Palladium Nanoparticle-Catalyzed Stereoselective Domino Synthesis of All-Carbon Tetrasubstituted Olefin Containing Oxindoles via Carbopalladation/C-H Activation

Article abstract of DOI:10.1021/acs.joc.0c00915

The binaphthyl stabilized palladium nanoparticles (Pd-BNP) catalyzed single-step, stereoselective domino synthesis of symmetrically and unsymmetrically all-carbon tetrasubstituted olefin containing oxindoles from readily accessible anilides has been devel

Full text of DOI:10.1021/acs.joc.0c00915

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Palladium Nanoparticle-Catalyzed Stereoselective Domino
Synthesis of All-Carbon Tetrasubstituted Olefin Containing
Oxindoles via Carbopalladation/C−H Activation
Naziya Parveen and Govindasamy Sekar*
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ABSTRACT: The binaphthyl stabilized palladium nanoparticles (Pd-BNP) catalyzed single-step, stereoselective domino synthesis
of symmetrically and unsymmetrically all-carbon tetrasubstituted olefin containing oxindoles from readily accessible anilides has
been developed. The Pd-BNP catalyst showed a wide range of functional group tolerance that enabled building a library of
heteroaromatics. This reusable Pd catalyst reflected its utility in the synthesis of biologically important AMP-activated protein kinase
deprived of any metal Pd contamination. The nanocatalyst was easily recovered and reused five times without any appreciable loss in
particle size or catalytic activity.
reported protocol. Later in 2006, Zhu and coworkers
developed an elegant method for the synthesis of 3-
(diarylmethylene)oxindoles via homogeneous palladium cata-
lyzed domino process using sp2 C−H bond of an anilide as one
of the coupling partners.6 Further, in 2008, Li and coworkers
reported the Pd(OAc)2 catalyzed synthesis of 3-(1-
arylmethylene)oxindoles using anilide with aryliodonium
salt.7 Most of the reported methodologies4−8 suffered from
major drawbacks like use of 2-haloanilides as starting material,
use of additives and toxic phosphine ligands, tedious workup
procedures, and presence of trace metal impurities in the final
product that hinder its utility in biomedical applications.
In recent years, metal nanoparticles, especially palladium
nanoparticles, have acquired specific interest among the
synthetic community due to their higher reactivity, selectivity
similar to that of homogeneous catalysts, recyclability, and easy
separation similar to that of heterogeneous catalysts.9 We
recently reported the undeniable potential of binaphthyl
INTRODUCTION
■
Oxindoles constitute an important group of the monoterpene
alkaloid family and possess high pharmaceutical value due to
their application in various therapeutic areas such as in
inflammation, the central nervous system, oncology, immunol-
ogy, and endocrinology.1 For example, in 2006, Pfizer
pharmaceutical introduced an oxindole derivative SU11248,2
a potent drug to treat renal cell carcinoma and gastrointestinal
stromal tumors (Figure 1). Similarly, Semaxanib (SU5416)
possess potent anticancer properties for the treatment of
colorectal cancer.3 The demanding pharmaceutical properties
of the oxindole skeleton make it a molecule of interest among
the scientific community.
Traditionally, the 3-(diarylmethylene)oxindoles were syn-
thesized by condensation of an oxindole with diarylketone.4
However, it suffered from major drawbacks like low selectivity
and tedium. In last few decades, considerable efforts have been
devoted to development of efficient protocols for synthesis of
3-(diarylmethylene)oxindoles. In 2005, Takemoto and cow-
orkers developed Pd-catalyzed synthesis of oxindoles by using
N-(2-iodophenyl)propiolamides with arylboronic or alkenes
via Heck/Suzuki, Heck/Heck, and Heck/carbonylation/Suzuki
domino reactions (Scheme 1).5 However, the use of 2-
iodoanilides as the starting materials and additives (e.g.,
phosphine ligands) and CuTC are the major concerns with the
Received: April 14, 2020
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© XXXX American Chemical Society
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A

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Figure 1. Representative examples of biologically active molecules containing the oxindole skeleton.
Scheme 1. Synthesis of Oxindole Skeleton
stabilized palladium nanocatalyst (Pd-BNP) in inter- and
intramolecular reductive Heck and C−H functionalization of
azaarenes with activated ketones and the synthesis of 3-
allylidene-2(3H)-oxindoles.10 This prompted us to investigate
the stereoselective synthesis of symmetrical and unsymmetrical
3-(diarylmethylene)oxindoles using stable and reusable hetero-
geneous Pd-BNP catalyst. Herein, we report a stereoselective
domino synthesis of (E)-3-(diarylmethylene)oxindoles and
their derivatives using Pd-BNP catalyst. The Pd-BNP offered a
scenic functional group tolerance, and the cogency of the
approach was probed using various electron-donating,
electron-withdrawing, and sterically hindered groups contain-
ing substrates, resulting in good to excellent yield of the
desired products. To the best of our knowledge, stereoselective
domino synthesis of oxindoles using Pd-BNP has not been
previously achieved.
major product in 66% yield with 6 endo-dig cyclized product 4a
as a minor product in 14% yield, respectively (Table 1 entry 1).
The formation of 6 endo-dig cyclized product 4a as a minor
product might be attributed to in situ formation of AcOH from
NaOAc ionization in the reaction mixture.12 The formation of
6 endo-dig cyclized product was completely omitted using an
organic base like NEt3, which further supported these findings
(entry 4). Further screening of different organic bases
suggested that the DABCO gives the highest yield with the
selective formation of 5 exo-dig cyclized product (Table 1,
entry 6). A brief screening of various solvents indicated that
DMF is the best solvent. In contrast, other polar aprotic
solvents like DMSO, acetonitrile, and polar protic solvents like
PEG-200 and MeOH failed to give satisfactory yields (entries 7
and 10−12). The nonpolar solvents like toluene and ethers like
dioxane and THF offered very poor yields (entry 9 and 13).
Any change in the reaction temperature resulted in a
substantial loss of reaction yields (entries 15 and 16). Similarly,
any fluctuation in the catalyst loading from 2 mol % affected
the reaction yield. Conclusively, 2 mol % of Pd-BNP in the
presence of 2 equiv of base (DABCO) in DMF at 110 °C
offered the highest output for the stereoselective synthesis of
diarylmethyleneoxindoles (entry 6). Notably, Pd-BNP possess
higher catalytic efficiency over commercially available Pd/C
catalyst that undeniably affirms the admirable potential of Pd-
BNP in catalysis.
RESULTS AND DISCUSSION
■
Our pursuit toward the stereoselective synthesis of (E)-3-
(diarylmethylene)oxindoles commenced with the synthesis of
anilide 1 from cheap and easily accessible aniline and
arylpropiolic acid.11 Initially, we examined the reaction of
diphenylpropiolamide 1a with para-methoxy iodobenzene 2a
in the presence of Pd-BNP (2 mol %) and NaOAc as a base
(2.0 equiv) in DMF at 110 °C. Delightfully, the reaction
resulted in the formation of 5 exo-dig cyclized product 3a as a
B
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a
Table 1. Optimization of the Reaction Conditions
b
yield (%)
entry
base
solvent (mL)
temp (°C)
time (h)
3a
4a
1
2
3
4
5
6
7
8
NaOAc
Na2CO3
Cs2CO3
NEt3
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
dioxane
PEG-200
CH3CN
MeOH
THF
DCE
DMF
DMF
DMF
110
110
110
110
110
110
110
110
110
110
110
110
110
110
120
90
12
12
12
24
24
12
12
36
36
12
12
12
36
36
12
24
12
12
12
66
62
67
40
45
88
59
16
14
64
59
61
10
5
14
9
12
DIPEA
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
9
10
11
12
13
14
15
16
17
18
19
67
59
c
110
110
110
80
64
43
d
DMF
DMF
e
a
b
Reaction condition: 1a (0.25 mmol), 2a (0.3 mmol), Pd-BNP (2 mol %), and base (2 equiv) in 1 mL of solvent for 12−36 h. Yield was
c
d
e
1
determined by H NMR (internal standard = 1,3,5-trimethoxybenzene). 3.0 mol % Pd-BNP. 1.0 mol % Pd-BNP. 2 mol % of commercially
available Pd/C (10 wt %).
Having the standard reaction condition in hand (Table 1,
entry 6), we investigated the substrate scope concerning
different anilides and haloarenes. The generality of the reaction
using different aryl iodides 2 such as electron-rich, electron-
deficient, halogenated, and sterically hindered aryl iodides was
examined first (Scheme 2), and interestingly, most of the
substituted aryl iodide reacted smoothly under the optimized
reaction condition to give the corresponding products (3a−
3m) in moderate to good yields.
Simultaneously, the effect of substitution on diphenylpro-
piolamide 1 was also examined (Scheme 3). Gratifyingly, the
substituted diphenylpropiolamide reacted smoothly with 2a
without compromising the optimized reaction conditions to
afforded their corresponding products (3n−3y) in acceptable
yields. Additionally, the E-stereoconformation of 3a, 3h, and
3u was confirmed by X-ray analysis (Section 2, Figure S38).
Meanwhile, the effect of various N-protecting groups on
diphenylpropiolamide (ethyl, propyl, benzyl, and octyl) groups
was also investigated; delightfully, all of the protected
diphenylpropiolamide groups reacted efficiently under the
standard reaction conditions to give the respective products
(3z−3ac) in good yields. Furthermore, the substrate scope
concerning heteroaromatic iodides (2-iodothiophene) and
least reactive aryl bromides was also examined, but the
reaction did not give the target product under the optimized
reaction conditions.
piolamide 1ad as a model substrate that reacted with 2c to
give para-cyclized 6-chloro-3-(diphenylmethylene)-1-methyl-
indolin-2-one 3ad in 73% yield together with an ortho-cyclized
product 3ad′ in 3% yield (Scheme 4). The regioselective
formation of 3ad over 3ad′ might be attributed to the relative
steric hindrance of −Cl at the ortho position compared to the
para position, which significantly restricts the carbopalladation
and C−H activation, followed by intramolecular cyclization as
witnessed earlier.7b
Further, the scalability of the reaction was probed with 1.5 g
(6.4 mmol) of diphenyl propiolamide and 1-iodo-4-methox-
ybenzene 2a under standard reaction condition that offered the
desirable product 3a (1.8 g) in 84% yield without any
compromise in the standard reaction conditions (Scheme 5).
One can notice from Scheme 2 that no dehalogenated
product formation has been observed with halogenated aryl
iodide, and the halogen substituent remains intact in the final
product. This enables further π-expansion of the 3-
(diarylmethylene)oxindoles skeleton; for instance, 3h readily
undergoes Suzuki coupling reaction to give the corresponding
product 5 in 73% yield (Scheme 6).
3-(Diarylmethylene)oxindoles were used as a key skeleton
for the synthesis of various pharmaceutical drugs.13 This
prompted us to utilize the present methodology for the
synthesis of AMP-activated protein kinase 6 (Scheme 7) using
an optimized reaction condition, and the product was isolated
in 74% yield. The isolated product possesses no trace of
palladium impurities, as confirmed by ICP-OES analysis. The
Additionally, the regioselectivity of the reaction was
examined using N-(3-chlorophenyl)-N-methyl-3-phenylpro-
C
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a
Scheme 2. Domino Synthesis of Diphenylallylidenemethylindolin-2-one Using Aryl Halides
a
Reaction conditions: 1a (0.25 mmol), 2 (0.3 mmol), Pd-BNP (2 mol %), and DABCO (2 equiv) in DMF (1 mL) at 110 °C for 9−14 h. Isolated
yield.
isolation of metal impurity-free drug molecules has significant
importance in pharmaceutical industries. The Pd-BNP offered
the isolation of metal impurity- free product; this might be due
to its heterogeneous nature that assists in the easy separation of
a metal catalyst (Pd-BNP) from desirable product and enables
the utilization of the drug molecule directly in biomedical
studies.
The recovery and recyclability of Pd-BNP were investigated
(Figure 2). The catalyst was recovered by centrifugation and
reused for five catalytic cycles without any significant loss in
the catalytic activity, which undoubtedly indicates that the
catalyst is free from any sort of agglomeration. Notably, a slight
decrease in the reaction yields in the subsequent catalytic
cycles might be attributed to the minor loss of Pd-BNP catalyst
during workup and recovery procedures.
The hot filtration test was carried out to investigate whether
the reaction is catalyzed by a heterogeneous Pd-BNP catalyst
or a leached Pd catalyst. In hot filtration test, the catalyst was
filtered by centrifugation in the middle of the reaction, and the
same reaction (without catalyst) continued to the optimized
reaction time. However, no improvement in the yield was
observed, indicating that no leaching of Pd-BNP catalyst was
observed during the course of the reactions.
The HRTEM analysis also shows the same particle size
without any agglomeration of nanoparticles before the catalytic
cycle and after the fifth catalytic cycle (Figure 3).
A plausible reaction pathway was proposed based on
literature precedent for the synthesis of oxindole 3a (Scheme
8).4−8 Oxidative addition of haloarene to Pd-BNP results in
the construction of arylpalladium species (A) that subse-
quently coordinate with the triple bond of propiolamide to
form intermediate (B), which undergoes syn carbopalladation
to give vinyl palladium intermediate (C). The intermediate
(C) undergoes C−H activation to provide a six-membered
palladacycle intermediate (D) followed by reductive elimi-
nation to afford 3a with the concomitant regeneration of Pd-
BNP catalyst.
CONCLUSIONS
■
In conclusion, we disclosed a stereoselective domino synthesis
of a library of all-carbon tetrasubstituted olefins containing 3-
(diarylmethylenyl)indolinone derivatives using external ligand-
free, stable, and reusable Pd-BNP catalyst. Additionally, the
synthesis of drug molecule AMP-activated protein kinase
inhibitor was carried out, which was found to be free from
trace palladium impurities, reflecting its utility in the near
D
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a
Scheme 3. Domino Synthesis of Diphenylallylidenemethylindolin-2-one Using Anilide
a
Reaction condition: 1 (0.25 mmol), 2 (0.3 mmol), Pd-BNP (2 mol %), and DABCO (2 equiv) in DMF (1 mL) at 110 °C for 9−12 h. Isolated
yield.
Scheme 4. Regioselectivity of 6-Chloro-3-(diphenylmethylene)-1-methylindolin-2-one
Scheme 5. Gram-Scale Synthesis
Scheme 6. Diversification of (E)-3-((4-
Bromophenyl)(phenyl)methylene)-1-methylindolin-2-one
future. The Pd-BNP was recycled for five catalytic cycles
without any change in the reactivity or particle size. The
present methodology signifies the use of cheap and readily
available reagents, mild reaction conditions, practical sim-
plicity, and high stereoselectivity.
E
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was in the low 10−10 mbar range during spectrum collection. Binding
energies of the core levels were calibrated with C 1s BE set at 284.7
eV. HRTEM analysis was performed using a JEOL 3010 microscope.
Samples for TEM analysis were prepared in carbon-coated copper
grids (nanoparticles in dichloromethane solutions). The instrument
was operated at 200 kV. An inductively coupled plasma-optical
emission spectrometer (ICP-OES) from PerkinElmer Optima 5300
DV was used to identify the Pd content of the nanoparticles. Samples
were prepared by digesting 10 mg of nanoparticles in 2.0 mL of
H2SO4 using a domestic microwave oven for 30 min, and the
solutions were made up to 25 mL in a standard flask. Pd emissions
were detected at 340.458 nm under the flow condition.
Scheme 7. Synthesis of AMP-Activated Protein Kinase
Inhibitor
The compound 1a was prepared using literature reported
procedure,11 and the characterization data agreed with the literature
report.
EXPERIMENTAL SECTION
■
Typical Procedure for Synthesizing 1,1′-Binaphthyl,-
2,2′bis(diazonium tetrafluoro borate).14 Sodium nitrite (1.2 g,
18.0 mmol) in 3 mL of water was added slowly to a stirred solution of
( )-BINAM (1.2 g, 4.0 mmol) and HBF4 (45% in H2O, 10 mL) at 0
°C. Then the reaction was stirred at 0 °C for 30 min and further
stirred at room temperature for 30 min. The resulting yellow solid was
filtered using a Buchner funnel and washed with cold HBF4 (2 × 5
mL), H2O (2 × 10 mL), and EtOH (10 mL). The diazonium salt
yellow solid was dried under a vacuum desiccator and store at 0 °C.
1H NMR (400 MHz, DMSO−D6): δ7.55 (d, J = 8.4 Hz, 2H), 7.88 (t,
Reactions were performed in an oven-dried reaction tube under a
closed atmosphere. Nanopure water was obtained from a Milli-Q
Integral Water Purification System. Extra pure analytical-grade DMF
and methanol were purchased from Sisco Research Laboratories Pvt.
Ltd. Solvents used for extraction and purification were of technical
grade and distilled before use. K2[PdCl4] (98%) and NaBH4 (99%)
were purchased from Aldrich and used without further purification.
( )-BINAM was purchased from Aldrich and used as received. 1,1′-
Binaphthyl-2,2′-bis(diazoniumtetrafluoroborate) was prepared using
the literature procedure. All other chemicals were obtained from
Aldrich, Acros, Avra, and Alfa Aesar and used as received unless
otherwise indicated. Reactions were monitored by thin-layer
chromatography (TLC) on precoated aluminum-packed plates
(0.25 mm, Merck Kieselgel 60 with fluorescent indicator UV254)
and visualized by fluorescence quenching. Column chromatography
was performed with silica gel (particle size 100−200 mesh). Infrared
spectra were recorded on an FTIR 4000 series spectrometer using a
KBr pellet. The wavenumbers of recorded IR signals are quoted in
J = 7.6 Hz, 2H), 8.17 (t, J = 7.2 Hz, 2H), 8.54 (d, J = 8.4 Hz, 2H),
8.84−8.99 (m, 4H); 13C{1H} NMR (100 MHz, DMSO−D6): δ
125.2, 127.5, 130.1, 130.6, 132.1, 133.6, 132.0, 133.4, 135.0, 135.1,
137.8.
Synthesis of Pd-Binaphthyl Nanoparticles (Pd-BNP).14 To a
250 mL round-bottom flask, potassium tetrachloropalladate (326.5
mg, 1.0 mmol) in nanopure water (50 mL) was added. 1,1′-
Binaphthyl,-2,2′-bis(diazoniumtetrafluoroborate) (482.1 mg, 1.0
mmol) and toluene (50 mL) were added and vigorously stirred in
magnetic stirrer for 1 h. The orange-brown color formation shows the
complexation of palladium with diazonium salt. NaBH4 (226.9 mg,
6.0 mmol) in water (2 mL) was added dropwise at room temperature
to the solution, and the immediate color change to dark greenish
black signifies the Pd NPs formation. The reaction mixture was stirred
at room temperature for 2 h. The toluene layer was separated and
washed with 0.5 M aq. H2SO4 (3 × 50 mL) and 0.5 M aq. NaHCO3
(3 × 50 mL) to remove unreacted metal complexes. Then, the solvent
was completely evaporated under a rotary evaporator. The solid
particles were suspended in ethanol (2 × 10 mL) and sonicated for
half an hour at room temperature. The suspension was centrifuged
(4500 rpm, approximately 30 min). The ethanol was removed and
dried in vacuo to furnish the Pd-binaphthyl nanoparticles crystalline
black solid.
1
cm−1. H and 13C NMR spectra were recorded in CDCl3 or DMSO-
d6 solvent using a Bruker AV-400 MHz spectrometer. Data are
expressed as a chemical shift in parts per million (ppm) relative to
residual chloroform and CDCl3 (1H: δ = 7.26 ppm, 13C: δ = 77.16
ppm; likewise for other solvents where applicable) and TMS as an
1
internal standard on the δ scale. H coupling constants J are given in
Hz and rounded to the nearest 0.1 Hz. HRMS were recorded on a Q-
Tof Micro mass spectrometer, and GC-MS was recorded with JEOL
GCMATE II. X-ray photoelectron spectroscopic analysis was
performed using an ESCA probe/TPD of Omicron Nanotechnology.
The sample was spotted on a Mo plate and allowed to dry in vacuum.
Because of the sensitivity of the sample, surface cleaning was not
attempted. Al Kα radiation was used for excitation; a 180°
hemispherical analyzer and a seven-channel detector were employed.
The spectrometer was operated in the constant analyzer energy mode.
Survey and high-resolution spectra were collected using pass energies
of 50 and 20 eV, respectively. The pressure in the analyzer chamber
General Experimental Procedure for Synthesizing (E)-3-((E)-
1,3-Diphenylallylidene)-1-methylindolin-2-one. In an oven-
Figure 2. (a) Pd-BNP recovery cycle. (b) Hot filtration test.
F
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Figure 3. HR-TEM images: (a) freshly prepared Pd-BNP and (b) recovered Pd-BNP after five catalytic cycles.
3055, 2986, 1605, 1687, 1266, 732 cm−1; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C23H20ON: 326.1539; found: 326.1550.
Scheme 8. Plausible Reaction Pathway
(E)-3-(Diphenylmethylene)-1-methylindolin-2-one (3c). 69.1 mg,
89% yield; orange solid; mp 165−166 °C (165.5−167.5 °C); Rf 0.45
(20% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3): δ 3.21
(s, 3H), 6.43 (d, J = 7.6 Hz, 1H), 6.69 (t, J = 7.6 Hz, 1H), 6.77 (d, J =
7.6 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.30−7.40 (m, 7H), 7.40−7.49
(m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 26.0, 107.8, 121.5,
123.2, 123.3, 124.3, 127.9, 128.9, 129.0, 129.2, 129.3, 129.4, 130.1,
140.1, 141.4, 143.4, 154.7, 166.9; FTIR (KBr): 3059, 2984, 1698,
1604, 1419, 1263, 729 cm−1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C22H18ON: 312.1383; found: 312.1379.
(E)-3-((4-Fluorophenyl)(phenyl)methylene)-1-methylindolin-2-
one (3d). 60.0 mg, 73% yield; yellow solid; mp 152−154 °C; Rf 0.42
(20% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3): δ 3.20
(s, 3H), 6.49 (d, J = 7.6 Hz, 1H), 6.72 (t, J = 7.6 Hz, 1H), 6.77 (d, J =
7.6 Hz, 1H), 7.12 (d, J = 8.8 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.23−
7.43 (m, 7H); 13C{1H} NMR (100 MHz, CDCl3): δ 26.0, 107.9,
116.2 (d, JC,F = 22 Hz), 121.5, 123.1, 123.2, 124.6, 128.0, 129.1,
129.4, 130.2, 131.7 (d, JC,F = 8.0 Hz), 137.3, 139.9, 143.5, 153.5,
163.4 (d, JC,F = 249.0 Hz), 166.8; 19F NMR (CDCl3, 470 MHz) δ
−164.90 (s, 1F); FTIR (KBr): 3051, 2926, 1695, 1605, 1490, 1338,
1093, 721 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C22H16ONFNa: 352.1294; found: 352.1115.
(E)-3-((4-Chlorophenyl)(phenyl)methylene)-1-methylindolin-2-
one (3e). 78.5 mg, 91% yield; orange liquid; Rf 0.4 (10% ethyl acetate
in hexanes); 1H NMR (400 MHz, CDCl3): δ 3.19 (s, 3H), 6.53 (d, J
= 7.6 Hz, 1H), 6.66−6.82 (m, 2H), 7.19 (t, J = 7.6 Hz, 1H) 7.23−
7.33 (m, 4H), 7.33−7.48 (m, 5H); 13C{1H} NMR (100 MHz,
CDCl3): δ 26.0, 107.9, 121.6, 123.0, 123.2, 124.7, 128.0, 129.2, 129.4,
129.4, 130.2, 131.1, 135.5, 139.7, 139.8, 143.6, 153.0, 166.7; FTIR
(neat): ν = 3051, 2986, 1699, 1598, 1273, 732 cm−1; HRMS (ESI-
TOF) m/z: [M + Na]+ calcd for C22H17ONCl: 346.0998; found:
346.1012.
dried reaction tube, a mixture of propiolamides 1 (0.25 mmol), aryl
iodide 2 (0.3 mmol), Pd-BNP (2 mol %), and DABCO (2 equiv) in
DMF (1 mL) was stirred at 110 °C in a preheated oil bath for the
desired time until complete consumption of starting material as
monitored by TLC. The reaction mixture was cooled to room
temperature; water was added to the reaction mixture and extracted
with ethyl acetate. The organic layer was dried with Na2SO4 and
evaporated under reduced pressure, and the residue was purified by
column chromatography (hexane/ethyl acetate) to afford the pure
product.
(E)-1-Methyl-3-(4-nitrophenyl)(phenyl)methylene)indolin-2-one
(E)-3-((4-Methoxyphenyl)(phenyl)methylene)-1-methylindolin-2-
one (3a). 73.2 mg, 86% yield; orange solid; mp 140−142 °C (Lit.6a
(3f). 62.3 mg, 70% yield; yellow solid; mp 128−130 °C; Rf 0.29 (20%
1
1
ethyl acetate in hexanes); H NMR (400 MHz, CDCl3): δ 3.13 (s,
mp 163.8−164.3 °C); Rf 0.35 (20% ethyl acetate in hexanes); H
3H), 6.29 (d, J = 7.6 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6
Hz, 1H), 7.09−7.27 (m, 4H), 7.27−7.37 (m, 3H), 7.46 (d, J = 8.8 Hz,
2H), 8.22 (d, J = 8.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3): δ
= 26.0, 108.3, 121.8, 122.3, 123.2, 124.4, 125.5, 125.7, 128.3, 129.7,
129.9, 129.9, 130.6, 138.8, 143.9, 147.9, 148.2, 150.9, 166.4; FTIR
(KBr): 3059, 2986, 1702, 1602, 1515, 1345, 1266, 732 cm−1; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd for C22H17O3N2: 357.1239; found:
357.1247.
(E)-4-(1-Methyl-2-oxoindolin-3-ylidene)(phenyl)methyl)-
benzonitrile (3g). 60.5 mg, 72% yield; red solid; mp 158−160 °C; Rf
0.26 (20% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3): δ
3.20 (s, 3H), 6.35 (d, J = 7.6 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 6.79
(d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.27−7.34 (m, 2H),
7.34−7.43 (m, 3H), 7.47 (d, J = 8.4 Hz, 2H) 7.74 (d, J = 8.0 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3): δ 26.0, 108.2, 112.9, 118.5,
NMR (400 MHz, CDCl3): δ 3.12 (s, 3H), 3.87 (s, 3H), 6.60−6.82
(m, 3H), 6.93 (d, J = 2.1 Hz, 2H), 7.16 (t, J = 7.6 Hz, 1H), 7.21−7.45
(m, 7H); 13C{1H} NMR (100 MHz, CDCl3): δ 26.0, 55.5, 107.8,
114.3, 121.4, 122.9, 123.6, 123.7, 127.9, 128.6, 129.2, 130.5, 131.7,
133.6, 140.6, 143.3, 154.9, 160.7, 167.1; FTIR (KBr): 3050, 2986,
1691, 1602, 1421, 725 cm−1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H20O2N: 342.1494; found: 342.1492.
(E)-1-Methyl-3-(phenyl(p-tolyl)methylene)indolin-2-one (3b).
70.6 mg, 87% yield; yellow solid; mp 150−152 °C (Lit.6a mp
1
169.7−171.6 °C); Rf 0.43 (20% ethyl acetate in hexanes); H NMR
(400 MHz, CDCl3): δ 2.43 (s, 3H), 3.19 (s, 3H), 6.56 (d, J = 7.6 Hz,
1H), 6.70 (t, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 7.10−7.26 (m,
5H), 7.26−7.40 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): δ 21.6,
26.0, 107.7, 121.4, 123.2, 123.5, 124.0, 127.9, 128.7, 129.1, 129.6,
129.7, 130.2, 138.5, 139.5, 140.4, 143.3, 155.0, 167.0; FTIR (KBr):
G
https://dx.doi.org/10.1021/acs.joc.0c00915
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
121.7, 122.4, 123.2, 125.5, 128.2, 129.6, 129.7, 130.0, 130.2, 130.3,
132.9, 138.9, 143.8, 145.9, 151.4, 166.4; FTIR (KBr): 3051, 2990,
1702, 1605, 1269, 728 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+
calcd for C23H17ON2: 337.1340; found: 337.1356.
(E)-3-((4-Bromophenyl)(phenyl)methylene)-1-methylindolin-2-
one (3h). 71.9 mg, 74% yield; orange solid; mp 138−140 °C; Rf 0.40
(20% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3): δ 3.20
(s, 3H), 6.54 (d, J = 7.6 Hz, 1H), 6.70−6.82 (m, 2H), 7.20 (t, J = 8.4
Hz, 3H), 7.27−7.34 (m, 2H), 7.34−7.43 (m, 3H), 7.57 (d, J = 8.4 Hz,
2H); 13C{1H} NMR (100 MHz, CDCl3): δ 26.0, 108.0, 121.6, 123.0,
123.2, 123.7, 124.6, 128.0, 129.2, 129.4, 130.2, 131.3, 132.3, 139.7,
140.2, 143.6, 153.0, 166.7; FTIR (KBr): 3048, 2980, 1699, 1478,
1424, 1262, 743 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C22H16ONBr: 390.0488; found: 390.0495.
(E)-1-Methyl-3-(phenyl(m-tolyl)methylene)indolin-2-one (3i).
47.9 mg, 59% yield; yellow liquid; Rf 0.45 (20% ethyl acetate in
hexanes); 1H NMR (400 MHz, CDCl3): δ 2.34 (s, 3H), 3.19 (s, 3H),
6.43 (d, J = 7.6 Hz, 1H), 6.89 (t, J = 8.0 Hz, 1H), 6.76 (d, J = 7.6 Hz,
1H), 7.05−7.20 (m, 3H), 7.23−7.42 (m, 7H); 13C{1H} NMR (100
MHz, CDCl3): δ 21.5, 25.9, 107.7, 121.5, 123.3, 123.4, 124.2, 126.4,
127.9, 128.8, 128.9, 129.1, 129.8, 130.0, 138.8, 140.1, 140.3, 143.4,
155.0, 167.9; FTIR (neat): 3059, 2980, 1699, 1598, 1471, 1262, 1089,
732 cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C23H19NONa: 348.1466; found: 348.1364.
(m, 7H), 7.41−7.50 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ
26.0, 55.5, 108.1, 109.6, 114.5, 124.1, 124.8, 127.9, 129.1, 129.2,
129.3, 129.4, 130.1, 132.6, 137.5, 139.8, 141.3, 154.8, 154.9, 166.8;
FTIR (KBr): 3055, 2990, 1691, 1590, 1436, 1269, 728 cm−1; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C23H20O2N: 342.1489; found:
342.1488.
3-(Diphenylmethylene)-1,5-dimethylindolin-2-one (3o). 54.4 mg,
67% yield; yellow solid; mp 134−136 °C (Lit.6a mp 147.0−149.7
1
°C); Rf 0.50 (20% ethyl acetate in hexanes); H NMR (400 MHz,
CDCl3): δ 2.05 (s, 3H), 3.19 (s, 3H), 6.21 (s, 1H), 6.66 (d, J = 8.0
Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H), 7.23−7.40 (m, 7H), 7.40−7.50 (m,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 21.2, 25.9, 107.5, 123.3,
124.1, 124.6, 127.9, 128.9, 129.1, 129.2, 129.4, 130.1, 130.7, 140.1,
141.2, 141.5, 154.3, 166.9; FTIR (KBr): 3059, 2986, 1699, 1605,
1482, 1262, 736 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C23H20ON: 326.1544; found: 326.1542.
3-(Diphenylmethylene)-5-fluoro-1-methylindolin-2-one (3p).
54.2 mg, 66% yield; yellow solid; mp 130−132 °C (Lit.6a mp
1
134.9−136.4 °C); Rf 0.48 (20% ethyl acetate in hexanes); H NMR
(400 MHz, CDCl3): δ 3.20 (s, 3H), 6.11 (dd, J = 9.6, 2.4 Hz, 1H),
6.67 (q, J = 4.4 Hz, 1H), 6.88 (td, J = 8.8, 2.4 Hz, 1H), 7.28 (m, 2H),
7.32−7.41 (m, 5H), 7.41−7.51 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 26.9, 108.0 (d, JC,F = 8.0), 110.8 (d, JC,F = 27 Hz), 115.0
(d, JC,F = 24 Hz), 124.0, 124.4 (d, JC,F = 9.2 Hz), 127.9, 129.2, 129.3,
129.5, 129.7, 130.2, 139.4, 139.6, 140.8, 156.3, 158.4 (d, JC,F = 235.9
Hz), 166.7; 19F NMR (CDCl3, 470 MHz) δ −164.90 (s, 1F); FTIR
(KBr): 3055, 2984, 1698, 1604, 1490, 1259, 730 cm−1.
(E)-1-Methyl-3-(phenyl(o-tolyl)methylene)indolin-2-one (3j).
47.9 mg, 59% yield; orange solid; mp 78−80 °C; Rf 0.48 (20%
1
ethyl acetate in hexanes); H NMR (400 MHz, CDCl3): δ 2.14 (s,
3H), 3.20 (s, 3H), 5.98 (d, J = 7.6 Hz, 1H), 6.65 (t, J = 7.6 Hz, 1H),
6.75 (d, J = 8.0 Hz, 1H), 7.10−7.22 (m, 2H), 7.25−7.32 (m, 2H),
7.32−7.50 (m, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 19.7, 25.9,
107.6, 121.9, 123.1, 123.5, 124.6, 126.8, 127.7, 128.4, 128.8, 129.1,
129.9, 131.1, 133.4, 138.4, 140.9, 143.3, 158.8, 166.6; FTIR (KBr):
3065, 2982, 1699, 1605, 1475, 1262, 1096 cm−1; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C23H19ON: 348.1466; found: 348.1366.
(E)-3-((3,5-Dimethoxyphenyl)(phenyl)methylene)-1-methyl indo-
lin-2-one (3k). 56.6 mg, 61% yield; yellow solid; mp 163−165 °C; Rf
0.32 (20% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3): δ
3.20 (s, 3H), 3.75 (s, 6H), 6.46 (d, J = 2.0 Hz, 2H), 6.54 (t, J = 2.0
Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H), 6.76 (q, J = 7.6 Hz, 2H), 7.19 (t, J
= 7.6 Hz, 1H), 7.37 (s, 5H); 13C{1H} NMR (100 MHz, CDCl3): δ
25.9, 55.6, 101.2, 106.9, 107.7, 121.6, 121.6, 123.1, 123.7, 124.2,
127.9, 128.9, 129.2, 129.8, 139.5, 143.2, 143.4, 154.3, 161.3, 166.9;
FTIR (KBr): 3059, 2984, 1702, 1592, 1431, 1271, 725 cm−1; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C24H22O3N: 372.1600; found:
372.1612.
5-Chloro-3-(diphenylmethylene)-1-methylindolin-2-one (3q).
57.8 mg, 67% yield; yellow solid; mp 134−136 °C (Lit.6a mp
1
136.5−137.2 °C); Rf 0.5 (20% ethyl acetate in hexanes); H NMR
(400 MHz, CDCl3): δ 3.61 (s, 3H), 6.36 (dd, J = 7.6, 2.0 Hz, 1H),
6.58 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.27−7.36 (m, 4H),
7.36−7.42 (m, 3H), 7.42−7.50 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 29.4, 115.4, 121.7, 122.0, 123.3, 126.2, 127.9, 129.1, 129.4,
129.5, 129.5, 130.2, 130.8, 139.1, 139.9, 141.1, 156.2, 167.1; FTIR
(KBr): 3055, 2984, 1706, 1596, 1431, 1263, 725 cm−1; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C22H17ONCl: 346.0999; found:
346.0998.
3-(Diphenylmethylene)-1-methyl-5-nitroindolin-2-one (3r). 53.4
mg, 60% yield; yellow solid; mp 218−220 °C (Lit.6a mp 191.2−193.8
1
°C); Rf 0.18 (20% ethyl acetate in hexanes); H NMR (400 MHz,
CDCl3): δ 3.28 (s, 3H), 6.83 (d, J = 8.8 Hz, 1H), 7.26 (s, 1H), 7.30
(d, J = 7.2 Hz, 2H), 7.34−7.46 (m, 5H), 7.50 (t, J = 7.2 Hz, 2H), 7.53
(m, 1H), 8.08−8.18 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ
26.4, 107.2, 118.9, 122.1, 123.7, 125.2, 128.0, 129.3, 129.4, 130.2,
130.4, 130.5, 139.0, 140.2, 142.7, 147.8, 159.8, 166.9; FTIR (KBr):
3055, 2986, 2308, 1713, 1608, 1424, 1269, 725 cm−1; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C22H17N2O3: 357.1239; found:
357.1250.
(E)-3-((3,4-Dimethoxyphenyl)(phenyl)methylene)-1-methylindo-
lin-2-one (3l). 55.6 mg, 60% yield; yellow semi liquid; Rf 0.32 (20%
1
ethyl acetate in hexanes); H NMR (400 MHz, CDCl3): δ 3.21 (s,
3H), 3.76 (s, 3H), 3.95 (s, 3H), 6.64−6.82 (m, 3H), 7.79−7.95 (m,
3H), 7.18 (t, J = 7.6 Hz, 1H), 7.29−7.44 (m, 5H); 13C{1H} NMR
(100 MHz, CDCl3): δ 26.0, 29.8, 56.0, 56.1, 107.8, 111.2, 112.9,
121.4, 123.1, 123.2, 123.6, 123.7, 127.9, 128.6, 129.3, 130.4, 133.7,
140.2, 143.2, 149.1, 151.1, 154.8 and 167.1; FTIR (neat): 3055, 2988,
1694, 1600, 1436, 1263, 894, 738 cm−1; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C24H22O3N: 372.1600; found: 372.1592.
(E)-1-Methyl-3-(phenyl(3,4,5-trimethoxyphenyl)methylene) in-
dolin-2-one (3m). 58.1 mg, 58% yield; yellow solid; mp 80−82 °C;
Rf 0.19 (20% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3):
δ 3.21 (s, 3H), 3.75 (s, 6H), 3.94 (s, 3H), 6.54 (s, 2H), 6.60 (d, J =
7.6 Hz, 1H), 6.76 (q, J = 7.6 Hz, 2H), 7.19 (t, J = 7.6 Hz, 1H), 7.34−
7.46 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3): δ 25.9, 56.3, 61.2,
106.6, 107.8, 121.5, 123.2, 123.4, 124.1, 127.9, 128.8, 129.3, 130.1,
136.5, 138.9,139.6, 143.3, 153.6, 154.4, 166.9; FTIR (KBr): 3059,
2988, 1690, 1604, 1416, 1267, 738 cm−1; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C25H24O4N: 402.1705; found: 402.1726.
5-Acetyl-3-(diphenylmethylene)-1-methylindolin-2-one (3s).
60.9 mg, 69% yield; yellow solid; mp 154−156 °C; Rf 0.25 (20%
1
ethyl acetate in hexanes); H NMR (400 MHz, CDCl3): δ 2.18 (s,
3H), 3.25 (s, 3H), 6.83 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 1.2 Hz, 1H),
7.30−7.45 (m, 7H), 7.45−7.56 (m, 3H), 7.88 (dd, J = 8.4, 1.6 Hz,
1H); 13C{1H} NMR (100 MHz, CDCl3): δ 26.1, 26.2, 107.6, 123.0,
123.3, 124.2, 127.9, 129.2, 129.3, 129.7, 129.7, 129.7, 130.2, 131.0,
139.2, 141.0, 146.9, 156.5, 167.1, 196.9; FTIR (KBr): 3051, 2986,
1706, 1677, 1262, 740 cm−1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C24H20O2N: 354.1489; found: 354.1490.
3-(Diphenylmethylene)-1-methyl-6-nitroindolin-2-one (3t). 57.8
mg, 65% yield; red solid; mp 150−152 °C Rf 0.59 (20% ethyl acetate
in hexanes); 1H NMR (400 MHz, CDCl3): δ 3.29 (s, 3H), 6.50 (d, J
= 9.2 Hz, 1H), 7.30 (d, J = 7.6 Hz, 2H), 7.33−7.42 (m, 4H), 7.42−
7.50 (m, 3H), 7.50−7.53 (m, 1H), 7.51−7.64 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3): δ 26.3, 102.6, 117.2, 122.6, 122.9, 127.9,
127.9, 129.3, 129.6, 129.7, 130.3, 130.4, 130.6, 139.0, 140.5, 143.6,
147.6, 160.4, 166.4; FTIR (KBr): 3059, 2990, 1695, 1594, 1436,
1269, 725 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C22H17N2O3: 357.1232; found: 357.1232.
3-(Diphenylmethylene)-5-methoxy-1-methylindolin-2-one (3n).
59.6 mg, 70% yield; orange solid; mp 68−70 °C (Lit.6a mp 135−
1
137 °C); Rf 0.40 (20% ethyl acetate in hexanes); H NMR (400
MHz, CDCl3): δ 3.18 (s, 3H), 3.46 (s, 3H), 5.99 (d, J = 2.4 Hz, 1H),
6.66 (d, J = 8.4 Hz, 1H), 6.73 (dd, J = 8.4, 2.4 Hz, 1H), 7.30−7.41
H
https://dx.doi.org/10.1021/acs.joc.0c00915
J. Org. Chem. XXXX, XXX, XXX−XXX

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pubs.acs.org/joc
Article
7-Chloro-3-(diphenylmethylene)-1-methylindolin-2-one (3u).
47.4 mg, 55% yield; yellow solid; mp 80−82 °C (Lit.6a 163.7−
MHz, CDCl3): δ 11.6, 21.0, 41.5, 108.1, 121.2, 123.4, 124.4, 127.9,
128.8, 129.1, 129.2, 129.2, 129.4, 130.2, 140.0, 141.5, 142.9, 154.6,
166.8; FTIR (KBr): 3056, 2980, 1695, 1602, 1265, 731 cm−1; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C24H22ON: 340.1701; found:
340.1717.
1-Benzyl-3-(diphenylmethylene)indolin-2-one (3ab). 67.7 mg,
70% yield; yellow liquid: Rf 0.62 (20% ethyl acetate in hexanes);
1H NMR (400 MHz, CDCl3): δ 4.95 (s, 2H), 6.44 (d, J = 8.0 Hz,
1H), 6.67 (q, J = 7.6 Hz, 2H), 7.07 (t, J = 8.0 Hz, 1H), 7.23−7.49 (m,
16H); 13C{1H} NMR (100 MHz, CDCl3): δ 43.6, 108.8, 121.5,
123.3, 123.5, 124.1, 127.5, 127.6, 127.9, 128.7, 129.1, 129.3, 129.5,
130.3, 136.4, 139.9, 141.5, 142.5, 155.1, 166.9; FTIR (neat): 3055,
2982, 1695, 1602, 1424, 1262, 750 cm−1; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C28H21ON: 388.1701; found: 388.1691.
1
165.2 °C); Rf 0.59 (20% ethyl acetate in hexanes); H NMR (400
MHz, CDCl3): δ 3.60 (s, 3H), 6.34 (d, J = 7.6 Hz, 1H), 6.57 (t, J =
8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.77−7.52 (m, 10H); 13C{1H}
NMR (100 MHz, CDCl3): δ 29.4, 115.5, 121.8, 123.4, 126.2, 127.9,
129.2, 129.5, 129.6, 130.2, 130.8, 139.2, 140.0, 141.2, 156.2, 167.2;
FTIR (KBr): 3055, 2982, 2301, 1266, 746 cm−1; HRMS (ESI-TOF)
m/z: [M + Na]+ calcd for C22H16ONClNa: 368.0998; found:
368.0816.
(E)-5-Methoxy-3-(4-methoxyphenyl)(phenyl)methylene)-1-meth-
ylindolin-2-one (3v). 74.2 mg, 80% yield; red solid; mp 166−168 °C;
Rf 0.31 (20% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3):
δ 3.17 (s, 3H), 3.54 (s, 3H), 3.58 (s, 3H), 6.30 (s, 1H), 6.66 (d, J =
8.4 Hz, 1H), 6.70−6.78 (m, 1H), 6.94 (d, J = 8.4, Hz, 2H), 7.23−7.42
(m, 7H); 13C{1H} NMR (100 MHz, CDCl3): δ 26.0, 55.5, 55.6,
107.9, 109.6, 113.9, 114.3, 123.9, 124.5, 127.8, 129.3, 130.5, 131.7,
137.4, 133.4, 140.4, 154.8, 155.0, 160.8, 170.0; FTIR (KBr): 3051,
2986, 1702, 1608, 1366, 1262, 736 cm−1; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C24H22O3N: 372.1594; found: 372.1540.
3-(Diphenylmethylene)-1-octylindolin-2-one (3ac). 86.9 mg, 85%
yield; yellow solid; mp 92−94 °C; Rf 0.59 (20% ethyl acetate in
1
hexanes); H NMR (400 MHz, CDCl3): δ 0.89 (t, J = 6.8 Hz, 3H),
1.22−1.40 (m, 10H), 1.62−1.73 (m, 2H), 3.70 (t, J = 7.6 Hz, 2H),
6.42 (d, J = 8.0 Hz, 1H), 6.67 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.0 Hz,
1H), 7.16 (t, J = 7.6 Hz, 1H), 7.30−7.40 (m, 7H), 7.40−7.49 (m,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 14.2, 22.7, 27.2, 27.7,
29.3, 29.4, 31.9, 40.0, 108.0, 121.2, 123.3, 123.5, 124.4, 127.9, 128.8,
129.0, 129.2, 129.2, 129.4, 130.2, 140.0, 141.5, 142.9, 154.5, 166.7;
FTIR (KBr): 3062, 2929, 2855, 1690, 1604, 1474, 1364, 1267, 742
cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C29H32ON:
410.2483; found: 410.2498.
(E)-5-Acetyl-3-((4-methoxyphenyl)(phenyl)methylene)-1-methyl
indolin-2-one (3w). 79.4 mg, 83% yield; yellow solid; mp 150−152
1
°C; Rf 0.18 (20% ethyl acetate in hexanes); H NMR (400 MHz,
CDCl3): δ 2.26 (s, 3H), 3.25 (s, 3H), 3.88 (s, 3H), 6.84 (d, J = 8.4
Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 7.6 Hz, 1H), 7.29 (d, J
= 8.4, Hz, 2H), 7.32−7.46 (m, 5H), 7.88 (d, J = 8.4, Hz, 1H);
13C{1H} NMR (100 MHz, CDCl3): δ 26.2, 26.2, 55.6, 107.6, 114.4,
6-Chloro-3-(diphenylmethylene)-1-methylindolin-2-one (3ad).
64.7 mg, 75% yield; yellow solid; mp 86−88 °C; Rf 0.43 (20%
122.4, 123.4, 123.6, 127.9, 129.4, 129.8, 130.6, 130.9, 131.8, 133.0,
139.8, 146.7, 156.7, 161.2, 167.3, 196.9; FTIR (KBr): 3055, 2986,
1695, 1262, 1096 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C25H21O3N: 384.1594; found: 384.1595.
1
ethyl acetate in hexanes); H NMR (400 MHz, CDCl3): δ 3.19 (s,
3H), 6.32 (d, J = 8.0 Hz, 1H), 6.65 (dd, J = 8.0, 1.6 Hz, 1H), 6.77 (d,
J = 1.6 Hz, 1H), 7.27−7.40 (m, 7H), 7.40−7.5 (m, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 26.1, 108.4, 121.4, 121.8, 123.4, 124.0,
128.0, 129.1, 129.4, 129.5, 129.5, 130.2, 134.5, 139.7, 141.2, 144.4,
155.4, 166.8; FTIR (KBr): 3055, 2984, 1706, 1596, 1431, 1263, 725
cm−1; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for C22H16ONClNa:
368.0998; found: 368.0813.
Experimental Procedure to Synthesize of (E)-3-([1,1′-
Biphenyl]-4-yl(phenyl)methylene)-1-methylindolin-2-one (5).
To a solution of (E)-3-((4-bromophenyl)(phenyl)methylene)-1-
methylindolin-2-one 3h (0.25 mmol, 97 mg) in THF/H2O solvent
under inert atmosphere, Pd(PPh3)4 (5 mol %), phenylboronic acid
(36 mg, 0.3 mmol), and K2CO3 (103 mg, 0.75 mmol) were
simultaneously added, and the solution was stirred for at 60 °C. Upon
completion (monitored by TLC), the reaction mixture was cooled to
room temperature, extracted with EtOAc, and dried over Na2SO4.
The residue was purified by column chromatography on silica gel
(hexane/EtOAc) to give desired product 5. 76.4 mg, 79% yield;
yellow solid; mp 86−88 °C; Rf 0.43 (20% ethyl acetate in hexanes);
1H NMR (400 MHz, CDCl3): δ 3.22 (s, 3H), 6.65 (d, J = 7.6 Hz,
1H), 6.72 (t, J = 7.6 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.6
Hz, 1H), 7.32−7.45 (m, 8H), 7.48 (t, J = 7.6 Hz, 2H); 7.63−7.72 (m,
3H); 13C{1H} NMR (100 MHz, CDCl3): δ 167.0, 154.4, 143.4,
142.1, 140.3, 140.2, 130.2, 129.3, 129.1, 128.9, 128.0, 127.9, 127.5,
127.2, 124.3, 123.4, 121.5, and 107.9. FTIR (KBr): ν = 26.0, 107.9,
121.5, 123.2, 124.3, 127.2, 127.5, 127.9, 128.0, 128.9, 129.0, 129.3,
130.2, 140.2, 140.3, 142.1, 143.4, 154.4, 167.0 cm−1; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C28H21NO: 388.1624; found:
388.1692.
Experimental Procedure to Synthesize of (E)-1-Benzyl-3-((4-
chlorophenyl)(phenyl)methylene)indolin-2-one (6). An oven-
dried reaction tube, a mixture of propiolamides 1p (0.25 mmol), aryl
iodide 2e (0.3 mmol), Pd-BNP (2 mol %), and DABCO (2 equiv) in
DMF (1 mL) were stirred at 110 °C preheated oil bath for the desired
time until complete consumption of starting material as monitored by
TLC. The reaction mixture was cooled to room temperature, and
water was added to the reaction mixture and extracted with ethyl
acetate. The organic layer was dried with Na2SO4 and evaporated
under reduced pressure, and the residue was purified by column
chromatography (hexane/ethyl acetate) to afford the pure product 6.
74 mg, 74% yield; yellow solid; mp 86−88 °C; Rf 0.59 (20% ethyl
(E)-5-Fluoro-3-((4-methoxyphenyl)(phenyl)methylene)-1-methyl
indolin-2-one (3x). 67.3 mg, 75% yield; red liquid; Rf 0.37 (20% ethyl
1
acetate in hexanes); H NMR (400 MHz, CDCl3): δ 3.19 (s, 3H),
3.88 (s, 3H), 6.40 (dd, J = 9.4, 1.6 Hz, 1H), 6.67 (q, J = 4.4 Hz, 1H),
6.88 (td, J = 9.2, 2.0 Hz, 1H), 6.94 (d, J = 8.4, Hz, 2H), 7.24 (d, J =
8.8, Hz, 2H), 7.30 (d, J = 8.8, Hz, 2H), 7.30−7.44 (m, 3H); 13C{1H}
NMR (100 MHz, CDCl3): δ 26.1, 55.5, 107.9 (d, JC,F = 8.0 Hz),
110.4 (d, JC,F = 26 Hz), 114.4, 114.7 (d, JC,F = 24 Hz), 123.2, 124.8
(d, JC,F = 9.0 Hz), 127.9, 129.6, 130.5, 131.7, 132.9, 139.3, 140.2,
156.5, 158.4 (d, JC,F = 235.0 Hz), 161.1, 167.0; 19F NMR (CDCl3,
470 MHz) δ −164.90 (s, 1F); FTIR (neat): 3051, 2986, 1691, 1598,
1486, 1258, 728 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C23H19O2NF: 360.1394; found: 360.1417.
3-(Diphenylmethylene)-1-methyl-1,3-dihydro-2H-benzo[g]indol-
2-one (3y). 73.1 mg, 81% yield; red solid; mp 180−184 °C; Rf 0.48
(20% ethyl acetate in hexanes); 1H NMR (400 MHz, CDCl3): δ 3.81
(s, 3H), 6.61 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.32−7.53
(m, 12H), 7.68−7.78 (m, 1H), 8.42 (d, J = 8.8 Hz, 1H); 13C{1H}
NMR (100 MHz, CDCl3): δ 30.7, 119.0, 120.9, 121.2, 121.4, 122.4,
124.7, 125.8, 126.0, 128.0, 128.9, 129.3, 129.4, 129.5, 130.2, 130.5,
134.9, 139.4, 140.5, 141.5, 154.9, 168.2; FTIR (KBr): 3055, 2982,
2301, 1266, 746 cm−1; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C26H20NO: 361.1466; found: 361.1467.
3-(Diphenylmethylene)-1-ethylindolin-2-one (3z). 66.2 mg, 82%
yield; yellow solid; mp 92−94 °C; Rf 0.59 (20% ethyl acetate in
1
hexanes); H NMR (400 MHz, CDCl3): δ 1.25 (t, J = 7.2 Hz, 3H),
3.77 (q, J = 7.2 Hz, 2H), 6.42 (d, J = 7.2 Hz, 1H), 6.67 (t, J = 7.6 Hz,
1H), 6.79 (d, J = 8.0 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.25−7.50 (m,
10H); 13C{1H} NMR (100 MHz, CDCl3): δ = 12.9, 34.5, 107.9,
121.3, 123.5, 123.6, 124.4, 127.9, 128.8, 129.0, 129.1, 129.2, 129.4,
130.2, 140.0, 141.5, 142.5, 154.6, 166.5; FTIR (KBr): 3051, 2982,
1691, 1605, 1266, 732 cm−1; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C23H20ON: 326.1572; found: 326.1532.
3-(Diphenylmethylene)-1-propylindolin-2-one (3aa). 69.4 mg,
82% yield; yellow solid; mp 89−90 °C; Rf 0.57 (20% ethyl acetate
in hexanes); 1H NMR (400 MHz, CDCl3): δ 0.95 (t, J = 7.6 Hz, 3H),
1.65−1.76 (m, 2H), 3.66 (t, J = 7.6 Hz, 2H), 6.41 (d, J = 7.6 Hz, 1H),
6.66 (t, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.15 (t, J = 8.0 Hz,
1H), 7.31−7.39 (m, 7H), 7.41−7.46 (m, 3H); 13C{1H} NMR (100
I
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J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1
acetate in hexanes); H NMR (400 MHz, CDCl3): δ 4.92 (s, 2H),
submitted for NMR analysis, which indicated the formation of 3a in
22% yield (NMR yields). From the remaining mother liquid, i.e., Pd-
BNP free-reaction mixture, the reaction was continued for 12 h. After
12 h, the reaction was stopped, and the reaction mixture was
submitted for NMR analysis after workup, which indicated that there
was no improvement of yield. This result indicated that there was no
active catalyst present to catalyze further reaction. The same
procedure was followed for another set of reactions.
6.53 (d, J = 7.6 Hz, 1H), 6.70 (t, J = 7.6 Hz, 2H), 7.08 (td, J = 7.6, 1.2
Hz, 1H), 7.24−7.34 (m, 8H), 7.35−7.44 (m, 6H);13C{1H} NMR
(100 MHz, CDCl3): δ 166.8, 153.5, 139.8, 139.7, 136.3, 135.5, 131.1,
130.4, 129.5, 129.4, 129.1, 128.8, 128.1, 127.6, 124.4, 123.2, 121.7,
109.0 and 43.6;
Experimental Procedure to Synthesize N,3-Diphenylpro-
piolamide. N,3-diphenylpropiolamide was synthesized using a
reported literature procedure with modification.11
A suspension of phenylpropiolic acid (2.49 g, 17.1 mmol) and
SOCl2 (2.47 mL, 34.2 mmol) in anhydrous benzene (20 mL) was
stirred for 3 h at 70 °C. After 30 min, a clear solution was obtained.
Excess SOCl2 and benzene were removed in vacuo. The oily residue
was dissolved in anhydrous benzene (20 mL) and cooled to 0 °C. A
solution of aniline (1.45 g, 15.6 mmol) in anhydrous benzene (9 mL)
was added over 10 min. The ice bath was removed, and the mixture
was stirred for 80 min at rt. The turbid beige mixture was poured into
ice-cold water (40 mL); the organic layer was separated, and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The combined
organic layers were washed with 5% HCl, H2O, 5% aq Na2CO3, and
again with H2O (30 mL each). The organic layer was dried over
Na2SO4; the excess solvent was removed in vacuo, and the crude
product was purified by column chromatography to give a white solid.
1H NMR (400 MHz, CDCl3): δ 7.14 (t, J = 7.6 Hz, 1H), 7.31−7.39
Mercury Poisoning Experiment.15 A mercury poisoning
experiment was performed to support that the reaction was
accelerated by heterogeneous Pd-BNP catalyst and not by the leached
homogeneous Pd.
In this experiment, Hg (30 equiv) and Pd-BNP (2 mol %) were
stirred at room temperature for 2 h, and then other reagents such as
1a (0.25 mmol), 2a (1.2 equiv), and DABCO (2 equiv) in DMF
1,3,5-trimethoxybenzene (1.0 equiv) was added and stirred at 110 °C.
Not even a trace amount of product 3a formation was detected in the
reaction even after 12 h.
In the second set of reactions, Hg (30 equiv) was added at the
same time with all other reagents (1a (0.25 mmol), 2a (0.3 mmol),
DABCO (2 equiv), Pd-BNP (2 mol %), and 1,3,5-trimethoxybenzene
as internal standard 0.1 equiv) and stirred at 110 °C for 12 h.
Complete inhibition of product 3a formation was observed.16
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00915.
(m, 4H), 7.42 (t, J = 7.6 Hz, 1H), 7.57 (dd, J = 16.4, 8.0 Hz, 4H),
7.91 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 83.6, 85.9, 120.1,
125.0, 128.7, 129.2, 130.4, 132.7, 137.5, 151.2.
■
sı
Experimental Procedure to Synthesize N-Methyl-N,3-diphe-
nylpropiolamide. N-Methyl-N,3-diphenylpropiolamide (1a) was
synthesized using a reported literature procedure with modification.11
A mixture of N,3-diphenylpropiolamide (10.0 mmol, 2.2 g), methyl
iodide (12.0 mmol, 1.7 g), and anhydrous K2CO3 (15 mmol, 2.07 g)
in DMF (10 mL) was stirred vigorously for 12 h at room temperature,
and completion of the reaction was examined by TLC analysis. The
reaction mixture was poured into water (100 mL), and the precipitate
was concentrated. The resulting crude product was purified by
column chromatography to give white solid as pure product. 1H NMR
(400 MHz, CDCl3): δ 3.31 (s, 3H), 7.13 (d, J = 7.6 Hz, 2H), 7.20−
7.28 (m, 2H), 7.28−7.48 (m, 6H); 13C{1H} NMR (100 MHz,
CDCl3): δ 36.5, 82.7, 90.9, 120.5, 127.5, 128.0, 128.4, 129.3, 130.5,
132.5, 143.3, 154.4.
Experimental Procedure for Recovery of the Pd-BNP
Catalyst.15 For the recyclability of Pd-BNP, the reaction was carried
out with N-methyl-N,3-diphenylpropiolamide 1a, and 2a as a
substrate at 1.0 mmol scale using the optimized reaction conditions.
After completion of the reaction, the reaction mixture was allowed to
cool to room temperature. EtOH (5 mL) was added to the reaction
mixture and centrifuged. The liquid was decanted to a 50 mL conical
flask. Again, EtOH (5 mL) was added, centrifuged, and decanted to
the same conical flask. This procedure was repeated up to three or
four times. After that, the catalyst was washed with nanopure water
and ethanol (three to four times). Finally, the resulting solid black
colored particle (Pd-BNP) was dried under vacuum. The dried
catalyst was reused for further catalytic cycles. The collected liquid
was extracted with ethyl acetate (3 × 10 mL), followed by a brine
solution. Then, the organic phase was dried over Na2SO4 and
concentrated in vacuum. The resulting reaction mixture was purified
by column chromatography.
1H and 13C{1H} NMR spectra for all compounds, X-ray
structures, and brief crystal data (PDF)
X-ray crystallographic information for 3a, 3h, and 3u
(ZIP)
AUTHOR INFORMATION
Corresponding Author
■
Govindasamy Sekar − Department of Chemistry, Indian
Institute of Technology Madras, Chennai 600 036, Tamil
Nadu, India; orcid.org/0000-0003-2294-0485;
Email: gsekar@iitm.ac.in
Author
Naziya Parveen − Department of Chemistry, Indian Institute of
Technology Madras, Chennai 600 036, Tamil Nadu, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00915
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
G.S. thanks IIT Madras for financial support (Grant CHY/17-
18/847/RFIR/GSEK). N.P. thanks IIT Madras for a
predoctoral research fellowship. We thank the department of
chemistry, IIT Madras for infrastructure and instrumentation
facilities.
Experimental Procedure for Hot Centrifugation Test.15 The
reaction was catalyzed by a heterogeneous catalyst, not by the leached
homogeneous catalyst. To verify this result, a hot centrifugation test
was performed under the standard reaction condition. For this
purpose, two separate reactions were carried out by using 1a (1.0
mmol, 1.0 equiv), 2a (1.2 equiv), DABCO (2 equiv) and Pd-BNP
catalyst (2 mol %) in 4 mL DMF at 110 °C. After 2 h of reaction, one
set of the reaction was removed and cooled to rt and EtOH was
added. The reaction mixture was centrifuged, and Pd-BNP catalyst
was removed from the reaction mixture. This process was repeated
multiple times sequentially. The mother liquid, which was completely
free from the catalyst (0.1 mL), was extracted with ethyl acetate and
DEDICATION
■
Dedicated to Prof. Krishna P. Kaliappan on the occasion of his
50th birthday.
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