Molecular sieve mediated sequential Knoevenagel condensation/decarboxylative Michael addition reaction: Efficient and mild conditions for the synthesis of 3,3-disubstituted oxindoles with an all carbon quaternary center

Article abstract of DOI:10.1039/c6ra16975a

A one-pot, molecular sieve mediated sequential Knoevenagel condensation/decarboxylative Michael addition reaction has been developed. We discovered that the molecular sieves not only promoted the Knoevenagel condensation of isatins and malononitrile to generate isatylidene malononitriles, but also promoted the later decarboxylative Michael addition reactions of β-ketoacids and malonic acid half thioesters (MAHTs) with isatylidene malononitriles. This protocol provides a mild and efficient method for the preparation of 3,3-disubstituted oxindoles with an all carbon quaternary center in high yields.

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ARTICLE
Molecular sieve mediated sequential Knoevenagel
condensation/decarboxylative Michael addition reaction: an
efficient and mild condition for the synthesis of 3,3-disubstituted
oxindoles with all carbon quaternary center
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Yi-Lin Guo,a Yu-Hsun Li,a Hsuan-Hao Chang ,a Ting-Shen Kuob and Jeng-Liang Han*a
www.rsc.org/
A one-pot, molecular sieve mediated sequential Knoevenagel condensation/decarboxylative Michael addition reaction has
been developed. We discovered that the molecular sieve not only promoted the Knoevenagel condensation of isatins and
malononitrile to generate isatylidene malononitriles, but also promoted the later decarboxylative Michael addition
reactions of β-ketoacids and malonic acid half thioesters (MAHTs) with isatylidene malononitriles. This protocol provides a
mild and efficient method to the preparation of 3,3-disubstituted oxindoles with an all carbon quaternary center in high
yields.
explored.13 The lower reactivity of both nucleophiles poses a
potential problem. We envisioned the decarboxylative Michael
addition of β-ketoacids and malonic acid half thioesters
Introduction
The 3,3-disubstituted oxindole framework is a common
scaffold found in a wide array of natural products and
pharmaceuticals, which show a broad spectrum of intriguing
biological activities.1 As
(MAHTs) to this Michael acceptor might be a solution to this
problem.
a consequence, the privileged
structure of 3,3-disubstituted oxindoles bearing complex
molecular architectures and functional diversity has attract
synthetic interest. As shown in Figure 1, amedalin shows
antidepressant effect, which was synthesized in the 1970s. 2
Linopiridine is an anti-Alzheimer drug candidate in phase III
clinical trials.3 Recently, (phenylpiperazinylbutyl)oxindoles,
which are selective 5-HT7 receptor antagonists, have been
synthesized and reported.4 Owing to the important
pharmaceutical value, numerous elegant methodologies for
the synthesis of 3,3-disubstituted oxindoles have been
developed.5
In recent years, isatylidene malononitriles, which are isatin
derived Michael acceptors, have been applied in the synthesis
of 3,3-disubstituted oxindoles with an all-carbon quaternary
center. Aliphatic Ketones,6 enones,7 1,3-diketones,8
phosphites,9 α,α-dicyanoalkenes,10 amides11 and enol ethers12
have been documented as nucleophiles in the organocatalytic
conjugate addition reactions to isatylidene malononitriles.
However, the Michael addition reactions of aromatic ketones
and thioesters with isatylidene malononitriles are less
Figure 1
However, the existing literature procedures show that most
decarboxylative addition reactions require a base, a metal
complex or an organic molecule serving as catalyst. Recently,
Lu and co-workers developed a catalyst-free, molecular sieve
mediated decarboxylative Mannich reaction of β-ketoacids
with sulfonyl imines.14 This protocol also promoted
decarboxylative aldol reaction between β-ketoacids and isatins.
Inspired by this work, we discovered that the molecular sieve
not only promoted the Knoevenagel condensation of isatins
and malononitrile to generate isatylidene malononitriles, but
also promoted the later decarboxylative Michael addition
reaction of β-ketoacids and MAHTs with isatylidene
malononitriles.
This journal is © The Royal Society of Chemistry 20xx
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This one-pot protocol meets the 12 Principles of Green
With the optimized conditions in hand, the general substrate
Chemistry15and provides the access to a broad range of 3,3- scope of both isatins 1a and β−ketoacid
3 were examined, and
disubstituted oxindoles in high yields. To the best of our the results are shown in table 2.
knowledge, there are no precedent methods for the
Generally, all reactions proceeded smoothly to give the
preparation of 3,3-disubstituted oxindoles with an all carbon corresponding 3,3-disubstituted oxindoles in good to high
quaternary center under catalyst-free condition. We herein yields (up to 99%). The effect of isatins with different-
wish to report our preliminary results about this work.
positioned halogens was first investigated. The 5-Cl, 6-Cl, and
7-Cl substituted isatins all showed good tolerance to this one-
pot reaction and gave the products 4c-e in good to high yields
(Table 2, entries 3-5). The 4-Cl substituted isatin, however,
Results and discussion
needed
2
equiv. of malononitrile and 50
℃
reaction
To initiate the investigation, we carried out the model
temperature to generate isatinylidene malononitrile, which
then proceeded to decarboxylative Michael addition reaction
to deliver the product 4b in moderated yield (55%, Table 2,
entry 2). The steric hindrance of 4-Cl substituted isatin might
be reducing the product yield. Isatins with other 5-halogen
substituents (5-F and 5-Br), electron-donating groups (5-Me
and 5-OMe), and electron-withdrawing groups (5-NO2) all
reacted well with malononitrile and β−ketoacid 3a to afford
the products 4f-4j in high yields (Table 2, entries 6-10). The
effect of different N-substituted isatins was also evaluated. N-
methyl, N-ethyl, and N-allyl substituted isatins all took part in
the reaction and furnished the products 4k-4m in excellent
yields (Table 2, entries 11-13).
reaction between isatin 1a, malononitrile
2 and β−ketoacid 3a,
and the results are summarized in Table 1. The rate for both
step 1 and step 2 were quite slow when no additive was added,
and only trace amount of 4a was detected by TLC analysis
(Table 1, entry 1). To our delight, the reaction proceeded
smoothly when 4Å molecular sieves were added as an additive,
and the product 4a was isolated in 94% yield (Table 1, entry 2).
Reducing the loading of 4Å molecular sieves from 300 to 100
and 50 (mg/mmol) led to a slight decrease in the product yield
(Table 1, entries 3 and 4). We then turned our attention to the
solvent screening and found EtOAc to be the ideal solvent
(Table 1, entries 5-8). The screening of drying agents showed
the 4Å molecular sieves were the utmost efficient. It seems
the basicities of drying agents (4Å>3Å>5Å>Na2SO4) play a
crucial role for the high yield of this reaction (Table 1, entries
9-11). There results were consistent with the report from Lu
and co-workers.14 We also found the SiO2 and Al2O3 had
catalytic activities for this reaction although longer reaction
times for step 2 and lower yields were observed (Table 1,
entries 12 and 13).
Table 2 One-pot reaction of isatins, malononitrile and β−ketoacidsa
Table 1 Optimization of reaction conditionsa
Entry
R1
R2
R3
4
4a
4b
4c
4d
4e
4f
Yield (%)b
94
1
2c
H
C6H5
H
4-Cl
5-Cl
6-Cl
7-Cl
5-F
5-Br
5-Me
5-OMe
5-NO2
H
C6H5
H
H
55
3
C6H5
91
Entry
1
Additive
None
Loading (mg/mmol)
Solvent
EtOAc
EtOAc
EtOAc
EtOAc
CH3CN
THF
Yield (%)b
trace
94
4
C6H5
H
89
-
5
C6H5
H
79
2
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
4Å MS
3Å MS
5Å MS
Na2SO4
300
100
50
6
C6H5
H
89
3
88
7
C6H5
H
4g
4h
4i
82
4
81
8
C6H5
H
97
5
300
300
300
300
300
300
300
300
300
93
9
C6H5
H
99
6
84
10
11
12
13
14d
15
16
17
C6H5
H
4j
84
7
acetone
CH2Cl2
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
78
C6H5
Me
Bn
Allyl
H
4k
4l
99
99 d
8
89
H
C6H5
9
66
H
C6H5
4m
4n
4o
4p
4q
85
10c
11c
12c
13d
51
H
4-BrC6H4
4-MeC6H4
Thienyl
CH3
99
<20
50
H
H
99
e
SiO2
H
H
76
f
Al2O3
70
H
H
96
aUnless otherwise noted, the reaction was carried out by using 0.1 mmol of 1a,
1.2 equiv. of 2, 30mg 4Å MS and 1.2 equiv of 3 in 1 mL of solvent at RT for 12h
(step 1) and 3h (step 2). bIsolated yields. cReaction time for step 2: 72h. dReaction
time for step 2: 24h. eSilicycle P60, 40-63 μm, 230-400 mesh. f MN, neutral.
aUnless otherwise noted, the reaction was carried out by using 0.1 mmol of 1a,
1.2 equiv. of 2, 30mg 4Å MS and 1.2 equiv of 3 in 1 mL of solvent at RT for 12h
(step 1) and 3h (step 2). bIsolated yields. c2 equiv. of 2 at 50℃for 18h. d3.6 equiv
of 3b was used.
2 | J. Name., 2012, 00, 1-3
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We then turn our attention to this one-pot reaction with
The structure of the products was also confirmed based on
isatin 1a, malononitrile, and different-substituted β−ketoacids the X-ray crystallographic analysis.16 Taking advantage of the
3b-3e. It was found that the reactions proceeded smoothly to crystallographic structure of 4g and 5g, all other product
deliver the desired products 4n-4q in good to excellent yields structures were deduced by referring to that (Figure 2).
(Table 2, entries 14-17). In the case of 4-Br substituted
β−ketoacid 3b, we discovered that it needed 3.6 equivalent of
3b to complete the reaction. It might be the deactivating
property of halogens decreasing the nucleophilicity of 3b
toward decarboxylative Michael addition reaction.
Having developed the above efficient one-pot sequential
Knoevenagel condensation/decarboxylative Michael addition
reaction of isatins, malononitrile and β−ketoacid, our next goal
is to extend this reaction to malonic acid half thioesters
(MAHTs). As shown in Table 3, to our delight, the one-pot
reaction between isatin 1a, malononitrile
2 and MAHT 6a
proceeded well in our conditions, affording the corresponding
5a in 99% yield (Table 3, entry 1). Isatins with different-
positioned Cl atoms, 5-halogen substituents, electron-donating
groups, and electron-withdrawing groups all equally worked
smoothly (Table 3, entries 2-10). The reaction was also
applicable to different N-substituted isatins and malonic acid
half thioesters (Table 3, entries 11-15). To our surprise, the
attempt on this one-pot reaction with malonic acid half ester
6d was unsuccessful. No any decarboxylative Michael addition
product was detected in our optimized conditions (Table 3,
entry 16).
Figure 2 X-ray crystal structures of 4g and 5g
To gain an insight into the role of 4Å molecular sieves in the
Knoevenagel condensation step, two control experiments
were performed. As shown in Scheme 1, the isatylidene
malononitrile
malononitrile
7
could be prepared from isatin 1a and
2
using EA as a solvent at room temperature for
Table 3 One-pot reaction of isatins, malononitrile and MAHTsa
12h without any additives (monitored by TLC) (Scheme 1a). To
our delight, the reaction time was reduced to 3h when 4Å MS
were added as an additive (Scheme 1b). From these data, we
realized the 4Å MS not only worked at the decarboxylative
Michael addition reaction step, but also promoted the reaction
rate of Knoevenagel condensation step. However, due to the
different electronic nature of isatins, we set up the reaction
time to 12h for Knoevenagel condensation step to insure the
completion of reaction.
Entry
1
R1
R2
SPh
SPh
SPh
SPh
SPh
SPh
SPh
SPh
SPh
SPh
SPh
SPh
SPh
SPMB
SBn
OPh
R3
5
Yield (%)b
99
H
H
5a
5b
5c
5d
5e
5f
5g
5h
5i
2c
4-Cl
5-Cl
6-Cl
7-Cl
5-F
5-Br
5-Me
5-OMe
5-NO2
H
H
68
3
H
99
4
H
99
5
H
80
6
H
98
7
H
90
8
H
95
9
H
78
10
11
12
13
14
15
16
H
5j
77
Me
Bn
Allyl
H
5k
5l
97
H
88
H
5m
5n
5o
-
91
Scheme 1 Control experiments
H
86
H
H
92
We then turn our attention to the practicality of our method
by employing the reaction in preparative scale and the
successful recycling of the molecular sieves. As illustrated in
Scheme 2, the recovered molecular sieves were able to
H
H
-
aUnless otherwise noted, the reaction was carried out by using 0.1 mmol of 1a,
1.2 equiv of 2, 30mg 4Å MS and 1.2 equiv of 3 in 1 mL of solvent at RT for 12h
d
(step 1) and 3h (step 2). bIsolated yields. c2 equiv. of 2 at 50℃for 18h. No
desired product was detected for step 2.
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catalyse the reaction for up to three runs in preparative scale
without any decrease in reactivity.
Conclusions
In conclusion, we have successfully developed a one-pot,
molecular sieve mediated sequential Knoevenagel
condensation/decarboxylative Michael additon reaction of β-
ketoacids and MAHTs with isatylidene malononitriles, which
are generated in situ from commercially available isatins and
malononitrile. The described synthetic protocols were highly
efficient, and were also broad in substrate scope, affording
3,3-disubstituted oxindoles with an all carbon quaternary
center in high yields. Notably, we had shown the above
reactions were carried out under very mild, base-free
conditions, and molecular sieves were the sole activator for
both reactions.
Scheme 2 Preparative scales experiments and results with recycled molecular
sieves.
Acknowledgements
Finally, the asymmetric feasibility of this one-pot reaction of
We are grateful for financial support from Ministry of Science
and Technology, Taiwan (104-2113-M-033-009-MY2). We
thank the mass center of institute of chemistry, Academia
Sinica for HRMS measurement. We also acknowledge Prof. Chi-
Wi Ong provides his helpful suggestion for preparing this
manuscript.
isatin 1a, malononitrile 2, and MAHT 6a was investigated. As
shown in table 4, various cinchona alkaloid catalysts 8a-e were
screened for this reaction, however, the product was furnished
in low enantioselectivities (<20% ee) (Table 4, entries 1-5). The
N-protected substrate 1l was also examined under different
reaction temperatures using 8d as a catalyst. The results
showed almost no enantioselectivity was observed (Table 4,
entries 6 and 7). These results indicated that the chirality of
the products was difficult to control under the current reaction
conditions.
Experimental
General Experimental Details
All commercially available reagents were used without further
purification unless otherwise stated. All reaction solvents were
used as received. Proton nuclear magnetic resonance (1H NMR)
spectra were recorded on a commercial instrument at 400
MHz. Carbon-13 nuclear magnetic resonance (13C NMR)
spectra were recorded at 100 MHz. The proton signal for
residual non-deuterated solvent (δ 7.26 for CHCl3) was used as
an internal reference for 1H NMR spectra. For 13C NMR spectra,
chemical shifts are reported relative to the δ77.0 resonance of
CHCl3. Coupling constants are reported in Hz. Infrared (IR)
spectra were recorded on a commercial FTIR instrument.
Melting points were determined on a BUCHI B-545 melting
point apparatus and are un-corrected. High resolution mass
spectra were recorded on a commercial high resolution mass
spectrometer. The TLC plates were visualized with UV light
and/or by staining with Hanessian solution (ceric sulfate and
ammonium molybdate in aqueous sulfuric acid). Column
chromatography was generally performed using Kieselgel 60
(230-400 mesh) silica gel, typically using a 50-100:1 weight
Table 4 Conditions Optimizationa
Entry
1
1a
1a
1a
1a
1a
1l
Catalyst Solvet
Yield (%)b
ee (%)c
1
2
8a
8b
8c
THF
THF
THF
THF
THF
THF
THF
90
47
95
93
88
98
76
4
0
3
10
20
14
0
ratio of silica gel to crude product. β-keto acids
3
and Malonic
4
8d
8e
8d
8d
acid half thioesters
procedure.13,17
6 were prepared according to the literature
5
6
7 d
1l
3
General Procedure for the Synthesis of 4
aUnless otherwise noted, the reaction was carried out by using 0.1 mmol of 1a,
1.2 equiv. of 2, 30mg 4Å MS, 20 mol% catalyst and 1.2 equiv of 3 in 1 mL of THF
at RT for 12h (step 1) and 3h (step 2). bIsolated yields. cDeterminated by chiral
HPLC analysis. dAt -20℃.
To a solution of isatins
mmol) and MS 4Å (30 mg) in EA (1 mL) was stirred at room
temperature (28-30 ) for 12h. β-keto acids (0.12 mmol) was
1 (0.1 mmol), malononitrile 2 (0.12
℃
3
added and the reaction mixture was stirred at room
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temperature for 3h. After completion of the reaction, the 18.2 Hz, 1H), 4.07 (dd, J = 18.2 Hz, 1H) ; 13C NMR (100 MHz, d-
mixture was concentrated in vacuum and the crude was acetone) δ 194.4, 175.0, 141.2, 135.7, 133.9, 130.2, 128.8,
purified by silica gel flash chromatography (Hexanes/EA 5:1 to 128.6, 128.1, 123.5, 122.2, 115.1, 111.1, 110.6, 50.1, 42.5, 30.6;
2:1) to afford the pure products
4.
HRMS (ESI): cacld for C19H12N3O235ClNa [M+Na]+: 372.0516;
found: 372.0519.
2-(2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)malononitrile
(4a). White powder; Yield : 94%; mp: 116-117 ; IR (neat): 2-(5-fluoro-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
℃
3672, 3232, 2988, 2970, 2901, 1718, 1684, 1619, 1597, 1580 malononitrile (4f). White powder; Yield : 89%; mp: 114-115
1
℃;
cm-1; H NMR (400 MHz, CDCl3) δ 8.77 (bs, 1H), 7.86-7.87 (m, IR (neat): 3672, 3232, 2988, 2970, 2902, 1723, 1683, 1632,
1
2H), 7.58 (t, J = 7.6 Hz, 1H), 7.42-7.47 (m, 3H), 7.31 (td, J = 7.8, 1597, 1581 cm-1; H NMR (400 MHz, CDCl3) δ 9.23 (bs, 1H),
1.1 Hz, 1H), 7.01-7.09 (m, 2H), 4.72 (s, 1H), 4.12 (d, J = 17.9 Hz, 7.88-7.86 (m, 2H), 7.60 (t, J = 7.2 Hz, 1H), 7.43-7.47 (m, 2H),
1H), 3.78 (d, J = 17.9 Hz, 1H) ; 13C NMR (100 MHz, CDCl3) δ 7.22 (dd, J = 7.6, 2.4 Hz,1H), 6.95-7.03 (m, 2H), 4.74 (s, 1H),
194.6, 175.9, 141.6 135.3, 134.3, 130.8, 128.9, 128.2, 125.8, 4.10 (d, J = 18.0 Hz, 1H), 3.80 (dd, J = 18.0 Hz, 1H) ; 13C NMR
123.8, 123.6, 111.3, 110.6, 109.7, 49.7, 42.2, 30.4; HRMS (ESI): (100 MHz, CDCl3) δ 194.6, 176.0, 159.2 (d, J = 246 Hz), 137.7 (d,
cacld for C19H13N3O2Na [M+Na]+: 338.0905; found: 338.0901.
J = 2.3 Hz), 135.1, 134.5, 129.0, 128.3, 127.1 (d, J = 7.8 Hz),
117.4 (d, J = 24.3 Hz), 112.3 (d, J = 1.5 Hz), 112.1 (d, J = 15.5 Hz),
110.4, 109.5, 50.1, 42.2, 30.2; HRMS (ESI): cacld for
℃;
C19H12N3O2FNa [M+Na]+: 356.0811; found: 356.0804.
2-(4-chloro-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
malononitrile (4b). White powder; Yield : 55%; mp: 206-207
1
IR (neat): 3250, 2907, 2874, 1716, 1706, 1685, 1618, cm-1; H 2-(5-bromo-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
NMR (400 MHz, CD3OD) δ 7.93-7.91 (m, 2H), 7.64-7.60 (m, 1H), malononitrile (4g). White powder; Yield : 82%; mp: 114-115
℃;
7.50-7.47 (m, 2H), 7.33 (t, J = 8.1 Hz, 1H), 7.00-6.97 (m, 2H), IR (neat): 3672, 3232, 2988, 2973, 2901, 1724, 1682, 1616,
1
4.66(d, J = 17.8 Hz, 1H), 3.86 (d, J = 17.8 Hz, 1H); 13C NMR (100 1596, 1580 cm-1; H NMR (400 MHz, CDCl3) δ 9.16 (bs, 1H),
MHz, CD3OD) δ 194.5, 175.4, 145.6, 135.3, 133.7, 131.6, 129.8, 7.87-7.86 (m, 2H), 7.63-7.57 (m, 2H), 7.47-7.41 (m, 3H), 6.90 (d,
128.6, 127.7, 122.9, 122.9, 110.0, 109.9, 109.2, 50.3, 40.6; J = 8.4 Hz, 1H), 4.68 (s, 1H), 4.10 (d, J = 18.0 Hz, 1H), 3.80 (d, J =
HRMS (ESI): cacld for C19H11N3O235ClNa [M+Na]+: 372.0516; 18.0 Hz, 1H) ; 13C NMR (100 MHz, CDCl3) δ 194.4, 175.5, 140.7,
found: 372.0515.
135.0, 134.6, 133.8, 129.0, 128.3, 127.8, 127.0, 116.2, 112.8,
110.3, 109.4, 49.8, 42.4, 30.3; HRMS (ESI): cacld for
C19H12N3O279BrNa [M+Na]+: 416.0011; found: 416.0015.
2-(5-chloro-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
malononitrile (4c). White powder; Yield : 91%; mp: 112-113
℃;
IR (neat): 3672, 3232, 2988, 2970, 2901, 1723, 1683, 1619, 2-(5-methyl-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
1
1597, 1581 cm-1; H NMR (400 MHz, CDCl3) δ 9.17 (bs, 1H), malononitrile (4h). White powder; Yield : 97%; mp: 121-122
℃;
7.85-7.86 (m, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.47-7.43 (m, 3H), IR (neat): 3672, 3232, 2988, 2970, 2902, 1717, 1688, 1625,
1
7.29-7.26 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 4.70 (d, J = 2.7 Hz, 1597, 1581 cm-1; H NMR (400 MHz, CDCl3) δ 9.09 (bs, 1H),
1H), 4.11 (d, J = 18.0 Hz, 1H), 3.80 (dd, J = 18.0, 2.7 Hz, 1H) ; 13
C
7.89-7.87 (m, 2H), 7.58 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H),
NMR (100 MHz, CDCl3) δ 194.4, 175.6, 140.3, 140.2, 135.0, 7.26 (s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H),
134.5, 130.9, 129.0, 128.9, 128.3, 127.4, 124.3, 112.4, 110.3, 4.73 (s, 1H), 4.10 (d, J = 17.8 Hz, 1H), 3.78 (d, J = 17.8 Hz, 1H),
109.5, 49.9, 42.3, 30.3; HRMS (ESI): cacld for C19H11N3O235Cl 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.7, 176.0, 139.1,
[M-H]-: 348.0546; found: 348.0540.
135.4, 134.2, 133.2, 131.2, 128.9, 128.3, 125.8, 124.4, 111.1,
110.7, 109.8, 49.8, 42.2, 30.5, 21.2; HRMS (ESI): cacld for
C20H15N3O2Na [M+Na]+: 352.1062; found: 352.1056.
2-(6-chloro-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
malononitrile (4d). Yellow powder; Yield : 89%; mp: 197-198
℃;
IR (neat): 3672, 3267, 2989, 2972, 2902, 1716, 1687, 1616, 2-(5-methoxy-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
1596, 1582 cm-1; 1H NMR (400 MHz, d-acetone) δ 10.3 (bs, 1H), malononitrile (4i). White powder; Yield : 99%; mp: 132-133
℃
;
7.99-7.97 (m, 2H), 7.67-7.62 (m, 1H), 7.55-7.49 (m, 3H), 7.15 IR (neat): 3672, 3232, 2988, 2971, 2902, 1717, 1688, 1598 cm-1;
(m, 1H), 7.09 (dd, J = 8.4, 2.0 Hz, 1H), 5.24 (s, 1H), 4.38 (d, J = 1H NMR (400 MHz, CDCl3) δ 9.09 (bs, 1H), 7.88-7.86 (m, 2H),
18.2 Hz, 1H), 4.05 (d, J = 18.2 Hz, 1H) ; 13C NMR (100 MHz, d- 7.58 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 2.5 Hz,
acetone) δ 194.5, 175.3, 144.8, 135.7, 135.3, 133.9, 128.8, 1H), 6.94 (d, J = 8.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.5 Hz, 1H), 4.75
128.1, 125.7, 125.1, 122.1, 111.2, 110.7, 110.6, 49.0, 42.3, 30.5; (s, 1H), 4.08 (d, J = 18.0 Hz, 1H), 3.77 (d, J = 18.0 Hz, 1H), 3.73
HRMS (ESI): cacld for C19H12N3O235ClNa [M+Na]+: 372.0516; (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.6, 175.8, 156.3, 135.3,
found: 3372.0518.
134.8, 134.3, 128.9, 128.2, 127.0, 115.1, 111.7, 111.1, 110.6,
109.8, 55.8, 50.1, 42.1, 30.4; HRMS (ESI): cacld for
C20H15N3O3Na [M+Na]+: 368.1011; found: 368.1007.
2-(7-chloro-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
malononitrile (4e). Orange solid; Yield : 79%; mp: 110-111
℃;
IR (neat): 3662, 2988, 2972, 2902, 1725, 1684, 1621, 1596, 2-(5-nitro-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-yl)
1580 cm-1; 1H NMR (400 MHz, d-acetone) δ 10.5 (bs, 1H), 8.00- malononitrile (4j). Yellow powder; Yield : 84%; mp: 187-188
℃;
7.97 (m, 2H), 7.67-7.62 (m, 1H), 7.53-7.49 (m, 3H), 7.42 (dd, J = IR (neat): 3664, 3237, 2988, 2973, 2901, 1727, 1716, 1686,
8.3, 1.0 Hz, 1H), 7.09 (t, J = 8.0, 1H), 5.26 (s, 1H), 4.39 (d, J = 1624, 1605 cm-1; 1H NMR (400 MHz, d-acetone) δ 10.8 (bs, 1H),
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8.51 (d, J = 2.3 Hz, 1H), 8.36 (dd, J = 8.8, 2.3 Hz, 1H), 8.01-7.98 2-(3-(2-(4-methylphenyl)-2-oxoethyl)-2-oxoindolin-3-
(m, 2H), 7.64 (td, J = 7.4, 1.3 Hz, 1H), 7.53-7.49 (m, 2H), 7.36 (d, yl)malononitrile (4o). White powder; Yield : 99%; mp: 175-176
J = 8.6 Hz, 1H), 5.39 (s, 1H), 4.65 (d, J = 18.2 Hz, 1H), 4.18 (d, J =
℃
; IR (neat): 3672, 3265, 2988, 2901, 1725, 1680, 1610 cm-1;
18.2 Hz, 1H) ; 13C NMR (100 MHz, d-acetone) δ 194.6, 175.6, 1H NMR (400 MHz, CDCl3) δ 8.94 (bs, 1H), 7.77 (d, J = 8.4 Hz,
149.6, 143.2, 135.5, 134.0, 128.8, 128.2, 127.9, 127.1, 120.0, 2H), 7.46 (d, J = 7.5 Hz, 1H), 7.31 (td, J = 7.7, 1.1 Hz, 1H), 7.23
110.9, 110.4, 110.4, 49.3, 42.6, 30.3; HRMS (ESI): cacld for (d, J = 8.4 Hz, 2H), 7.07 (td, J = 7.7, 0.9 Hz, 1H), 7.01 (d, J = 7.7
C19H11N4O4 [M-H]-: 359.0780; found: 359.0774.
Hz, 1H), 4.72 (s, 1H), 4.09 (d, J = 17.7 Hz, 1H), 3.74 (d, J = 17.7
Hz, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 194.2, 175.9,
145.4, 141.5, 132.9, 130.8, 129.6, 128.4, 125.8, 123.9, 123.5,
2-(1-methyl-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-
yl)malononitrile (4K). White powder; Yield : 99%; mp: 153-154 111.3, 110.6, 109.7, 49.7, 42.0, 30.4, 21.8; HRMS (ESI): cacld
; IR (neat): 3672, 2989, 2969, 2914, 1712, 1694, 1615, 1597 for C20H15N3O2Na [M+Na]+: 352.1062; found: 352.1065.
℃
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87-7.84 (m, 2H), 7.58 (t, J =
7.4 Hz, 1H), 7.49-7.42 (m, 4H), 7.12 (td, J = 7.6, 0.8 Hz, 1H), 2-(2-oxo-3-(2-oxo-2-(thiophen-2-yl)ethyl)indolin-3-
7.02 (d, J = 7.9 Hz, 1H), 4.63 (s, 1H), 4.10 (d, J = 17.6 Hz, 1H), yl)malononitrile (4p). White powder; Yield : 76%; mp: 168-169
3.71 (d, J = 17.6 Hz, 1H), 3.67 (s, 3H); 13C NMR (100 MHz, CDCl3)
℃; IR (neat): 3681, 3255, 2973, 2923, 2866, 2845, 1726, 1693,
δ 194.1, 173.9, 144.5, 135.4, 134.2, 130.8, 128.9, 128.1, 125.2, 1659, 1618 cm-1; H NMR (400 MHz, CDCl3) δ 9.20 (bs, 1H),
123.6, 123.5, 110.6, 109.5, 109.4, 49.3, 42.2, 30.6, 27.0; HRMS 7.74 (d, J = 3.8 Hz, 1H), 7.67 (d, J = 4.9 Hz, 1H), 7.47 (d, J = 7.4
(ESI): cacld for C20H15N3O2Na [M+Na]+: 352.1062; found: Hz, 1H), 7.30 (t, J = 7.4 Hz, 1H), 7.11-7.00 (m, 3H), 4.79 (s, 1H),
1
352.1060.
4.00 (d, J = 17.5 Hz, 1H), 3.71 (d, J = 17.5 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 187.5, 175.7, 142.3, 141.6, 135.5, 133.5, 130.9,
128.7, 125.5, 123.9, 123.6, 111.4, 110.6, 109.8, 49.7, 42.2, 30.2;
℃
; IR HRMS (ESI): cacld for C17H11N3O2SNa [M+Na]+: 344.0470; found:
2-(1-benzyl-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-
yl)malononitrile (4l). Red solid; Yield : 99%; mp: 120-121
(neat): 3671, 2989, 2972, 2902, 1713, 1687, 1612, 1597 cm-1; 344.0467.
1H NMR (400 MHz, CDCl3) δ 7.90-7.88 (m, 2H), 7.59 (t, J = 7.5
Hz, 1H), 7.51-7.28 (m, 9H), 7.08 (td, J = 7.6, 0.8 Hz, 1H), 6.86 (d, 2-(2-oxo-3-(2-oxopropyl)indolin-3-yl)malononitrile
(4q)6
.
1
J = 8.0 Hz, 1H), 5.07 (s, 2H), 4.70 (s, 1H), 4.16 (d, J = 17.7 Hz, Known compound; White powder; Yield : 96%; H NMR (400
1H), 3.76 (d, J = 17.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ MHz, d-acetone) δ 10.0 (bs, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.34
194.0, 174.2, 143.8, 135.4, 134.8, 134.2, 130.7, 128.9, 128.8, (td, J = 7.7, 1.2 Hz, 1H), 7.09-7.03 (m, 2H), 5.10 (s, 1H), 3.67 (d,
128.2, 127.9, 127.5, 125.3, 123.7, 123.6, 110.7, 110.6, 109.7, J = 18.1 Hz, 1H), 3.38 (d, J = 17.5 Hz, 1H), 2.12 (s, 3H).
49.4, 44.9, 42.4, 30.7; HRMS (ESI): cacld for C26H19N3O2Na
[M+Na]+: 428.1375; found: 428.1376.
General Procedure for the Synthesis of 5
2-(1-allyl-2-oxo-3-(2-oxo-2-phenylethyl)indolin-3-
To a solution of isatins 1 (0.1 mmol), malononitrile 2 (0.12
yl)malononitrile (4m). Colorless oil; Yield : 85%; IR (neat): 3672, mmol) and MS 4Å (30 mg) in EA (1 mL) was stirred at room
1
℃) for 12h. Malonic acid half thioesters 6
2923, 2845, 1714, 1688, 1612 cm-1; H NMR (400 MHz, CDCl3) temperature (28-30
δ 7.87-7.85 (m, 2H), 7.60-7.56 (m, 1H), 7.50-7.38 (m, 4H), 7.11 (0.12 mmol) was added and the reaction mixture was stirred at
(td, J = 7.7, 1.0 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 5.99-5.89 (m, room temperature for 3h. After completion of the reaction,
1H), 5.49 (dd, J = 17.2, 1.0 Hz, 1H), 5.33 (dd, J = 10.3, 1.0 Hz, the mixture was concentrated in vacuum and the crude was
1H), 4.63 (s, 1H), 4.56-4.42 (m, 2H), 4.12 (d, J = 17.8 Hz, 1H), purified by silica gel flash chromatography (Hexanes/EA 5:1 to
3.72 (d, J = 17.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 194.0, 2:1) to afford the pure products
5.
173.7, 143.8, 135.4, 134.2, 130.7, 130.7, 128.9, 128.1, 125.2,
123.6, 123.5, 118.6, 110.7, 110.4, 109.6, 49.2, 43.3, 42.4, 30.7; S-phenyl 2-(3-(dicyanomethyl)-2-oxoindolin-3-yl)ethanethio-
HRMS (ESI): cacld for C22H17N3O2Na [M+Na]+: 378.1218; found: ate (5a). White powder; Yield : 99%; mp: 73-74
; IR (neat):
3356, 2988, 2909, 1727,1699 cm-1; 1H NMR (400 MHz, CDCl3) δ
℃
378.1212.
8.77 (s, 1H), 7.45 (d, J = 7.5 Hz, 1H), 7.21-7.18 (m, 2H), 7.12 (t, J
= 7.6 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 4.52 (s, 1H), 3.50 (d, J =
2-(3-(2-(4-bromophenyl)-2-oxoethyl)-2-oxoindolin-3-
yl)malononitrile (4n). White powder; Yield : 99%; mp: 205-206 16.2 Hz, 1H), 3.36 (d, J = 16.2 Hz, 1H); 13C NMR (100 MHz,
℃
; IR (neat): 3271, 2923, 2866, 2845, 1716, 1683, 1617, 1586 CDCl3) δ 193.4, 174.7, 141.3, 134.5, 131.2, 130.3, 129.5, 129.6,
cm-1; 1H NMR (400 MHz, d-acetone) δ 10.13 (bs, 1H), 7.92 (d, J 126.0, 124.5, 124.1, 123.8, 111.6, 110.3, 109.5, 50.2, 45.6, 30.1;
= 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 7.6 Hz, 1H), HRMS (ESI): cacld for C19H13N3O2SNa [M+Na]+: 370.0626; found:
7.35 (td, J = 7.8, 1.2 Hz, 1H), 7.11-7.03 (m, 2H), 5.21 (s, 1H), 370.0626.
4.33 (d, J = 18.0 Hz, 1H), 3.99 (d, J = 18.0 Hz, 1H); 13C NMR (100
MHz, d-acetone) δ 193.8, 175.2, 143.3, 132.0, 130.2, 130.0, S-phenyl
2-(4-chloro-3-(dicyanomethyl)-2-oxoindolin-3-yl)-
128.3, 126.7, 123.7, 122.3, 111.3, 110.6, 110.4, 49.2, 42.1, 30.6; ethanethioate (5b). Light brown powder; Yield : 68%; mp: 166-
1
HRMS (ESI): cacld for C19H12N3O279BrNa [M+Na]+: 416.0011; 167
℃
; IR (neat): 3750, 3141, 2988, 2901, 1717, 1699 cm-1; H
found: 416.0018.
NMR (400 MHz, d6-DMSO) δ 10.1 (s, 1H), 6.98-6.91 (m, 3H),
6.78 (t, J = 7.9 Hz, 1H), 6.71-6.69 (m, 2H), 6.51 (d, J = 8.8 Hz,
6 | J. Name., 2012, 00, 1-3
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1H), 6.29 (d, J = 7.2 Hz, 1H), 6.02 (s, 1H), 3.31 (d, J = 15.3 Hz, 7.28 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 5.26 (s, 1H), 3.86 (d, J =
1H), 2.88 (d, J = 15.3 Hz, 1H); 13C NMR (100 MHz, d6-DMSO) δ 16.5 Hz, 1H), 3.67 (d, J = 16.5 Hz, 1H); 13C NMR (100 MHz, d6-
192.6, 176.7, 144.5, 134.2, 131.3, 130.6, 129.7, 129.4, 126.8, acetone) δ 193.1, 174.6, 143.1, 135.3, 134.3, 130.7, 130.2,
126.2, 122.3, 108.7, 74.0, 48.3; HRMS (ESI): cacld for 128.6, 128.1, 127.5, 115.2, 113.3, 111.7, 111.1, 50.5, 46.3, 30.7;
C19H12N3O2SNa35Cl [M+Na]+: 404.0326; found: 404.0238.
HRMS (ESI): cacld for C19H13N3O2SNa79Br [M+Na]+: 447.9731;
found: 447.9733.
S-phenyl
2-(5-chloro-3-(dicyanomethyl)-2-oxoindolin-3-yl)-
ethanethioate (5c). White powder; Yield : 99%; mp 194-195
1
℃
;
S-phenyl 2-(3-(dicyanomethyl)-5-methyl-2-oxoindolin-3-yl)-
IR (neat): 3750, 3335, 2971, 2901, 1724, 1619 cm-1; H NMR ethanethioate (5h). White powder; Yield : 95%; mp: 180-181
(400 MHz, d6-acetone) δ 10.2(s, 1H), 7.64 (d, J = 2.2 Hz, 1H),
℃; IR (neat): 3750, 3671, 3327, 2973, 2923, 1726, 1702, 1623
7.43-7.38 (m, 4H), 7.30-7.28 (m, 2H), 7.08 (d, J = 8.4 Hz, 1H), cm-1; H NMR (400 MHz, d6-acetone) δ 9.99 (s, 1H), 7.43-7.37
5.26 (s, 1H), 3.86 (d, J = 16.5 Hz, 1H), 3.68 (d, J = 16.5 Hz, 1H); (m, 4H), 7.27-7.25 (m, 2H), 7.20 (dt, J = 7.9, 0.8 Hz, 1H), 6.94 (d,
13C NMR (100 MHz, d6-acetone) δ 192.2, 174.0, 141.9, 134.5, J = 8.0 Hz, 1H), 5.18 (s, 1H), 3.71 (d, J = 16.1 Hz, 1H), 3.59 (d, J =
130.6, 129.9, 129.4, 127.4, 127.2, 126.7, 124.5, 112.0, 110.9, 16.1 Hz, 1H), 2.35 (s, 3H); 13C NMR (100 MHz, d6-acetone) δ
110.3, 49.8, 45.5, 29.9; HRMS (ESI): cacld for 192.8, 175.0, 141.2, 135.2, 132.8, 131.7, 130.5, 130.1, 127.6,
1
C19H12N3O2SNa35Cl [M+Na]+: 404.0326; found: 404.0232.
126.2, 125.4, 112.0, 111.3, 111.2, 50.5, 46.4, 30.9, 21.1; HRMS
(ESI): cacld for C20H15N3O2SNa [M+Na]+: 384.0783; found:
S-phenyl
ethanethioate (5d). Light brown powder; mp: 67-68
(neat): 3750, 3335, 2988, 2901, 1734, 1670 1615 cm-1; 1H NMR S-phenyl 2-(3-(dicyanomethyl)-5-methoxy-2-oxoindolin-3-yl)-
2-(6-chloro-3-(dicyanomethyl)-2-oxoindolin-3-yl)- 384.0774.
℃
; IR
(400 MHz, CDCl3) δ 8.84 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.43- ethanethioate (5i). White powder; Yield : 78%; mp: 141-142℃;
1
7.39 (m, 3H), 7.32-7.29 (m, 2H), 7.18 (dd, J = 8.1, 1.8 Hz, 1H), IR (neat): 3341, 2973, 2923, 1709, 1683, 1610 cm-1; H NMR
6.86 (d, J = 1.8 Hz, 1H), 4.53 (s, 1H), 3.60 (d, J = 16.3 Hz, 1H), (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.40-7.34 (m, 3 H), 7.27 (dd, J =
3.46 (d, J = 16.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.5, 7.8, 1.6 Hz, 2H), 7.08 (d, J = 2.4 Hz, 1H), 6.85 (dd, J = 8.6, 2.5 Hz,
174.6, 142.5, 137.1, 134.5, 130.5, 129.7, 125.7, 125.0, 123.8, 1H), 6.79 (d, J = 8.6 Hz, 1H), 4.58 (s,1H), 3.80 (s, 3H), 3.52 (d, J =
122.8, 112.2, 110.1, 109.3, 49.9, 45.6, 30.1; HRMS (ESI): cacld 16.3 Hz, 1H), 3.69 (d, J = 16.3 Hz, 1H); 13C NMR (100 MHz,
for C19H12N3O2SNa35Cl [M+Na]+: 404.0326; found: 404.0235.
CDCl3) δ 193.4, 174.5, 156.5, 134.5, 134.4, 130.2, 129.6, 126.1,
125.7, 115.8, 112.2, 111.0, 110.3, 109.5, 50.6, 56.0, 45.5, 30.1;
S-phenyl
ethanethioate (5e). Orange powder; Yield : 80%; mp: 142-143 400.0723.
; IR (neat): 3750, 3287, 2988, 2908, 1721, 1702, 1619 cm-1;
1H NMR (400 MHz, d6-acetone) δ 10.4 (s, 1H), 7.56 (d, J = 7.5 S-phenyl
Hz, 1H), 7.46-7.38 (m, 4H), 7.29-7.26 (m, 2H), 7.12 (t, J = 7.9 Hz, ethanethioate (5j). Light yellow powder; Yield : 77%; mp: 187-
1H), 5.24 (s, 1H), 3.81 (d, J = 16.4 Hz, 1H), 3.68 (d, J = 16.4 Hz, 188 ; IR (neat): 3681, 2973, 2923, 2867, 2845, 1735, 1698,
2-(7-chloro-3-(dicyanomethyl)-2-oxoindolin-3-yl)- HRMS (ESI): cacld for C20H15N3O3SNa [M+Na]+: 400.0732; found:
℃
2-(3-(dicyanomethyl)-5-nitro-2-oxoindolin-3-yl)-
℃
1H); 13C NMR (100 MHz, d6-acetone) δ 193.0, 174.8, 141.6, 1604 cm-1; H NMR (400 MHz, d6-acetone) δ 9.74 (s, 1H), 7.56
135.3, 131.6, 130.7, 130.3, 128.1, 127.6, 124.7, 123.6, 116.3, (d, J = 2.3 Hz, 1H), 7.38 (dd, J = 8.7, 2.3 Hz, 1H), 6.46-6.38 (m,
111.7, 111.2, 51.4, 46.6, 31.0; HRMS (ESI): cacld for 3H), 6.32-6.28 (m, 3H), 4.41 (s, 1H), 3.08 (d, J = 16.7 Hz, 1H),
1
C19H11N3O2S35Cl [M-H]-: 380.0261; found: 380.0269.
2.81 (d, J = 16.7 Hz, 1H); 13C NMR (100 MHz, d6-acetone) δ
193.3, 145.3, 149.8, 144.0, 135.2, 130.6, 130.1, 128.2, 127.2,
S-phenyl
2-(3-(dicyanomethyl)-5-fluoro-2-oxoindolin-3-yl)- 127.2, 121.0, 111.5, 111.3, 110.8, 50.2, 46.2, 30.5; cacld for
C19H11N4O4S [M-H]-: 391.0501 ; found: 391.0504.
ethanethioate (5f). Pink powder; Yield : 98%; mp: 203-204
℃
;
IR (neat): 3750, 3337, 2973, 2922, 2845, 1728, 1697, 1624, S-phenyl
2-(3-(dicyanomethyl)-1-methyl-2-oxoindolin-3-
1607 cm-1; 1H NMR (400 MHz, d6-acetone) δ 10.1 (s, 1H), 7.45- yl)ethanethioate (5k). White powder; Yield : 97%; mp: 142-
1
7.38 (m, 4 H), 7.27-7.30 (m, 2H), 7.16-7.21 (m, 1H), 7.07 (dd, J 143
℃
; IR (neat): 3672, 2973, 2893, 1717, 1685, 1613 cm-1; H
= 8.6, 4.3 Hz, 1H), 5.24 (s, 1H), 3.82 (d, J = 16.5 Hz, 1H), 3.66 (d, NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.8
J = 16.5 Hz, 1H); 13C NMR (100 MHz, d6-acetone) δ 193.0, Hz, 1H), 7.35-7.41 (m, 3H), 7.25-7.28 (m, 2H), 7.20 (t, J = 7.6 Hz,
175.0, 159.6 (d, J = 238 Hz), 140.0 (d, J = 2.3 Hz), 135.3, 130.7, 1H), 6.96 (d, J = 7.8 Hz, 1H), 4.55 (s, 1H), 3.53 (d, J = 16.1 Hz,
130.2, 127.8 (d, J = 8.4 Hz), 127.6, 117.9 (d, J = 23.7 Hz), 112.9 1H), 3.37 (d, J = 16.1 Hz, 1H), 3.29 (s, 3H); 13C NMR (100 MHz,
(d, J = 25.3 Hz), 112.5 (d, J = 8.3 Hz), 111.7, 111.2, 50.9 (d, J = CDCl3) δ 192.6, 172.7, 144.2, 134.5, 131.2, 130.2, 129.5, 126.1,
1.4 Hz), 46.4, 30.8; HRMS (ESI): cacld for C19H12N3O2SNaF 124.1, 123.9, 110.4, 109.7, 109.4, 49.9, 45.5, 30.3, 27.1; HRMS
[M+Na]+: 388.0532; found: 388.0527.
(ESI): cacld for C20H15N3O2SNa [M+Na]+: 384.0783; found:
384.0779.
S-phenyl 2-(5-bromo-3-(dicyanomethyl)-2-oxoindolin-3-yl)-
ethanethioate (5g). White powder; Yield : 90%; mp: 172-173
℃
;
S-phenyl
2-(1-benzyl-3-(dicyanomethyl)-2-oxoindolin-3-yl)-
IR (neat): 3750, 3671, 2973, 2920, 2844, 1734, 1670, 1616 cm-1; ethanethioate (5l). White powder; Yield : 88%; mp: 106-107
℃;
1H NMR (400 MHz, d6-acetone) δ 10.2 (s, 1H), 7.77 (d, J = 2.0 IR (neat): 3672, 2973, 2902, 1721, 1686, 1611 cm-1; H NMR
1
Hz, 1H), 7.57 (dd, J = 8.4, 2.0 Hz, 1H), 7.46-7.39 (m, 3H), 7.30- (400 MHz, CDCl3) δ 7.56 (d, J = 7.5 Hz, 1H), 7.45-7.26 (m, 11H),
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DOI: 10.1039/C6RA16975A
ARTICLE
Journal Name
5. For reviews, see: (a) C. V. Galliford and K. A. Scheidt, Angew.
Chem., Int. Ed., 2007, 46, 8748; (b) C. Marti and E. M.
Carreira, Eur. J. Org. Chem., 2003, 2209; (c) R. M. Williams
and R. J. Cox, Acc. Chem. Res., 2003, 36, 127; (d) F. Zhou, Y.
−L. Liu and J. Zhou, Adv. Synth. Catal., 2010, 352, 1381; (e) K.
Shen, X. −H. Liu, L. −L. Lin and X. −M. Feng, Chem. Sci., 2012,
7.17 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 5.06 (d, J = 15.8
Hz, 1H), 4.94 (d, J = 15.8 Hz, 1H), 4.65 (s, 1H), 3.56 (d, J = 16.0
Hz, 1H), 3.40 (d, J = 16.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
192.6, 173.0, 143.3, 134.6, 134.5, 131.1, 130.1, 129.5, 129.0,
128.0, 127.5, 126.2, 124.2, 124.0, 123.9, 110.8, 110.5, 109.5,
50.0, 45.8, 44.9, 30.1 ; HRMS (ESI): cacld for C26H19N3O2SNa
[M+Na]+: 460.1062; found: 460.1070.
3
, 327; (f) R. Dalpozzo, G. Bartoli and G. Bencivenni, Chem.
Soc. Rev., 2012, 41, 7247; (g) G. S. Singh and Z. Y. Desta,
Chem. Rev., 2012, 112, 6104; (h) J. Cheng, Y. Ishihara, B. Tan
and C. F. Barbas, III, ACS Catal., 2014, 4, 743.
S-phenyl
ethanethioate (5m). Light brown powder; Yield : 91%; mp:
135-136 ; IR (neat): 3672, 2973, 2923, 2900, 1717, 1686,
2-(1-allyl-3-(dicyanomethyl)-2-oxoindolin-3-yl)-
6. (a) L. Liu, D. Wu, X. Li, S. Wang, H. Li, J. Li and W. Wang
Chem. Commun., 2012, 48, 1692; (b) H. Zhao, Y. −B. Lan, Z.
−M. Liu, Y. Wang, X. −W. Wang and J. −C. Tao, Eur. J. Org.
Chem., 2012, 1935; (c) A. Kumar and S. S. Chimni Beilstein J.
Org. Chem. 2014, 10, 929.
7. (a) Y. –B. Lan, H. Zhao, Z. –M. Liu, G. –G. Liu, J. –C. Tao and X.
–W. Wang, Org. Lett., 2011, 13, 4866; (b) D. B. Ramachary, C.
Venkaiah and R. Madhavachary, Org. Lett., 2013, 15, 3042.
8. (a) W. –B. Chen, Z. –J. Wu, Q. –L. Pei, L. –F. Cun, X. –M. Zhang
and W. –C. Yuan, Org. Lett., 2010, 12, 3132; (b) X. Jiang, Y.
Sun, J. Yao, Y. Cao, M. Kai, N. He, X. Zhang, Y. Wang and R.
Wang, Adv. Synth. Catal., 2012, 354, 917; (c) F. –F. Pan, W.
℃
1610 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.4 Hz, 1H),
7.43-7.35 (m, 4H), 7.27-7.25 (m, 2H), 7.19 (td, J = 7.6, 0.6 Hz,
1H), 6.96 (d, J = 7.9 Hz, 1H), 5.89-5.79 (m, 1H), 5.36 (d, J = 17.2
Hz, 1H), 5.26 (d, J = 10.5 Hz, 1H), 4.59 (s, 1H), 4.54-4.28 (m, 2H),
3.53 (d, J = 16.0 Hz, 1H), 3.36 (d, J = 16.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 192.5, 172.6, 143.4, 134.5, 131.1, 130.5, 130.1,
129.5, 126.2, 124.1, 123.9, 123.8, 118.7, 110.6, 110.5, 109.4,
49.8, 45.7, 43.3, 30.2; HRMS (ESI): cacld for C22H16N3O2SNa
[M+Na]+: 386.0963; found: 386.0957.
Yu, Z. –H. Qi, C. Qiao and X. –W. Wang, Synthesis, 2014, 46
,
1143; (d) H. –W. Zhao, B. Li, T. Tian, W. Meng, Z. Yang, X. –Q.
Song, X. –Q. Chen and H. –L. Pang, Eur. J. Org. Chem., 2015,
3320.
S-(4-methoxyphenyl) 2-(3-(dicyanomethyl)-2-oxoindolin-3-yl)-
9. Z. –M. Liu, N. –K. Li, X. –F. Huang, B. Wu, N. Li, C. –Y. Kwok, Y.
Wang and X. –W. Wang, Tetrahedron, 2014, 70, 2406; (b) Z. –
H. Qi, Y. Zhang, G. –Y. Ruan, Y. Zhang, Y. Wang and X. –W.
ethanethioate (5n). White powder; Yield : 86%; mp: 178-179
1
℃
; IR (neat): 3371, 2974, 2889, 1736, 1682, 1621 cm-1; H
NMR (400 MHz, CDCl3) δ 8.43 (s, 1H), 7.49 (d, J = 7.5 Hz, 1H),
7.35 (td, J = 7.8, 1.0 Hz, 1H), 7.18-7.14 (m, 3H), 6.90-6.87 (m,
3H), 4.55 (s, 1 H), 3.77 (s, 3H), 3.52 (d, J = 16.2 Hz, 1H), 3.35 (d,
J = 16.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 194.3, 174.4,
161.2, 141.2, 136.2, 131.2, 124.6, 124.2, 123.8, 116.6, 115.2,
111.5, 110.3, 109.4, 55.5, 50.3, 45.4, 30.1; HRMS (ESI): cacld
for C20H15N3O3SNa [M+Na]+: 400.0732; found: 400.0730.
Wang, RSC Adv., 2015, 5, 34314.
10. (a) X. –F. Huang, Y. –F. Zhang, Z. –H. Qi, N. –K. Li, Z. –C. Geng,
K. Li and X. –W. Wang, Org. Biomol. Chem., 2014, 12, 4372;
(b) V. P. R. Gajulapalli, P. Vinayagam and V. Kesavan, RSC
Adv., 2015, 5, 7370.
11. T. –Z. Li, J. Xie, Y. Jiang, F. Sha and X. –Y. Wu, Adv. Synth.
Catal., 2015, 357, 3507.
12. J. –S. Yu, F. –M. Liao, W. –M. Gao, K. Liao, R. –L. Zuo and J.
Zhou, Angew. Chem. Int. Ed., 2015, 54, 7381.
13. K. Higashiyama and H. Otomasu, Chem. Pharm. Bull., 1980,
28, 1540.
14. F. Zhong, C. Jiang, W. Yao, L. –W. Xu and Y. Lu, Tetrahedron
Lett., 2013, 54, 4333.
15. P. T. Anastas and M. M. Kirchhoff, Acc. Chem. Res., 2002, 35
686 and references therein.
16. CCDC 1481435 and CCDC 1481433. See ESI† for detailed
crystallographic data.
17. H. Y. Bae, J. H. Sim, J. –W. Lee, B. List and C. E. Song, Angew.
Chem. Int. Ed., 2013, 52, 12143.
S-benzyl
ethanethioate (5o). White powder; Yield : 92%; mp: 169-170
; IR (neat): 3672, 3363, 2973, 2902, 2874, 1711, 1668, 1624
2-(3-(dicyanomethyl)-2-oxoindolin-3-yl)-
℃
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.42-7.34 (m,
2H), 7.26-7.22 (m, 3H), 7.13-7.07 (m, 3H), 7.00 (d, J = 7.8 Hz,
1H), 4.60 (s, 1H), 4.03 (s, 2H), 3.44 (d, J = 15.8 Hz, 1H), 3.31(d, J
= 15.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 193.9, 174.9, 141.2,
136.3, 131.2, 128.8, 128.8, 127.6, 124.5, 124.2, 123.9, 111.5,
110.4, 109.6, 50.4, 45.7, 33.7, 30.1; HRMS (ESI): cacld for
C20H15N3O2SNa [M+Na]+: 384.0783; found: 384.0781.
,
Notes and references
1. J. J. Badillo, N. V. Hanhan and A. K. Franz, Curr. Opin. Drug
Discovery Dev., 2010, 13, 758.
2. (a) A. Canas-Rodriguez and P. R. Leeming, J. Med. Chem.,
1972, 15, 762; (b) M. K. Uddin, S. G. Reignier, T. Coulter, C.
Montalbetti, C. Grånäs, S. Butcher, C. KrogJensen and J.
Felding, Bioorg. Med. Chem. Lett., 2007, 17, 2854.
3. S. W. Tam and R. Zaczek, Adv. Exp. Med. Biol., 1995, 363, 47.
4. (a) B. Volk, J. Barkóczy, E. Hegedus, S. Udvari, I. Gacsályi, T.
Mezei, K. Pallagi, H. Kompagne, G. Lévay, A. Egyed, L. G.
Hársing, M. Spedding and G. Simig, J. Med. Chem., 2008, 51
,
2522; (b) B. Volk, I. Gacsályi, K. Pallagi, L. Poszávácz, I.
Gyönös, É. Szabó, T. Baký, M. Spedding, G. Simig and G.
Szénási, J. Med. Chem., 2011, 54, 6657.
8 | J. Name., 2012, 00, 1-3
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