Advanced palladium free approach to the synthesis of substituted alkene oxindoles: Via aluminum-promoted Knoevenagel reaction

Article abstract of DOI:10.1039/c8ra07576j

A synthetic route for the synthesis of C24, as well as for the design of focused libraries of direct AMPK activators was developed based on a convergent strategy. The proposed scheme corresponds to the current trends in C-H bond functionalization. The use of aluminum isopropoxide for the Knoevenagel condensation of oxindole with benzophenones is a noticeable point of this work.

Full text of DOI:10.1039/c8ra07576j

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Advanced palladium free approach to the synthesis
of substituted alkene oxindoles via aluminum-
promoted Knoevenagel reaction†
Cite this: RSC Adv., 2018, 8, 34543
a
a
b
*
Daria S. Novikova,
Tatyana A. Grigoreva,
Andrey A. Zolotarev,
Alexander V. Garabadzhiua and Vyacheslav G. Tribulovich
a
Received 11th September 2018
Accepted 2nd October 2018
A synthetic route for the synthesis of C24, as well as for the design of focused libraries of direct AMPK
activators was developed based on a convergent strategy. The proposed scheme corresponds to the
current trends in C–H bond functionalization. The use of aluminum isopropoxide for the Knoevenagel
condensation of oxindole with benzophenones is a noticeable point of this work.
DOI: 10.1039/c8ra07576j
rsc.li/rsc-advances
AMP-activated protein kinase (AMPK) has been extensively Antitumor activity, identied for 3-(benzylidene)indolin-2-
studied over the last decades. A key role of AMPK in the ones,11 allows to design multitarget compounds that affect both
regulation of energy balance suggests it to be a promising the metabolic signaling cascades of a cancer cell through AMPK
target for energy metabolism-related diseases.1 To date, AMPK and the proliferative signaling pathway by reactivating p53,12
is considered as a therapeutic target in type 2 diabetes, obesity, since high lipophilicity of the considered structures provides
cardiovascular diseases, atherosclerosis, and cancer.2
number of indirect AMPK activators are already used in clin-
ical practice for their benecial metabolic effects.3 However, studying the AMPK activation and the small molecule devel-
A
potent binding to the active cavity of the MDM2 protein.13
Despite all the advantages of 2-oxindole derivatives in
there are no drugs that directly activate AMPK on the phar- opment, the synthetic routes for obtaining this series remain
maceutical market yet.
rather laborious. Here, we present a simple and effective route
The demand for direct AMPK activators inspired pharma- of C24 synthesis. This route takes into account both the possi-
ceutical companies to start a campaign to design such mole- bility of synthesis of small molecule libraries as well as current
cules.4 To date, several classes of compounds that potently trends in organic synthesis.
activate AMPK have been identied: AICAR and other AMP
Linear synthesis and convergent synthesis are the main
mimetics,5 thienopyridones,6 benzimidazoles,7 and alkene strategies in organic chemistry. The convergent strategy is
oxindole derivatives.8 The latter activate AMPK by the much more suitable for providing the diversity of a library of
most
These compounds show good target activity, and C24 through divergent stages of the synthetic scheme. However, the
(YLF-466D; (E)-3-((3-((4-chlorophenyl)(phenyl)methylene)-2- divergence of the synthetic scheme at earlier stages leads to the
interesting
and
least
studied
mechanism.9 complex biologically active compounds. The diversity is realized
oxoindolin-1-yl)methyl) benzoic acid) is the most potent 2- individualization of the synthesis of each compound and,
oxindole derivative.8 The structure of these compounds consequently, an increase in the efforts to synthesize
provides ample opportunities for both the development of a compound library.14
soluble forms and wide structural variations. Small molecules
Following the linear scheme, we synthesized C24 from 3-
based on 2-oxindole scaffold have a broad spectrum of biolog- phenylpropiolic acid by amidation with aniline, alkylation with
ical activity.10 The high druglikeness of these compounds is 3-(bromomethyl)benzoic acid methyl ester, ring formation of
determined by the fact that 2-oxindole is a tryptophan metab- the resulting intermediate, followed by removal of the ester
olite and can mimic its affinity to various protein substrates. group (Scheme 1).15 It is interesting that at the ring formation
step we observed the formation of dehalogenated compound
along with the target product. The resulting mixture of the
products cannot be separated by crystallization. Single crystals
of mixed composition are formed when crystallizing (Fig. 1).
aLaboratory of Molecular Pharmacology, Saint Petersburg State Institute of Technology
(Technical University), Moskovskii pr. 26, Saint Petersburg 190013, Russia. E-mail: dc.
novikova@gmail.com
They can be separated only using reversed-phase silica gel, but
bDepartment of Crystallography, Saint Petersburg State University, per. Dekabristov
extremely low solubility of the esters makes the purication
16, Saint Petersburg 199155, Russia
process difficult. In addition to the above difficulties, the rst
† Electronic supplementary information (ESI) available. CCDC 1585543. For ESI
stages of the synthesis are divergent, so to introduce
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c8ra07576j
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Scheme 1 Linear scheme of C24 synthesis.
simplest way to build the carbon skeleton of substituted alkene
oxindoles is to perform the Knoevenagel condensation of
oxindole with benzophenones. The condensation of oxindole
with aldehydes and alkylphenones proceeds practically with
quantitative yields under common conditions: toluene, pyrro-
lidine, azeotropic distillation of water. Reduction of yields is
observed only in the case of ketones and aldehydes substituted
in position 2 of the aromatic ring. However, there is the diffi-
culty to realize the condensation of oxindole with benzophe-
nones,18 and under the same conditions the reaction product is
formed only in trace amounts when benzophenone is taken as
a carbonyl compound (Table 1).
Varying of solvents and bases does not lead to a signicant
increase in the conversion of the starting compounds. A positive
result was reached using equimolar amounts of anhydrous
ammonium acetate; the degree of oxindole conversion was
increased, and the condensation product was obtained in 20%
yield (Table 2).
Among the modern methods for performing the Knoevena-
gel condensation, we should highlight a method with inter-
mediate formation of titanium enolate,19 which was successfully
used for the synthesis of 3-alkylidene oxindoles.20 We found that
the proposed method shows good results not only for benzo-
phenone condensation, as it was shown, but also when using
diversely substituted benzophenones, for example 4-chlor-
obenzophenone (Table 2).
Fig. 1 ORTEP representation of the crystal structure corresponding to
C30H22.25Cl0.75NO3 crystals.
a substituent into ring A it is necessary to obtain substituted
phenylpropiolic acid, for example, by the Sonogashira coupling.
It appears that the diversity is provided before the most difficult
stage of building the carbon skeleton.
Current synthetic schemes based on propiolic acid have
various modications, including one pot and domino multi-
component ones.16 However, the modern names do not relieve
them of the shortcomings inherent to the linear scheme;
moreover, the use of active catalysts can lead to undesirable
rearrangements of the carbon skeleton of the target substrate.17
The convergent synthesis (Scheme 2) can be implemented
based on the route obtained using obvious disconnections. The
However, the reaction turned out to be very sensitive to the
quality of titanium isopropoxide used. Long-term storage of the
reagent resulted in a signicant drop in the yield of the target
compound. Accordingly, high requirements are imposed on the
THF dryness (distillation over LAH).
When looking for less capricious, but no less effective
condensation catalyst, we paid attention to aluminum iso-
propoxide. The homogeneous catalysis of the Knoevenagel
Scheme 2 Convergent scheme of C24 synthesis.
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Table 1 Knoevenagel condensation of carbonyl compounds with
unsubstituted oxindole
reaction, we obtained a series of condensed oxindole derivatives
with good yields under mild conditions (Table 3). Aluminum
isopropoxide can be readily obtained in the laboratory, and its
prolonged storage does not lead to a signicant drop in the
reaction yields.
It should be noted that due to the presence of the double
bond in position 3, alkene oxindoles exist as E- and Z-isomers
exhibiting different biological activity.15 This requires the
isolation of single isomers and separate biological evaluation.
In the case of the condensation of aldehydes and alkylphe-
nones in the presence of pyrrolidine, E-isomers are predomi-
nantly formed. However, it was shown that the condensation of
oxindole with acetophenone and propiophenone via titanium
enolates leads to a prevalence of Z-isomer in the product
mixture.20
Titanium- and aluminum-promoted condensation of oxin-
dole with 4-chlorobenzophenone resulted in similar ratio of E-
and Z-isomers when compared (E/Z ratio 40/60 and 37/63,
respectively). This E,Z-isomer mixture of the condensation
products can be successfully separated by column chromatog-
raphy (Rf(E) ¼ 0.32, Rf(Z) ¼ 0.46, n-hexane/ethyl acetate 3 : 1).
The isomers can be clearly distinguished in 1H NMR spectra by
the chemical shis of protons H4 and H5 of the oxindole core
(Fig. 2).
Entry
R1
R2
Time, h
Yield (E/Z ratio)
1
2
3
4
5
6
7
8
4-Cl
2-Cl
H
4-Cl
2-Cl
H
H
H
H
0.25
3
0.5
1
3
2
2
1
24
24
24
96 (63/36)
72 (98/2)
94 (96/4)
91 (96/4)
65 (99/1)
85 (95/5)
76 (95/5)
80 (98/2)
Traces
CH3
CH3
CH3
C2H5
n-C3H7
CH3
Ph
30,40-Methylenedioxy
H
4-Cl
4-OCH3
9
10
11
Ph
Ph
Tracesb
Tracesb
a
Reaction conditions: 2-oxindole (1 equiv.), corresponding ketone (1.2
equiv.), pyrrolidine (2 equiv.), toluene, reux with the Dean–Stark
trap. b E/Z ratio not determined.
Despite the differences in the E,Z-isomer ratio obtained
during the condensation of oxindoles with aldehydes or
unsymmetrical ketones under different synthetic conditions,
from the preparative point of view, optimization of the selec-
tivity of this stage by manipulation with the reaction mecha-
nism is meaningless due to a relatively easy transition between
the E,Z-isomers.
reaction by aluminum alkoxides has not been described previ-
ously, although studies on heterogeneous catalysis using
aluminum oxide were conducted.21
We proposed that aluminum isopropoxide is able of similar
formation of enolates with carbonyl groups of oxindole
observed for titanium isopropoxide. Thus, rst using aluminum
isopropoxide as a condensing agent in the Knoevenagel type
One isomer can be transferred to another by UV irradiation
until the equilibrium is reached.22 The isomerization reaction
Table 2 Knoevenagel reaction conditions
Entry
Base/catalyst
Amount
Solvent
Yield
1
2
3
Piperidine
NH3
NaH
2
Ethanol
Toluene
THF
Trace
Trace
8
Excessa
1.1
4
NaH
1.1
DMF
6
5
6
7
8
9
10
11
NaOH
NaOH
NH4COOCH3
Pyridine/Ti[OCH(CH3)2]4
Pyridine/Ti[OCH(CH3)2]4
Pyridine/Ti[OCH(CH3)2]4, (2 days of storage)
Pyridine/Ti[OCH(CH3)2]4, (5 days of storage)
1
1
Ethanol
Butanol
Toluene
THF (rt)
THF (60 ꢀC)
THF (60 ꢀC)
THF (60 ꢀC)
5
7
20
58
86
34
Trace
Excessa
3/2
3/2
3/2
3/2
a
About 20 equivalents.
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Table 3 Aluminum-promoted Knoevenagel condensationa
Table 4 Alkylation of 3-((4-chlorophenyl)(phenyl)methylene)indolin-
2-one with 3-(bromomethyl)benzoic acid methyl ester
Entry
R1
R2
Yieldb
Isomer ratio, E/Zc
1
2
3
4
5
6
7
8
H
2-Cl
4-Cl
4-Cl
H
H
H
4-Cl
2,4-Cl
H
76
80
82
86
83
77
73
83
80
79
72
—
62/38
37/63
—
56/44
50/50
38/62
42/58
50/50
46/54
50/50
Entry
Base
Amount
Solvent
Yield
1
2
3
4
5
6
7
8
Na2CO3
K2CO3
NaH
NaH
TEA
TEA
K2CO3
K2CO3
3
3
1.5
1.1
3
3
3
3
DMF
DMF
THF
DMF
4
93
62
4-Cl
4-OH
4-OCH3
3-CH3
3-CH3
4-CH3
4-CH3
78–83a
Trace
29
H
4-Cl
4-OH
4-Cl
4-OH
DMF
9
10
11
Toluene
DMSO
Acetone
47
34
a
a
Reaction conditions: 2-oxindole (1 equiv.), benzophenone (1.2 equiv.),
Simultaneous hydrolysis of ester group was observed.
pyridine (2 equiv.), aluminum isopropoxide (3 equiv.), THF, 40 ꢀC, 12 h.
b
c
Total yield is given (for both E- and Z-isomer). Determined by NMR
aer work up.
Conclusions
In summary, we developed advanced route of C24 synthesis within
the convergent strategy. The used synthetic methods, despite of
their simplicity, correspond to the current trends in the C–H bond
functionalization without recruiting halogens or halogenoids as
leaving groups.23 Thus, using the previously proposed schemes the
halogen acts as a leaving group three times during the
synthesis,15,16 while in the developed scheme only once at the N-
alkylation step. One of the most interesting points of the work is
the use of aluminum isopropoxide as a condensing agent in the
Knoevenagel reaction. The given scheme and methods of synthesis
provide the most comfortable opportunity for the development of
focused libraries with high variability of external fragments
including those with hydroxy group.
proceeds without the by-product formation. Particularly, the Z/E
equilibrium ratio for the condensation products of oxindole
with 4-chlorobenzophenone is 51/49. Using a series of sequen-
tial irradiations and separations, it is possible to achieve the
preparative yield of the desired isomer (E- or Z-isomer) up to
80%.
Thus, the most rational way to obtain individual isomeric
forms of the compounds is to separate the mixture at the nal
stages of the synthetic scheme. So, methyl ester of C24 can be
prepared by direct alkylation of the E,Z-isomer mixture of the
condensation products with 3-(bromomethyl)benzoic acid
methyl ester as an alkylating agent (Table 4) and subsequent
separation of the alkylated derivatives (Rf(Ealk) ¼ 0.21, Rf(Zalk) ¼
0.30, n-hexane/ethyl acetate 6 : 1).
Alkaline hydrolysis in a water–THF mixture is the nal
stage of the synthesis. It is carried out using the trivial
procedure with yields close to quantitative. Scheme 2 repre-
sents a simple and effective route based on the convergent
strategy, which can be used for obtaining C24 with the total
yield of 58%, as well as for the synthesis of 3-(benzylidene)
indolin-2-one series.
Experimental
All starting compounds and reagents used, except 2-oxindole
which was obtained according to the known procedure,24 are
commercially available.
The progress of reactions was monitored by TLC on Silica gel
60 F254 plates (Merk) using n-hexane/ethyl acetate eluent.
Purication of the products was carried out using an Isolera
Four ash chromatograph on SNAP KP-Sil 100 g cartridges
(Biotage) with n-hexane/ethyl acetate eluent. For separation of
the mixture of C24 methyl ester and its dehalogenated product,
an Omnit glass column (DIBA) packed with LiChroprep RP-18
sorbent 25–40 mm (Merck) was used.
1H and 13C NMR spectra were recorded on a Bruker Avance III
400 (400 MHz) device in DMSO-d6. To determine the spatial
conguration of the compounds (E or Z isomer), previously ob-
tained crystallographic data or NOESY/ROESY spectra were
considered. The isomer ratio was evaluated only by 1H-NMR, since
Fig. 2 Chemical shifts of characteristic proton signals for pair of 3((4-
chlorophenyl)(phenyl)methylene)indolin-2-one isomers.
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the isomers have different absorption at 254 nm commonly used (t, J ¼ 7.7, 1H), 6.33 (d, J ¼ 7.6, 1H), 4.96 (s, 2H), 3.87 (s, 3H);
for detection in chromatographic devices. Mass spectra were 13C NMR (101 MHz, DMSO-d6) d (ppm): 166.48, 166.06, 153.00,
recorded on a LCMS-2020 device (Shimadzu) with a single quad- 142.50, 140.26, 139.90, 137.98, 134.52, 132.59, 131.17, 130.46,
rupole detector under positive mode, electrospray ionization (ESI). 130.36, 129.80, 129.71, 129.63, 129.38, 128.65, 128.45,
128.23, 124.29, 122.97, 122.85, 122.00, 109.41, 52.66, 42.62; MS
(ESI) m/z: 480 [M + H]+.
General procedure for C24 synthesis using the linear scheme
(E)-3-((3-((4-Chlorophenyl)(phenyl)methylene)-2-oxoindolin-
Originally, the synthesis of C24 was carried out according to the 1-yl)methyl)benzoic acid (C24). Lithium hydroxide (1.2 g, 0.05
known procedure15 with some modications concerning mainly mol) dissolved in 50 mL water was added to the corresponding
the work up of the reactions and the use of preobtained tetra- methyl ester (2.4 g, 0.005 mol) dissolved in 50 mL THF. The
kis(triphenylphosphine)palladium instead of in situ generation reaction mixture was stirred at rt and monitored by TLC. The
(total yield 29%).
organic solvent was then distilled off. The mixture was acidied
N,3-Diphenylpropiolamide. Aniline (3 g, 0.032 mol) and with 15% HCl, the precipitate was ltered off, washed with
phenylpropiolic acid (5.12 g, 0.035 mol) were dissolved in 50 mL water and dried. The crude product was puried by
100 mL dichloromethane, and then 7.7 g N,N0-dicyclohex- recrystallization from ethyl acetate. Yellow crystals in 88% yield;
ylcarbodiimide (0.037 mol) was added in one portion at 0 C. mp 204–206 ꢀC (decomp.); 1H NMR (400 MHz, DMSO-d6)
ꢀ
The reaction mixture was intensively stirred overnight at room d (ppm): 7.91 (s, 1H), 7.85 (d, J ¼ 7.7, 1H), 7.61–7.53 (m, 3H),
temperature. The mixture then was poured into water and 7.47 (t, J ¼ 7.7, 1H), 7.41–7.30 (m, 7H), 7.15 (t, J ¼ 7.8, 1H), 6.92
extracted with dichloromethane (3 ꢁ 50 mL). The organic layers (d, J ¼ 7.8, 1H), 6.73 (t, J ¼ 7.5, 1H), 6.29 (d, J ¼ 7.7, 1H), 4.97 (s,
were combined, dried over anhydrous Na2SO4, the solvent was 2H); 13C NMR (101 MHz, DMSO-d6) d (ppm): 167.55, 166.04,
then evaporated under reduced pressure. The product was 152.98, 142.55, 140.27, 139.91, 137.75, 134.48, 132.22, 131.59,
puried by ash chromatography (n-hexane/ethyl acetate 9 : 1). 131.16, 130.32, 129.81, 129.73, 129.44, 129.36, 128.79, 128.53,
Colorless crystals in 78% yield (5.44 g), mp 125–126 ꢀC; 1H NMR 128.24, 124.29, 122.96, 122.81, 122.00, 109.43, 42.66; MS (ESI)
(400 MHz, DMSO-d6) d (ppm): 10.84 (s, 1H), 7.66 (d, J ¼ 7.7, 4H), m/z: 466 [M + H]+.
7.55–7.47 (m, 3H), 7.34 (t, J ¼ 7.8, 2H), 7.11 (t, J ¼ 7.3, 1H); MS
(ESI) m/z: 222 [M + H]+.
Methyl 3-((N,3-diphenylpropiolamido)methyl)benzoate. N,3-
Diphenylpropiolamide (4 g, 0.018 mol), methyl 3-(bromo-
General procedure for Knoevenagel condensation of carbonyl
compounds (aldehydes or alkylphenones) with oxindol
methyl)benzoate (4.8 g, 0.022 mol) and cesium carbonate (8.8 g, 2-Oxindole (2 g, 0.015 mol) was suspended in 50 mL of toluene.
0.027 mol) were dissolved in 100 mL dimethylformamide and The corresponding ketone (0.018 mol, 1.2 equiv.), 2.5 mL of
stirred overnight at room temperature. The solvent was evapo- pyrrolidine (0.03 mol, 2 equiv.) were added to the suspension.
rated under reduced pressure, and then 200 mL water was The reaction mixture was reuxed with the Dean–Stark trap.
added to the residue. The precipitate was ltered off, dissolved The reaction was monitored by TLC until the starting oxindole
in ethyl acetate, dried over anhydrous Na2SO4 and evaporated disappeared. Than the mixture was cooled, the solvent was
under reduced pressure. The crude product was puried by evaporated under reduced pressure. The crude product was
recrystallization from isopropanol to give 5.8 g (87%). Colorless treated with a small amount of ethyl acetate and then ltered
crystals, mp 110–111 ꢀC; 1H NMR (400 MHz, DMSO-d6) d (ppm): off, or recrystallized from n-hexane/ethyl acetate, or puried by
7.89–7.83 (m, 2H), 7.54–7.30 (m, 10H), 5.08 (s, 2H), 3.85 (s, 3H); ash chromatography using n-hexane/ethyl acetate eluent (if
MS (ESI) m/z: 370 [M + H]+.
pair of isomers formed).
(E)-3-((3-((4-Chlorophenyl)(phenyl)methylene)-2-oxoindolin-
3-(4-Chlorobenzylidene)indolin-2-one. Yellow crystals in
1-yl)methyl)benzoic acid methyl ester. Tetrakis(tri-phenyl- 96% total yield. E-isomer: 1H NMR (400 MHz, DMSO-d6)
phosphine)palladium (0.58 g, 0.0005 mol), 1-chloro-4- d (ppm): 10.63 (s, 1H), 7.73 (d, J ¼ 8.3 Hz, 2H), 7.60 (s, 1H), 7.59
iodobenzene (2.6 g, 0.011 mol) and cesium uoride (4.6 g, (d, J ¼ 8.3 Hz, 2H), 7.49 (d, J ¼ 7.6 Hz, 1H), 7.24 (t, J ¼ 7.7, 1H),
0.03 mol) were added to a solution of methyl 3-((N,3-diphenyl- 6.88 (d, J ¼ 7.7 Hz, 1H), 6.86 (t, J ¼ 7.6 Hz, 1H); 13C NMR (101
propiolamido)methyl)benzoate (3.7 g, 0.01 mol) in 50 mL MHz, DMSO-d6) d (ppm): 168.93, 143.55, 134.75, 134.59, 133.83,
dimethylformamide. The reaction mixture was stirred for 3 h at 131.59, 130.85, 129.33, 128.67, 122.95, 121.69, 121.12, 110.68;
110 ꢀC under argon atmosphere, and then 200 mL water was MS (ESI) m/z: 256 [M + H]+. Z-isomer: 1H NMR (400 MHz, DMSO-
added. The mixture was extracted with ethyl acetate, dried over d6) d (ppm): 10.67 (s, 1H), 8.40 (d, J ¼ 8.6 Hz, 2H), 7.79 (s, 1H),
anhydrous Na2SO4 and evaporated under reduced pressure. The 7.70 (d, J ¼ 7.5 Hz, 1H), 7.52 (d, J ¼ 8.6 Hz, 2H), 7.28–7.15 (m,
mixture of products was rst isolated by ash chromatography 1H), 6.99 (t, J ¼ 7.6 Hz, 1H), 6.83 (d, J ¼ 7.7 Hz, 1H); 13C NMR
using n-hexane/ethyl acetate eluent (9 : 1), and then the title (101 MHz, DMSO-d6) d (ppm): 167.55, 141.38, 135.55, 135.29,
product was separated from dehalogenated product on 134.01, 133.31, 129.69, 128.69, 127.86, 125.16, 121.59, 120.42,
a reversed-phase silica gel column with methanol/water eluent 109.90; MS (ESI) m/z: 256 [M + H]+.
1
(3 : 1). Yellow crystals in 49% yield; mp 181–182 ꢀC; H NMR
(E)-3-(2-Chlorobenzylidene)indolin-2-one. Yellow crystals in
(400 MHz, DMSO-d6) d (ppm): 7.96 (s, 1H), 7.87 (d, J ¼ 7.7, 1H), 72% yield. 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.67 (s, 1H),
7.57 (d, J ¼ 7.8, 1H), 7.54 (d, J ¼ 8.4, 2H), 7.47 (t, J ¼ 7.7, 1H), 7.77 (dd, J ¼ 7.0, 2.2 Hz, 1H), 7.64 (dd, J ¼ 7.7, 1.5 Hz, 1H), 7.55–
7.39–7.29 (m, 7H), 7.12 (t, J ¼ 7.6, 1H), 6.87 (d, J ¼ 7.8, 1H), 6.69 7.47 (m, 2H), 7.59 (s, 1H), 7.24 (t, J ¼ 7.7 Hz, 1H), 7.15 (d, J ¼
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7.6 Hz, 1H), 6.88 (d, J ¼ 7.7 Hz, 1H), 6.81 (t, J ¼ 7.6 Hz, 1H); 13
C
drying tube until aluminum was completely dissolved. The
NMR (101 MHz, DMSO-d6) d (ppm): 168.55, 143.63, 133.41, isopropanol was distilled off and the crude product was
133.36, 131.94, 131.73, 131.12, 130.79, 130.30, 130.01, 127.90, immediately puried by distillation (0.4 bar, 134–137 ꢀC).
123.04, 121.75, 120.98, 110.75; MS (ESI) m/z: 256 [M + H]+.
Freshly distilled aluminum isopropoxide was obtained as high-
(E)-3-(1-Phenylethylidene)indolin-2-one. Yellow crystals in viscosity liquid in 94% yield, solidifying within several hours.
94% yield; 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.49 (s, 1H),
7.54–7.43 (m, 3H), 7.30 (d, J ¼ 6.9, 2H), 7.01 (t, J ¼ 7.6, 1H), 6.76
(d, J ¼ 7.7, 1H), 6.50 (t, J ¼ 7.6, 1H), 5.98 (d, J ¼ 7.7, 1H), 2.71 (s,
3H); 13C NMR (101 MHz, DMSO-d6) d (ppm): 169.30, 154.15,
General procedure for aluminum-promoted Knoevenagel
condensation of benzophenones
143.08, 141.20, 129.67, 128.83, 128.73, 126.74, 123.99, 123.17,
122.71, 120.85, 109.72, 22.49; MS (ESI) m/z: 236 [M + H]+.
2-Oxindole (2 g, 0.015 mol) was dissolved in dried and freshly
(E)-3-(1-(4-Chlorophenyl)ethylidene)indolin-2-one.
Yellow distilled THF, the corresponding benzophenone (0.018 mol),
1
crystals in 91% yield; H NMR (400 MHz, DMSO-d6) d (ppm): pyridine (2.42 mL, 0.03 mol) and aluminum isopropoxide (9.2 g,
10.51 (s, 1H), 7.54 (d, J ¼ 8.3, 2H), 7.35 (d, J ¼ 8.3, 2H), 7.04 (t, J 0.045 mol) were added. The reaction mixture was heated to
¼ 7.6, 1H), 6.77 (d, J ¼ 7.7, 1H), 6.57 (t, J ¼ 7.6, 1H), 6.07 (d, J ¼ 40 ꢀC and kept overnight. Then the reaction mixture was
7.7, 1H), 2.68 (s, 3H); 13C NMR (101 MHz, DMSO-d6) d (ppm): quenched with 3% Na2CO3 solution, extracted with ethyl
169.16, 152.49, 141.75, 141.32, 133.56, 129.75, 128.98, 128.94, acetate, dried over anhydrous Na2SO4 and evaporated under
124.33, 122.92, 122.66, 120.99, 109.84, 22.29; MS (ESI) m/z: 270 reduced pressure. The product (mixture of products) was iso-
[M + H]+.
(E)-3-(1-(2-Chlorophenyl)ethylidene)indolin-2-one.
lated by ash chromatography with n-hexane/ethyl acetate
Yellow eluent.
crystals in 65% yield; H NMR (400 MHz, DMSO-d6) d (ppm):
3-(Diphenylmethylene)indolin-2-one. Yellow crystals in 76%
1
10.48 (s, 1H), 7.32–7.25 (m, 2H), 7.49 (dd, J ¼ 6.9, 2.4 Hz, 1H), yield; 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.49 (s, 1H), 7.50–
7.41 (dd, J ¼ 7.8, 1.6 Hz, 1H), 7.05 (t, J ¼ 7.7, 1H), 6.79 (d, J ¼ 7.6, 7.47 (m, 3H), 7.35–7.25 (m, 7H), 7.09 (td, J ¼ 7.7, 0.8 Hz, 1H),
1H), 6.59 (t, J ¼ 7.7, 1H), 6.04 (d, J ¼ 7.8, 1H), 2.65 (s, 3H); 13C 6.78 (d, J ¼ 7.7 Hz, 1H), 6.57 (t, J ¼ 7.6 Hz, 1H), 6.09 (d, J ¼
NMR (101 MHz, DMSO-d6) d (ppm): 168.67, 151.97, 142.14, 7.7 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d (ppm): 167.57,
141.68, 135.22, 134.43, 129.64, 129.19, 128.09, 127.27, 126.67, 153.20, 142.46, 141.81, 140.30, 130.14, 129.65, 129.47, 129.43,
123.75, 123.32, 121.23, 110.26, 22.18; MS (ESI) m/z: 270 [M + H]+. 128.93, 128.89, 128.09, 125.28, 123.75, 123.12, 120.92, 109.88;
(E)-3-(1-Phenylpropylidene)indolin-2-one. Yellow crystals in MS (ESI) m/z: 298 [M + H]+.
85% yield; 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.52 (s, 1H),
3-((2-Chlorophenyl)(phenyl)methylene)indolin-2-one. Yellow
7.56–7.45 (m, 3H), 7.27 (d, J ¼ 6.7, 2H), 7.03 (t, J ¼ 7.5, 1H), 6.76 crystals in 80% total yield. E-isomer: 1H NMR (400 MHz, DMSO-
(d, J ¼ 7.7, 1H), 6.50 (t, J ¼ 7.5, 1H), 5.85 (d, J ¼ 7.7, 1H), 3.24 (q, J d6) d (ppm): 10.49 (s, 1H), 7.56 (d, J ¼ 8.4 Hz, 2H), 7.36–7.30 (m,
¼ 7.4, 2H), 1.00 (t, J ¼ 7.7, 3H); 13C NMR (101 MHz, DMSO-d6) 5H), 7.29–7.25 (m, 2H), 7.12 (t, J ¼ 7.7 Hz, 1H), 6.79 (d, J ¼
d
(ppm): 168.94, 159.65, 141.36, 141.32, 129.61, 128.78, 7.7 Hz, 1H), 6.65 (t, J ¼ 7.7 Hz, 1H), 6.20 (d, J ¼ 7.7 Hz, 1H); 13
C
127.18, 123.60, 123.23, 122.80, 120.85, 109.70, 27.37, 12.26; MS NMR (101 MHz, DMSO-d6) d (ppm): 167.41, 151.55, 142.57,
(ESI) m/z: 250 [M + H]+.
140.53, 140.03, 134.22, 131.09, 130.22, 129.77, 129.71, 129.07,
(E)-3-(1-Phenylbutylidene)indolin-2-one. Yellow crystals in 128.17, 125.63, 123.47, 123.06, 121.10, 110.01; MS (ESI) m/z: 332
76% yield; 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.55 (s, 1H), [M + H]+. Z-isomer: 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.52
7.55–7.45 (m, 3H), 7.27 (d, J ¼ 7.9 Hz, 2H), 7.03 (t, J ¼ 7.6 Hz, (s, 1H), 7.52–7.47 (m, 3H), 7.41–7.36 (m, 2H), 7.33–7.27 (m, 4H),
1H), 6.76 (d, J ¼ 7.6 Hz, 1H), 6.51 (t, J ¼ 7.7 Hz, 1H), 5.85 (d, J ¼ 7.10 (t, J ¼ 7.6 Hz, 1H), 6.78 (d, J ¼ 7.8 Hz, 1H), 6.59 (t, J ¼ 7.6 Hz,
7.7 Hz, 1H), 3.23 (t, J ¼ 7.6 Hz, 2H), 1.44–1.34 (m, 2H), 0.90 (t, J ¼ 1H), 6.11 (d, J ¼ 7.8 Hz, 1H); 13C NMR (101 MHz, DMSO-d6)
7.3 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) d (ppm): 169.04, d (ppm): 167.55, 151.43, 142.56, 141.30, 139.11, 133.70, 132.00,
158.26, 141.50, 141.30, 129.61, 128.78, 127.13, 124.25, 123.22, 129.73, 129.61, 128.95, 128.19, 128.08, 125.79, 123.52, 123.18,
122.80, 120.84, 109.67, 35.77, 20.85, 14.21; MS (ESI) m/z: 264 [M 121.01, 109.98; MS (ESI) m/z: 332 [M + H]+.
+ H]+.
(E)-3-(1-(Benzo[d][1,3]dioxol-5-yl)ethylidene)indolin-2-one.
3-((4-Chlorophenyl)(phenyl)methylene)indolin-2-one. Yellow
crystals in 82% total yield. E-isomer: mp 153–155 ꢀC (decomp.);
Yellow crystals in 80% yield; 1H NMR (400 MHz, DMSO-d6) 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.46 (s, 1H), 7.54 (d, J ¼
d (ppm): 10.56 (s, 1H), 7.09–7.01 (m, 2H), 6.95 (d, J ¼ 1.3 Hz, 1H), 8.3 Hz, 2H), 7.29–7.36 (m, 5H), 7.24–7.28 (m, 2H), 7.10 (t, J ¼
6.81 (dd, J ¼ 7.9, 1.5 Hz, 1H), 6.78 (d, J ¼ 7.7, 1H), 6.63 (t, J ¼ 7.7, 7.6 Hz, 1H), 6.78 (d, J ¼ 7.7 Hz, 1H), 6.63 (t, J ¼ 7.6 Hz, 1H), 6.22
1H), 6.25 (d, J ¼ 7.7, 1H), 6.11 (s, 2H), 2.66 (s, 3H); 13C NMR (101 (d, J ¼ 7.7 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d (ppm):
MHz, DMSO-d6) d (ppm): 169.33, 154.01, 148.37, 147.76, 141.10, 167.41, 151.55, 142.57, 140.52, 140.03, 134.21, 131.07, 130.19,
136.65, 128.67, 124.06, 123.23, 122.82, 120.96, 120.61, 109.70, 129.76, 129.71, 129.06, 128.16, 125.63, 123.47, 123.06, 121.09,
109.45, 107.65, 101.80, 22.57; MS (ESI) m/z: 280 [M + H]+.
110.00; MS (ESI) m/z: 332 [M + H]+. Z-isomer: mp 229–230 ꢀC; 1H
NMR (400 MHz, DMSO-d6) d (ppm): 10.52 (s, 1H), 7.46–7.51 (m,
3H), 7.38 (d, J ¼ 8.5 Hz, 2H), 7.27–7.33 (m, 4H), 7.09 (t, J ¼
7.6 Hz, 1H), 6.79 (d, J ¼ 7.7 Hz, 1H), 6.58 (t, J ¼ 7.6 Hz, 1H), 6.13
Procedure for aluminum isopropoxide preparation
Finely attened aluminium (2.7 g, 0.1 mol) in 100 mL iso- (d, J ¼ 7.8 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d (ppm):
propanol with a catalytic amount of iodine was reuxed with 167.56, 151.41, 142.57, 141.29, 139.11, 133.71, 131.98, 129.71,
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129.59, 128.94, 128.18, 125.81, 123.53, 123.19, 121.00, 109.98; (101 MHz, DMSO-d6) d (ppm): 167.70, 160.55, 153.48, 142.05,
MS (ESI) m/z: 332 [M + H]+.
132.68, 132.02, 129.58, 129.56, 129.40, 128.93, 124.32, 124.14,
3-(Bis(4-chlorophenyl)methylene)indolin-2-one. Yellow crys- 122.84, 120.77, 113.40, 109.73, 55.63; MS (ESI) m/z: 328 [M + H]+.
tals in 86% yield; 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.54
3-((4-Chlorophenyl)(m-tolyl)methylene)indolin-2-one. Yellow
(s, 1H), 7.57 (d, J ¼ 8.4 Hz, 2H), 7.40 (d, J ¼ 8.4 Hz, 2H), 7.35 (d, J crystals in 83% total yield. E-isomer: 1H NMR (400 MHz, DMSO-
¼ 8.4 Hz, 2H), 7.29 (d, J ¼ 8.5 Hz, 2H), 7.13 (t, J ¼ 7.7 Hz, 1H), d6) d (ppm): 10.50 (s, 1H), 7.41–7.36 (m, 3H), 7.32–7.28 (m, 3H),
6.79 (d, J ¼ 7.7 Hz, 1H), 6.66 (t, J ¼ 7.7 Hz, 1H), 6.23 (d, J ¼ 7.12–7.07 (m, 3H), 6.78 (d, J ¼ 7.7 Hz, 1H), 6.59 (td, J ¼ 7.7,
7.7 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d (ppm): 167.41, 1.0 Hz, 1H), 6.14 (d, J ¼ 7.7 Hz, 1H), 2.31 (s, 3H); 13C NMR (101
149.82, 142.67, 140.01, 138.85, 134.41, 133.86, 132.11, 131.16, MHz, DMSO-d6) d (ppm): 167.57, 151.64, 142.50, 141.27, 139.10,
129.94, 129.85, 128.26, 126.14, 123.27, 123.15, 121.19, 110.10; 133.67, 131.97, 130.22, 129.65, 129.62, 129.17, 128.17, 125.99,
MS (ESI) m/z: 366 [M + H]+.
125.64, 123.57, 123.23, 121.03, 109.95, 21.37; MS (ESI) m/z: 346
[M + H]+. Z-isomer: 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.48
3-((4-Chlorophenyl)(2,4-dichlorophenyl)methylene)indolin-
2-one. Yellow crystals in 83% yield. E-isomer: 1H NMR (400 (s, 1H), 7.56 (d, J ¼ 8.4 Hz, 2H), 7.32 (d, J ¼ 8.4 Hz, 2H), 7.22 (t, J
MHz, DMSO-d6) d (ppm): 10.60 (s, 1H), 7.86 (d, J ¼ 2.0 Hz, 1H), ¼ 7.7 Hz, 1H), 7.18–7.04 (m, 4H), 6.79 (d, J ¼ 7.7 Hz, 1H), 6.65 (t,
7.62 (dd, J ¼ 8.3, 2.1 Hz, 1H), 7.53 (d, J ¼ 8.3 Hz, 1H), 7.40 (s, J ¼ 7.6 Hz, 1H), 6.19 (d, J ¼ 7.7 Hz, 1H), 2.27 (s, 3H); 13C NMR
4H), 7.16 (t, J ¼ 7.7 Hz, 1H), 6.80 (d, J ¼ 7.7 Hz, 1H), 6.70 (t, J ¼ (101 MHz, DMSO-d6) d (ppm): 167.40, 151.79, 142.51, 140.52,
7.6 Hz, 1H), 5.92 (d, J ¼ 7.7 Hz, 1H); 13C NMR (101 MHz, DMSO- 140.10, 137.19, 134.19, 131.04, 130.41, 129.76, 129.66, 128.13,
d6) d (ppm): 167.01, 145.65, 142.81, 138.45, 136.69, 134.92, 127.39, 125.57, 123.49, 123.01, 121.08, 109.99, 21.41; MS (ESI)
133.92, 132.80, 131.95, 131.90, 130.48, 130.42, 129.24, 128.16, m/z: 346 [M + H]+.
127.39, 123.00, 122.95, 121.67, 110.21; MS (ESI) m/z: 400 [M +
3-((4-Hydroxyphenyl)(m-tolyl)methylene)indolin-2-one.
H]+. Z-isomer: 10.58 (s, 1H), 7.65 (d, J ¼ 2.0 Hz, 1H), 7.58 (d, J ¼ Yellow crystals in 80% total yield. E-isomer: 1H NMR (400 MHz,
8.6 Hz, 2H), 7.47 (d, J ¼ 8.6 Hz, 2H), 7.44 (d, J ¼ 2.0 Hz, 1H), 7.42 DMSO-d6) d (ppm): 10.39 (s, 1H), 9.79 (s, 1H), 7.37 (t, J ¼ 7.7 Hz,
(s, 1H), 7.19 (td, J ¼ 7.7, 1.1 Hz, 1H), 6.82 (d, J ¼ 7.6 Hz, 1H), 6.73 1H), 7.31 (d, J ¼ 7.4 Hz, 1H), 7.12 (d, J ¼ 8.6 Hz, 2H), 7.06–7.00
(td, J ¼ 7.7, 1.0 Hz, 1H), 6.50 (d, J ¼ 7.7 Hz, 1H)); 13C NMR (101 (m, 3H), 6.74 (d, J ¼ 7.5 Hz, 1H), 6.70 (d, J ¼ 8.7 Hz, 2H), 6.54 (td,
MHz, DMSO-d6) d (ppm): 167.15, 144.82, 143.20, 138.97, 137.89, J ¼ 7.7, 1.0 Hz, 1H), 5.99 (d, J ¼ 7.7 Hz, 1H), 2.32 (s, 3H); 13C
134.46, 133.47, 132.89, 131.74, 130.72, 129.76, 129.31, 128.10, NMR (101 MHz, DMSO-d6) d (ppm): 167.77, 159.25, 154.37,
128.01, 123.32, 121.94, 121.43, 110.39; MS (ESI) m/z: 400 [M + 142.17, 141.75, 138.81, 133.01, 130.29, 130.13, 129.79, 129.40,
H]+.
3-((4-Hydroxyphenyl)(phenyl)methylene)indolin-2-one.
128.57, 126.58, 124.64, 123.35, 122.76, 120.70, 114.77, 109.60,
21.38; MS (ESI) m/z: 328 [M + H]+. Z-isomer: 1H NMR (400 MHz,
Yellow crystals in 77% total yield. E-isomer: 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.36 (s, 1H), 9.90 (s, 1H), 7.24–7.13 (m, 2H),
DMSO-d6) d (ppm): 10.40 (s, 1H), 9.93 (s, 1H), 7.36–7.29 (m, 3H), 7.09–6.99 (m, 5H), 6.84 (d, J ¼ 8.2 Hz, 2H), 6.76 (d, J ¼ 7.6 Hz,
7.23 (dd, J ¼ 7.6, 1.8 Hz, 2H), 7.10–7.05 (m, 3H), 6.85 (d, J ¼ 1H), 6.63 (t, J ¼ 7.5 Hz, 1H), 6.42 (d, J ¼ 7.6 Hz, 1H), 2.27 (s, 3H);
8.5 Hz, 2H), 6.77 (d, J ¼ 7.7 Hz, 1H), 6.64 (t, J ¼ 7.6 Hz, 1H), 6.44 13C NMR (101 MHz, DMSO-d6) d (ppm): 167.79, 159.04, 154.31,
(d, J ¼ 7.7 Hz, 1H); 13C NMR (101 MHz, DMSO-d6) d (ppm): 142.05, 140.96, 136.92, 132.14, 131.40, 130.94, 129.73, 128.91,
167.81, 159.06, 154.09, 142.11, 140.90, 132.15, 131.44, 130.69, 127.91, 127.88, 124.33, 124.20, 122.63, 120.79, 116.20, 109.72,
129.04, 128.97, 127.98, 124.31, 124.27, 122.70, 120.82, 116.22, 21.41; MS (ESI) m/z: 328 [M + H]+.
109.75; MS (ESI) m/z: 314 [M + H]+. Z-isomer: 1H NMR (400 MHz,
3-((4-Chlorophenyl)(p-tolyl)methylene)indolin-2-one. Yellow
DMSO-d6) d (ppm): 10.42 (s, 1H), 9.82 (s, 1H), 7.51–7.46 (m, 3H), crystals in 79% total yield. E-isomer: 1H NMR (400 MHz, DMSO-
7.26–7.21 (m, 2H), 7.13 (d, J ¼ 8.6 Hz, 2H), 7.03 (td, J ¼ 7.7, d6) d (ppm): 10.48 (s, 1H), 7.55 (d, J ¼ 8.4 Hz, 2H), 7.30 (d, J ¼
1.0 Hz, 1H), 6.75 (d, J ¼ 7.6 Hz, 1H), 6.71 (d, J ¼ 8.7 Hz, 2H), 6.52 8.4 Hz, 2H), 7.18–7.07 (m, 5H), 6.77 (d, J ¼ 7.7 Hz, 1H), 6.64 (t, J
(t, J ¼ 7.7 Hz, 1H), 5.95 (d, J ¼ 7.7 Hz, 1H); 13C NMR (101 MHz, ¼ 7.7 Hz, 1H), 6.18 (d, J ¼ 7.7 Hz, 1H), 2.33 (s, 3H); 13C NMR (101
DMSO-d6) d (ppm): 167.76, 159.28, 154.19, 142.19, 141.80, MHz, DMSO-d6) d (ppm): 167.48, 151.85, 142.38, 140.67, 138.95,
133.06, 130.29, 129.52, 128.62, 124.59, 123.49, 122.73, 120.69, 137.02, 134.24, 131.30, 130.57, 129.71, 129.49, 128.75, 125.21,
114.79, 109.64; MS (ESI) m/z: 314 [M + H]+.
123.71, 122.94, 121.03, 109.94, 21.42; MS (ESI) m/z: 346 [M + H]+.
Z-isomer: 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.51 (s, 1H),
3-((4-Methoxyphenyl)(phenyl)methylene)indolin-2-one.
Yellow crystals in 73% total yield. E-isomer: 1H NMR (400 MHz, 7.37 (d, J ¼ 8.5 Hz, 2H), 7.30 (d, J ¼ 7.9 Hz, 2H), 7.26 (d, J ¼
DMSO-d6) d (ppm): 10.42 (s, 1H), 7.35–7.30 (m, 3H), 7.25–7.21 8.5 Hz, 2H), 7.17 (d, J ¼ 8.0 Hz, 2H), 7.09 (t, J ¼ 7.7 Hz, 1H), 6.78
(m, 2H), 7.19 (d, J ¼ 8.7 Hz, 2H), 7.09 (td, J ¼ 7.7, 0.9 Hz, 1H), (d, J ¼ 7.7 Hz, 1H), 6.61 (t, J ¼ 7.6 Hz, 1H), 6.28 (d, J ¼ 7.7 Hz,
7.04 (d, J ¼ 8.7 Hz, 2H), 6.77 (d, J ¼ 7.7 Hz, 1H), 6.63 (td, J ¼ 7.7, 1H), 2.38 (s, 3H); 13C NMR (101 MHz, DMSO-d6) d (ppm): 167.63,
0.7 Hz, 1H), 6.37 (d, J ¼ 7.7 Hz, 1H), 3.82 (s, 3H); 13C NMR (101 151.69, 142.46, 139.38, 138.37, 133.72, 132.17, 130.22, 129.58,
MHz, DMSO-d6) d (ppm): 167.71, 160.48, 153.42, 142.24, 140.78, 129.23, 128.13, 125.48, 123.68, 123.06, 120.99, 109.95, 21.43; MS
133.78, 131.21, 130.57, 129.17, 129.04, 128.02, 124.68, 124.11, (ESI) m/z: 346 [M + H]+.
122.75, 120.89, 114.88, 109.81, 55.73; MS (ESI) m/z: 328 [M + H]+.
3-((4-Hydroxyphenyl)(p-tolyl)methylene)indolin-2-one.
Z-isomer: 1H NMR (400 MHz, DMSO-d6) d (ppm): 10.45 (s, 1H), Yellow crystals in 72% total yield. E-isomer: 1H NMR (400 MHz,
7.54–7.45 (m, 3H), 7.28–7.21 (m, 4H), 7.05 (td, J ¼ 7.7, 1.1 Hz, DMSO-d6) d (ppm): 10.38 (s, 1H), 9.92 (s, 1H), 7.12 (s, 4H), 7.08–
1H), 6.89 (d, J ¼ 8.9 Hz, 2H), 6.76 (d, J ¼ 7.5 Hz, 1H), 6.55 (td, J ¼ 7.03 (m, 3H), 6.84 (d, J ¼ 8.6 Hz, 2H), 6.76 (d, J ¼ 7.6 Hz, 1H),
7.7, 1.0 Hz, 1H), 6.00 (d, J ¼ 7.7 Hz, 1H), 3.79 (s, 3H); 13C NMR 6.62 (t, J ¼ 8.1 Hz, 1H), 6.40 (d, J ¼ 7.7 Hz, 1H), 2.33 (s, 3H); 13
C
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NMR (101 MHz, DMSO-d6) d (ppm): 167.89, 159.10, 154.38,
141.90, 138.88, 137.87, 132.26, 131.65, 131.03, 128.73, 128.58,
124.57, 123.79, 122.57, 120.75, 116.17, 109.68, 21.44; MS (ESI)
m/z: 328 [M + H]+. Z-isomer: 1H NMR (400 MHz, DMSO-d6)
d (ppm): 10.38 (s, 1H), 9.79 (s, 1H), 7.29 (d, J ¼ 7.9 Hz, 2H), 7.12
(d, J ¼ 8.0 Hz, 2H), 7.09 (d, J ¼ 8.7 Hz, 2H), 7.02 (t, J ¼ 7.2 Hz,
1H), 6.75 (d, J ¼ 7.6 Hz, 1H), 6.70 (d, J ¼ 8.6 Hz, 2H), 6.55 (t, J ¼
7.3 Hz, 1H), 6.11 (d, J ¼ 7.7 Hz, 1H), 2.39 (s, 3H); 13C NMR (101
MHz, DMSO-d6) d (ppm): 167.83, 159.30, 154.43, 141.69, 139.24,
133.19, 130.57, 130.03, 129.80, 128.49, 124.74, 123.17, 122.58,
120.67, 114.75, 109.60, 21.45; MS (ESI) m/z: 328 [M + H]+.
Acknowledgements
This work was nancially supported by the Russian Science
Foundation (project no. 16-13-10358). XRD studies were per-
formed at the Centre for X-ray Diffraction Methods of Research
park of St. Petersburg State University.
Notes and references
1 (a) G. R. Steinberg and B. E. Kemp, Physiol. Rev., 2009, 89,
1025; (b) D. G. Hardie and M. L. Ashford, Physiology, 2014,
29, 99.
2 (a) D. G. Hardie, Diabetes, 2013, 62, 2164; (b) E. A. Day,
R. J. Ford and G. R. Steinberg, Trends Endocrinol. Metab.,
2017, 28, 545.
3 (a) L. G. Fryer, A. Parbu-Patel and D. Carling, J. Biol. Chem.,
2002, 277, 25226; (b) D. G. Hardie, F. A. Ross and
S. A. Hawley, Chem. Biol., 2012, 19, 1222.
General procedure for alkylation of alkene oxindole compounds
with 3-(bromomethyl)benzoic acid methyl ester exemplied by
the isomer mixture of 3-((4-chlorophenyl)(phenyl)methylene)
indolin-2-one
Isomer mixture of 3-((4-chlorophenyl)(phenyl)methylene)
indolin-2-one (2 g, 0.006 mol) and potassium carbonate (2.5 g,
0.018 mol) were dissolved in 100 mL dimethylformamide, and
methyl 3-(bromomethyl)benzoate (2 g, 0.007 mol) dissolved in
dimethylformamide was added gradually for an hour. The
reaction mixture was stirred overnight at room temperature.
The solvent was evaporated under reduced pressure, and then
water was added to the residue. The precipitate was ltered off,
dissolved in ethyl acetate, dried over anhydrous Na2SO4 and
evaporated under reduced pressure. The product mixture was
puried by ash chromatography (n-hexane/ethyl acetate 9 : 1).
3-((3-((4-Chlorophenyl)(phenyl)methylene)-2-oxoindolin-1-
yl)methyl)benzoic acid methyl ester. Yellow crystals in 93% total
yield. Spectral characteristics for E-isomer are given above (C24
synthesis). Z-isomer: 1H NMR (400 MHz, DMSO-d6) d (ppm):
7.96 (s, 1H), 7.87 (d, J ¼ 7.8 Hz, 1H), 7.58 (d, J ¼ 7.7 Hz, 1H),
7.50–7.54 (m, 3H), 7.48 (t, J ¼ 7.7 Hz, 1H), 7.41 (d, J ¼ 8.5 Hz,
2H), 7.31–7.36 (m, 4H), 7.11 (t, J ¼ 7.7 Hz, 1H), 6.89 (d, J ¼
7.8 Hz, 1H), 6.65 (t, J ¼ 7.6 Hz, 1H), 6.22 (d, J ¼ 7.7 Hz, 1H), 4.97
(s, 2H), 3.86 (s, 3H); MS (ESI) m/z: 480 [M + H]+.
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General procedure for alkaline hydrolysis for esters of N-alkylated
alkene oxindole compounds
Lithium hydroxide (1.2 g, 0.05 mol) dissolved in 50 mL water
was added to the corresponding methyl ester (2.4 g, 0.005 mol)
dissolved in 50 mL THF. The reaction mixture was stirred at rt
and monitored by TLC. Then the mixture was acidied with
15% HCl and THF was almost completely distilled from the
aqueous mixture. Aer THF was removed, the formed precipi-
tate was ltered off, washed with 50 mL water and dried. The
crude product was puried by recrystallization from ethyl
acetate.
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Conflicts of interest
There are no conicts to declare.
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