), 111.12, 119.97, 120.21, 123.08, 125.86, 126.18, 129.88, 130.29,
131.66, 143.09, 149.11, 169.48.
Diethyl [4-Bromo-3-(dicyanomethyl)-2-oxindol-3-yl]phosphonate
(4g)25
31P NMR (162 MHz, DMSO-d6): δ = 5.56.
Yield: 358 mg (87%); white solid; mp 193–195 °C.
1H NMR (400 MHz, DMSO-d6): δ = 1.10 (t, J = 6.8 Hz, 3 H, CH3), 1.25 (t,
J = 6.8 Hz, 3 H, CH3), 3.92–4.06 (m, 2 H, OCH2), 4.10–4.18 (m, 2 H,
OCH2), 6.08 (s, 1 H, CH), 6.99–7.02 (m, 1 H, ArH), 7.31–7.33 (m, 2 H,
ArH), 11.58 (s, 1 H, NH).
Ethyl 2-Cyano-2-[3-(diethoxyphosphoryl)-2-oxindol-3-yl]acetate
(4l)13c
Yield: 297 mg (78%); white solid; mp 187–189 °C.
1H NMR (400 MHz, DMSO-d6): δ = 0.86 (t, J = 6.8 Hz, 3 H, CO2CH2CH3),
1.16–1.26 (m, 6 H, CH3), 3.85–3.91 (m, 2 H, CO2CH2), 4.01–4.10 (m, 4
H, OCH2), 4.90 (t, J = 7.2 Hz, 1 H, CH), 6.90 (d, J = 7.2 Hz, 1 H, ArH),
7.00–7.06 (m, 1 H, ArH), 7.30 (t, J = 6.8 Hz, 1 H, ArH), 7.44 (d, J = 7.2
Hz, 1 H, ArH), 11.04 (s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): δ = 13.11, 15.90, 53.61 (d, 1JCP = 134.4
Hz, C-P), 62.60, 63.85, 64.16, 109.87, 114.84, 121.52, 122.67, 125.45,
129.85, 143.56, 162.84, 172.09.
13C NMR (100 MHz, DMSO-d6): δ = 16.37, 16.51, 25.63, 56.26 (d, 1JCP
=
131.8 Hz, C-P), 65.02, 65.55, 110.51, 119.84, 121.76, 127.59, 132.98,
145.46, 170.58.
31P NMR (162 MHz, DMSO-d6): δ = 11.26.
Diethyl [3-(Dicyanomethyl)-1-methyl-2-oxindol-3-yl]phospho-
nate (4h)25
31P NMR (162 MHz, DMSO-d6): δ = 14.38.
Yield: 340 mg (98%); white solid; mp 114–116 °C.
1H NMR (400 MHz, CDCl3): δ = 1.30 (t, J = 6.8 Hz, 3 H, CH3), 1.36 (t, J =
7.2 Hz, 3 H, CH3), 3.30 (s, 3 H, CH3), 4.17–4.23 (m, 4 H, OCH2), 4.79 (d,
J = 6.4 Hz, 1 H, CH), 6.98 (d, J = 8 Hz, 1 H, ArH), 7.23 (t, J = 7.6 Hz, 1 H,
ArH), 7.49 (t, J = 7.6 Hz, 1 H, ArH), 7.76 (d, J = 7.6 Hz, 1 H, ArH).
Diethyl [1-(Dicyanomethyl)-2-oxo-1,2-dihydroacenaphthylen-1-
yl)phosphonate (5)13b
Yield: 350 mg (95%); purple solid; mp 153–155 °C.
13C NMR (100 MHz, CDCl3–DMSO-d6): δ = 11.24, 22.53, 48.32 (d, 1JCP
139.3 Hz, C-P), 59.83, 60.77, 104.46, 105.27, 115.25, 118.94, 121.17,
126.37, 139.58, 164.23.
=
1H NMR (400 MHz, DMSO-d6): δ = 0.96 (t, J = 7.2 Hz, 3 H, CH3), 1.20 (t,
J = 6.8 Hz, 3 H, CH3), 3.82–3.91 (m, 1 H, OCH2), 3.96–4.02 (m, 1 H,
OCH2), 4.04–4.12 (m, 2 H, OCH2), 6.18 (d, J = 8.0 Hz, 1 H, CH), 7.89–
7.98 (m, 3 H, ArH), 8.21 (t, J = 7.6 Hz, 2 H, ArH), 8.47 (d, J = 8.0 Hz, 1 H,
ArH).
31P NMR (162 MHz, CDCl3–DMSO-d6): δ = 7.42.
13C NMR (100 MHz, DMSO-d6): δ = 15.63, 15.94, 26.49, 56.88 (d, 1JCP
135.9 Hz, C-P), 64.27, 64.75, 124.07, 127.17, 128.98, 129.32, 130.35,
133.69, 141.74, 194.63.
=
Diethyl [1-Benzyl-3-(dicyanomethyl)-2-oxindol-3-yl]phospho-
nate (4i)13b
Yield: 423 mg (100%); white solid; mp 178–180 °C.
31P NMR (162 MHz, DMSO-d6): δ = 12.96.
1H NMR (400 MHz, CDCl3): δ = 1.27 (t, J = 6.8 Hz, 3 H, CH3), 1.35 (t, J =
6.8 Hz, 3 H, CH3), 4.11–4.26 (m, 4 H, OCH2), 4.85 (d, J = 6 Hz, 1 H, CH),
4.89 (d, J = 16 Hz, 1 H, NCH2), 5.09 (d, J = 16 Hz, 1 H, NCH2), 6.81 (d, J =
7.6 Hz, 1 H, ArH), 7.18 (t, J = 7.6 Hz, 1 H, ArH), 7.25–7.36 (m, 6 H, ArH),
7.77 (d, J = 7.6 Hz, 1 H, ArH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G

G
L.-L. Song et al.
Paper
Synthesis
Acknowledgement
410, 162. (d) Hashem, S.; Sakineh, E.; Mohammad, M. D. Tetra-
hedron 2013, 69, 4708. (e) Kulkarni, M. A.; Pandurangi, V. R.;
Desai, U. V.; Wadgaonkar, P. P. C. R. Chim. 2012, 15, 745.
(f) Gaikwad, D. S.; Undale, K. A.; Shaikh, T. S.; Pore, D. M. C. R.
Chim. 2011, 14, 865. (g) Mohammadi, R.; Kassaee, M. Z. J. Mol.
Catal. A: Chem. 2013, 380, 152. (h) Sobhani, S.; Pakdin-Parizi, Z.
RSC Adv. 2014, 4, 13071. (i) Kolla, S. R.; Lee, Y. R. Tetrahedron
2012, 68, 226. (j) Dar, B. A.; Pandey, N.; Singh, S.; Bamezai, R. K.;
Sharma, M.; Vishwakarma, R. A.; Singh, B. Tetrahedron Lett.
2014, 55, 623. (k) Sobhani, S.; Jahanshahi, R. Synth. Commun.
2013, 43, 3247. (l) Sobhani, S.; Ghasemzadeh, M. S.;
Honarmand, M. Catal. Lett. 2014, 144, 1515. (m) Sobhani, S.;
Parizi, Z. P.; Rezazadeh, S. J. Organomet. Chem. 2011, 696, 813.
(n) Sobhani, S.; Rezazadeh, S. Synlett 2010, 1485. (o) Sobhani, S.;
Bazrafshan, M.; Delluei, A. A.; Parizi, Z. P. Appl. Catal., A 2013,
454, 145.
This work was financially supported by the National Natural Science
Foundation of China (NSFC) (No. 21302101), NFFTBS (No. J1103306),
and National Training Programs of Innovation and Entrepreneurship
for Undergraduates (No. 201610055092, 201610055085). We also
thank the Nankai University State Key Laboratory of Elemento-Organic
Chemistry for support.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588357.
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References
(13) (a) Shakibaei, G. I.; Samadi, S.; Ghahremanzadeh, R.; Bazgir, A.
J. Comb. Chem. 2010, 12, 295. (b) Imani Shakibaei, G.; Feiz, A.;
Ghahremanzadeh, R.; Bazgir, A. Chem. Pharm. Bull. 2010, 58,
896. (c) Hosseini-Sarvari, M.; Tavakolian, M. New J. Chem. 2012,
36, 1014.
(14) (a) Jain, N.; Kumar, A.; Chauhan, S.; Chauhan, S. M. S. Tetrahe-
dron 2005, 61, 1015. (b) Park, S.; Kazlauskas, J. Curr. Opin. Bio-
technol. 2003, 14, 432.
(15) (a) Luo, S. Z.; Mi, X. L.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J. P.
Angew. Chem. Int. Ed. 2006, 45, 3093. (b) Ni, B.; Zhang, Q. Y.;
Headley, A. D. Green Chem. 2007, 9, 737. (c) Ranu, B. C.;
Banerjee, S. Org. Lett. 2005, 7, 3049. (d) Xu, J.-M.; Qian, C.; Liu,
B.-K.; Wu, Q.; Lin, X.-F. Tetrahedron 2007, 63, 986. (e) Xu, J.-M.;
Wu, Q.; Zhang, Q.-Y.; Zhang, F.; Lin, X.-F. Eur. J. Org. Chem. 2007,
1798.
(1) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
(b) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123. (c) Ugi, I. Pure Appl.
Chem. 2001, 73, 187. (d) Toure, B. B.; Hall, D. G. Chem. Rev. 2009,
109, 4439. (e) Sunderhaus, J. D.; Martin, S. F. Chem. Eur. J. 2009,
15, 1300.
(2) (a) Cacchi, S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873. (b) Joucla,
L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673. (c) Bandini,
M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48, 9608.
(d) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010,
39, 4449. (e) Kamano, Y.; Zhang, H. P.; Ichihara, Y.; Kizu, H.;
Komiyama, K.; Pettit, G. R. Tetrahedron Lett. 1995, 36, 2783.
(3) Sundberg, R. J. The Chemistry of Indoles; Academic: New York,
1996.
(16) (a) Zhou, L.; Wang, L. Chem. Lett. 2007, 35, 628. (b) Luo, S. Z.; Mi,
X. L.; Zhang, L.; Liu, S.; Xu, H.; Cheng, J. P. Tetrahedron 2007, 63,
1923. (c) Hu, S. Q.; Jiang, T.; Zhang, Z. F.; Zhu, A. L.; Han, B. X.;
Song, J. L.; Xie, Y.; Li, W. J. Tetrahedron Lett. 2007, 48, 5613.
(17) (a) Albert, S. C. Green Chem. 2010, 12, 949. (b) Sayin, S.; Yilmaz,
M. RSC Adv. 2014, 4, 2219. (c) Petrović, V. P.; Simijonović, D.;
Živanović, M. N.; Košarić, J. V.; Petrović, Z. D.; Markovića, S.;
Marković, S. D. RSC Adv. 2014, 4, 24635.
(18) (a) Wasserscheid, P.; Sesing, M.; Korth, W. Green Chem. 2002, 4,
134. (b) Luo, Y.; Pan, A. X.; Xing, M.; Chen, M.; Xie, J. M. Adv.
Mater. Res. 2012, 443, 917. (c) Tran, P. H.; Duus, F.; Le, T. N. Tet-
rahedron Lett. 2012, 53, 222.
(4) (a) Galliford, C. V.; Scheidt, K. A. Angew. Chem. Int. Ed. 2007, 46,
8748. (b) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209.
(5) (a) Fields, S. C. Tetrahedron 1999, 55, 12237. (b) Seto, H.;
Kuzuyama, T. Nat. Prod. Rep. 1999, 16, 589.
(6) (a) Onouchi, H.; Miyagawa, T.; Furuko, A.; Maeda, K.; Yashima, E.
J. Am. Chem. Soc. 2005, 127, 2960. (b) Queffelec, C.; Petit, M.;
Janvier, P.; Knight, D. A.; Bujoli, B. Chem. Rev. 2012, 112, 3777.
(7) (a) Chelucci, G.; Orru, G.; Pinna, G. A. Tetrahedron 2003, 59,
9471. (b) Surry, D. S.; Buchwald, S. L. Angew. Chem. Int. Ed. 2008,
47, 6338. (c) Guo, Y.; Fu, H.; Chen, H.; Li, X. Catal. Commun.
2008, 9, 1842. (d) Li, Y.; Lu, L.-Q.; Das, S.; Pisiewicz, S.; Junge, K.;
Beller, M. J. Am. Chem. Soc. 2012, 134, 18325.
(19) (a) Ying, A. G.; Xu, S. L.; Liu, S.; Ni, Y. X.; Yang, J. G.; Wu, C. L. Ind.
Eng. Chem. Res. 2014, 53, 547. (b) Epishina, M. A.; Ovchinnikov, I.
V.; Kulikov, A. S.; Makhova, N. N.; Tartakovsky, V. A. Mendeleev
Commun. 2011, 21, 21. (c) Li, Z. H.; Zhou, Z. M.; Hao, X. Y.;
Zhang, J.; Dong, X.; Liu, Y. Q.; Sun, W. W.; Cao, D. Appl. Catal., A
2012, 425, 28.
(20) Xu, D.-Z.; Liu, Y.; Shi, S.; Wang, Y. Tetrahedron: Asymmetry 2010,
21, 2530.
(21) (a) Xu, D.-Z.; Liu, Y.; Shi, S.; Wang, Y. Green Chem. 2010, 12, 514.
(b) Xu, D.-Z.; Shi, S.; Wang, Y. RSC Adv. 2013, 3, 23075.
(22) Yu, Y.-Q.; Xu, D.-Z. Synthesis 2015, 47, 1869.
(23) Tong, J.; Yang, C.; Xu, D.-Z. Synthesis 2016, 48, 3559.
(24) (a) Yu, Y.-Q.; Xu, D.-Z. RSC Adv. 2015, 5, 28857. (b) Yu, Y.-Q.; Xu,
D.-Z. Tetrahedron 2015, 71, 2853.
(25) Liu, Z.-M.; Li, N.-K.; Huang, X.-F.; Wu, B.; Li, N.; Kwok, C.-Y.;
Wang, Y.; Wang, X.-W. Tetrahedron 2014, 70, 2406.
(8) (a) Peyman, A.; Budt, K. H.; Paning, J. S.; Stowasser, B.; Ruppert,
D. Tetrahedron Lett. 1992, 33, 4549. (b) Alonso, E.; Solis, A.; Del
Pozo, C. Synlett 2000, 698.
(9) Kafarski, P.; Lejczak, B. Phosphorus Sulfur Silicon Relat. Elem.
1991, 63, 193.
(10) Allerberger, F.; Klare, I. J. J. Antimicrob. Chemother. 1999, 43, 211.
(11) (a) Chung, S. K.; Kang, D. H. Tetrahedron: Asymmetry 1996, 7, 21.
(b) Dang, Q.; Liu, Y.; Cashion, D. K.; Kasibhatla, S. R.; Jiang, T.;
Taplin, F.; Jacintho, J. D.; Li, H.; Sun, Z.; Fan, Y.; Dare, J.; Tian, F.;
Li, W.; Gibson, T.; Lemus, R.; Van Poelje, P. D.; Potter, S. C.; Erion,
M. D. J. Med. Chem. 2011, 54, 153. (c) Chen, X.; Kopecky, D. J.;
Mihalic, J.; Jeffries, S.; Min, X.; Heath, J.; Deignan, J.; Lai, S.; Fu,
Z.; Guimaraes, C.; Shen, S.; Li, S.; Johnstone, S.; Thibault, S.; Xu,
H.; Cardozo, M.; Shen, W.; Walker, N.; Kaysers, F.; Wang, Z.
J. Med. Chem. 2012, 55, 3837.
(12) (a) Jiang, Z.; Zhang, Y.; Ye, W.; Tan, C. H. Tetrahedron Lett. 2007,
48, 51. (b) Sobhani, S.; Parizi, Z. P. Tetrahedron 2011, 67, 3540.
(c) Sobhani, S.; Parizi, Z. P.; Razavi, N. Appl. Catal., A 2011, 409–
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–G