Nontraditional Application of the Photo-Fenton Process: A Novel Strategy for Molecular Construction Using Formamide and Flow Chemistry

Article abstract of DOI:10.1021/acs.oprd.0c00057

Instead of destroying organic compounds, for the first time the photo-Fenton reaction was employed to construct them. Oxindole and spiro-oxindole scaffolds, which are frequently found in natural products, were selected as molecular targets. The development of a photochemical flow reactor employing the photo-Fenton reaction in formamide resulted in an excellent synthetic methodology for oxindoles. Non-anhydrous conditions are required, and readily available chemicals and mild conditions are employed. Also, novel synthetic approaches for new spiro compounds were efficiently developed using functionalized oxindoles as key intermediates.

Full text of DOI:10.1021/acs.oprd.0c00057

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Nontraditional Application of the Photo-Fenton Process: A Novel
Strategy for Molecular Construction Using Formamide and Flow
Chemistry
Marialy N. Sanabria, Milene M. Hornink, Valquíria G. Correia, and Leandro H. Andrade*
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ABSTRACT: Instead of destroying organic compounds, for the first time the photo-Fenton reaction was employed to construct
them. Oxindole and spiro-oxindole scaffolds, which are frequently found in natural products, were selected as molecular targets. The
development of a photochemical flow reactor employing the photo-Fenton reaction in formamide resulted in an excellent synthetic
methodology for oxindoles. Non-anhydrous conditions are required, and readily available chemicals and mild conditions are
employed. Also, novel synthetic approaches for new spiro compounds were efficiently developed using functionalized oxindoles as
key intermediates.
KEYWORDS: photo-Fenton, formamide, construction, oxindoles, spiro-oxindoles
avoids overexposure of organic compounds to UV light and
Fenton’s reagents (Scheme 1). Our strategy relies on the fast
reaction of the hydroxyl radical with formamide (2) to
generate another radical, carbamoyl, which can react with
acceptors (acrylamides 1).14 After tandem addition−cycliza-
tion−rearomatization steps, the desired heterocycles (oxin-
doles 3) are produced. In addition, functionalized oxindoles
can be applied as key intermediates for novel spiro compounds
(4−6).
1. INTRODUCTION
The Fenton reaction was discovered nearly 125 years ago when
H. J. H. Fenton found that iron in combination with hydrogen
peroxide can oxidize tartaric acid.1 Since then, the chemical
nature of this process has been explored. In the main reaction,
Fe2+ reacts with H2O2 in an acidic medium to generate
hydroxyl radical, which is a nonselective and powerful oxidant
that is traditionally used for the mineralization of organic
compounds.2
Over the years, several studies of the Fenton reaction have
revealed some process disadvantages, such as a narrow pH
range and accumulation of Fe3+ in the reaction medium as a
consequence of the inefficient regeneration of Fe2+.2 In order
to improve the traditional Fenton process, heterogeneous
Fenton,3 electro-Fenton,4 and photo-Fenton5 processes have
emerged.
The photo-Fenton process is currently considered an
advanced oxidation process (AOP) that is widely applied for
the treatment of industrial wastewaters. This photochemical
methodology employs UV light to increase the rate of
reduction of Fe3+ to Fe2+.5 Consequently, fast generation of
hydroxyl radical and the application of small amount of catalyst
(Fe2+) can be achieved.
Inspired by all of these features, we found the opportunity to
create a novel and nontraditional application of the photo-
Fenton process to synthesize organic compounds using
formamide and flow chemistry as key components (Figure 1).
For our purpose, oxindoles6−9 and spiro-oxindoles10−13 were
chosen as molecular targets, since these scaffolds are
widespread in natural products with important biological
activities (Figure 2). Therefore, the development of general
and fast synthetic methodologies to access oxindoles and spiro-
oxindoles with structural diversity is highly desirable.
Considering the degradation profile of the photo-Fenton
process, a continuous flow methodology was designed that
2. RESULTS AND DISCUSSION
Our initial experiments were dedicated to the evaluation of the
light source for the photo-Fenton process in the presence of
formamide and the radical acceptor N-methyl-N-phenyl-
methacrylamide (1a). Phosphor light, a blue light-emitting
diode, and UV light (450 W Hg lamp) were selected to
perform the reactions under batch conditions (Table S1). A
glass flask containing formamide, chemicals for hydroxyl
radical generation (Fenton’s reagents: hydrogen peroxide,
sulfuric acid, and FeSO4), and 1a was exposed to each light
source for 30 min. Only the reaction exposed to UV light (450
W Hg lamp) was able to produce the desired heterocycle,
oxindole 3a, after 30 min (60% conversion). The high light
output and the emission spectrum of the Hg lamp were
indispensable to achieve such a good result in a short light
exposure time. We chose the Hg lamp to set up a flow
photochemical reactor for continuous operation.
Special Issue: Flow Chemistry Enabling Efficient
Synthesis
Received: February 14, 2020
Published: April 8, 2020
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© XXXX American Chemical Society
A

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Figure 1. Traditional and nontraditional applications of the photo-Fenton process.
continuous flow conditions. One syringe was loaded with 1a
(0.4 M), sulfuric acid (0.4 M), and FeSO4 (0.004 M; 1 mol %)
in N-methylformamide. The other syringe was loaded with
H2O2 (0.8 M) in N-methylformamide. A syringe pump was
used to infuse the two solutions through the photoreactor. The
results are summarized in Table 1.
Fortunately, our initial experiments under the continuous
flow conditions revealed excellent performance to produce the
desired oxindole 3k. After a residence time (tR) of 10 min, the
starting material was completely transformed into the desired
product (Table 1, entry 1). Aiming at high productivities, we
employed a high concentration of 1a (final concentration
inside the reactor = 200 mmol/L), and excellent results were
observed (full conversion). Even after this excellent perform-
ance, different reaction conditions (varying the iron and
hydrogen peroxide concentrations, the temperature, and the
residence time) were evaluated. A smaller amount of Fe2+ (1
mol % FeSO4·7H2O) still provided full conversion of 3k
(Table 1, entry 2). When the oxidant (H2O2) concentration
was reduced, a decrease in the reaction rate was observed
(Table 1, entry 3). This result can be explained by the
important role of hydrogen peroxide in the reaction
mechanism, involving hydroxyl radical generation. A set of
reactions at different temperatures (55, 45, 40, and 25 °C)
were performed under continuous flow conditions with tR = 10
min. In all cases, we observed full conversion of the starting
material to the desired product (Table 1, entries 4−7), even
when formamide (2a) was used as the carbamoyl radical
precursor (Table 1, entry 8).
Figure 2. Selected examples of bioactive oxindoles and spiro-
oxindoles.
The continuous flow photochemical reactor employed a 450
W Hg UV lamp that was inserted in a glass filter sleeve
(Pyrex). Both the UV lamp and filter sleeve were inserted into
a quartz immersion well. A tube reactor (volume = 1 mL) was
wrapped around the quartz immersion well and connected to
two syringes via a Y-adapter.
The photo-Fenton reaction of 1a in N-methylformamide
(2b) was chosen as model system to perform under
Scheme 1. Molecular Construction Using the Photo-Fenton Reaction
B
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Finally, the carbamoyl radical generated from N-methylforma-
mide was used to produce oxindoles 3k−n in good yields.
Next, the reaction mechanism was investigated. Some
control experiments were performed under continuous flow
conditions at room temperature (Figure 4A). One experiment
without illumination gave only traces of the desired product
3a. This result reveals the main role of the UV light, namely,
the photoreduction of Fe3+ to Fe2+, which is also known in the
traditional photo-Fenton process.5 Another experiment was
carried out to evaluate the possibility of generating hydroxyl
radical from direct photolysis of H2O2 without iron (FeSO4).
In this case, only the starting material was observed.
Table 1. Synthesis of Oxindoles 3a and 3k via the Photo-
Fenton Reaction in Formamide and N-Methylformamide,
a
Respectively, under Continuous Flow Conditions
On the basis of these results, a plausible mechanism for this
reaction is presented in Figure 4B. First, the photo-Fenton
reaction is responsible for hydroxyl radical generation as
follows: hydrogen peroxide reacts with Fe2+ to produce
hydroxyl radical, Fe3+, and water, and then Fe3+ is reduced
to Fe2+ mediated by UV light.5 Once formed, hydroxyl radical
removes a hydrogen from the formamide, generating the
desired carbamoyl radical. In the presence of α,β-unsaturated
amides (N-arylacrylamides 1a−n), the carbamoyl radical can
add to the C−C double bond to give radical I, followed by
intramolecular cyclization. Finally, hydroxyl radical or
carbamoyl radical can remove a hydrogen from cyclic radical
II to regenerate the aromatic ring.
Aiming to apply the oxindoles for the synthesis of novel
spiro compounds, we designed key intermediates 3g and 3h
containing an allyl group properly attached to carbon C-3
(Scheme 2). Fortunately, these oxindoles were efficiently
synthesized using the photo-Fenton reaction in formamide,
and the desirable allyl group remained intact.
b
entry
R
FeSO4 (mol %) equiv of H2O2 T (°C) yield of 3 (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
H
5
1
1
1
1
1
1
1
1
1
2
2
1
2
2
2
2
2
2
2
65
65
65
55
45
40
25
25
25
25
100
100
72
100
100
100
100
100
41
c
9
10
H
H
d
11
a
Reaction conditions inside the reactor: 1a (0.2 mol/L), H2SO4 (0.2
mol/L), FeSO4 (1−5 mol %), H2O2 (30% aqueous solution, 1−2
equiv), and formamide (R = H) or N-methylformamide (R = Me) as
the solvent; residence time (tR) = 10 min; reactor volume = 1 mL;
450 W Hg lamp; back-pressure regulator (BPR) set at 75 psi.
b
c
d
Conversions were determined by GC/MS analysis. tR = 5 min. tR =
2.5 min.
Initially, a spiro[oxindole-3,4-dihydropyridin-2-one] core
was efficiently created after oxidative cleavage of the CC
bond and thermal cyclization (Scheme 2A). The protocol
involved ruthenium-catalyzed oxidative cleavage to afford
aldehyde int-4.15 Upon heating of the crude material, thermal
cyclization gave the desired product, spiro-[oxindole-3,4-
dihydropyridin-2-one] 4, in 83% overall yield.
The second spiro scaffold was spiro[oxindole-δ-lactone] 5.
An iodolactonization protocol was applied to oxindole 3g, and
the spiro compound 5 was obtained as a single diastereomer
(Scheme 2B). The reaction was performed with I2 and water
for 1.5 h at 0 °C.16 The first step is iodonium ion formation at
the allyl group, followed by attack of the amide carbonyl group
from the opposite side of the iodonium ion to give an iminium
ion intermediate. Hydrolysis of this iminium can afford 5. (A
mechanism proposal and NMR analysis are described in the
Supporting Information).
Finally, a spiro[oxindole-γ-lactone] scaffold was created
using a one-pot protocol (Scheme 2C). The first step was an
allylic hydroxylation reaction mediated by selenium dioxide.17
Since the selenium coproduct is selenous acid, in situ
lactonization gave the desired spiro[oxindole-γ-lactones] 6a
and 6b. This reaction was diastereoselective for both oxindoles
(6a and 6b; 2:1 dr). (For NMR analysis, see the discussion in
the Supporting Information).
It is noteworthy that these synthetic routes represent novel
accesses to three different spiro compounds, spiro[oxindole-
3,4-dihydropyridin-2-one], spiro[oxindole-δ-lactone], and
spiro[oxindole-γ-lactone].
We also carried out the reaction with very short residence
times (5 and 2.5 min) at room temperature. However, the
starting material 1a was not fully consumed in either case
(Table 1, entries 9 and 10). Since we did not consider
increasing reaction temperature, we chose tR = 10 min and
room temperature for further studies.
Having established the optimal flow conditions, we turned
our attention to the substrate scope (Figure 3). The reactivities
of several N-arylacrylamides toward the photo-Fenton process
in formamide or N-methylformamide were evaluated, and a
variety of 3,3-disubstituted oxindoles 3a−n were obtained in
good to excellent yields.
The influence of the substituents on the aromatic ring of N-
methyl-N-arylmethacrylamides 1 was evaluated. Several func-
tional groups were tolerated, including p-Me, p-OMe, p-Cl, o-
Ph, and m-OMe substituents. Among the para substituents,
both electron-donating and electron-withdrawing groups gave
oxindoles 3b−d in good yields. When the o-phenyl-substituted
N-methyl-N-arylacrylamide was evaluated, oxindole 3e was
obtained in good yield. The m-methoxy-substituted N-methyl-
N-arylmethacrylamide provided a mixture of regioisomers 3j as
expected (81% yield; 2:3 ratio of isomers). N-Methyl-N-
phenylacrylamides containing a benzyl or allyl group provided
oxindoles 3f and 3g in high yields. N-Arylacrylamides
containing different N-protecting groups such as benzyl and
Boc were evaluated. However, only the N-Bn-protected
acrylamides were compatible with this transformation,
providing oxindoles 3h and 3i in excellent yields. In the case
of N-arylacrylamides containing N-Boc and free N−H, no
reaction was observed, and the starting material was recovered.
C
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Figure 3. Continuous flow production of oxindoles 3a−n using the photo-Fenton reaction in formamide or N-methylformamide. Isolated yields are
reported.
1
procedures when required. H NMR spectra were recorded
on a Varian Inova 300 (300 MHz) or Bruker 500 (500 MHz)
spectrometer. The chemical shifts (δ) are reported in parts per
million using tetramethylsilane as an internal standard (CDCl3
at 7.26 ppm). Proton-decoupled 13C NMR spectra were
recorded on a Varian Inova 300 (75 MHz) or Bruker 500 (125
MHz) spectrometer and are reported in parts per million
relative to the residual solvent peak (CDCl3 at 77.2 ppm).
GC/MS analysis were recorded using a GCM-QP2010SE
instrument (Shimadzu) with low-resolution electron impact
(EI, 70 eV) equipped with an RTX-5MS capillary column.
GC/MS conditions: injector, 260 °C; detector, 110 °C;
pressure, 100 kPa; column temperature, from 80 to 280 °C at 1
°C/min. IR spectra were recorded using a PerkinElmer
Frontier spectrometer. High-resolution mass spectra were
3. CONCLUSION
For the first time, the photo-Fenton process in formamide was
employed to construct heterocycles under continuous flow
conditions. The fast generation of hydroxyl and carbamoyl
radicals by the photo-Fenton reaction allowed the develop-
ment of an excellent synthetic methodology for oxindoles. Our
synthetic strategy represents a step-forward protocol since non-
anhydrous conditions are required and readily available
chemicals and mild conditions are employed. In addition,
allyl oxindoles were designed as key intermediates to produce
new spiro compounds via novel synthetic approaches.
4. EXPERIMENTAL SECTION
General Information. Reagents and solvents were
purchased from Sigma-Aldrich and purified by standard
D
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N-Arylacrylamides 1a−l were prepared according to the
literature protocols (for more details, see the Supporting
Information).14,18
Setup for the Photochemical Flow Reactor. The
photochemical reactor consisted of a UV lamp (450 W Hg
lamp) that was inserted into a filter sleeve (glass type: Pyrex).
Both the UV lamp and filter sleeve were inserted into a quartz
immersion well. A tube reactor (reactor volume = 1 mL; high-
purity perfluoroalkoxyalkane (HPFA) tubing; 19 mm × 9 mm
× 2.21 m) was wrapped around the quartz immersion well. A
water bath was employed to control the reaction temperature.
A back-pressure regulator (BPR) set at 75 psi was connected.
The entire system was placed inside an aluminum-foil-covered
box called the “photobox”. The photobox had a size of 46 cm
× 64 cm × 44 cm (W × H × D) and fit conveniently onto a lab
bench. The tube reactor was connected to the syringes via a Y-
adapter. One syringe was loaded with solution 1 and the other
with solution 2. A syringe pump was used to infuse the two
solutions through the photochemical reactor.
General Procedure for the Photo-Fenton Process in
Formamide under Continuous Flow Conditions. Two
solutions containing the chemicals were prepared in volumetric
flasks as follows:
Solution 1: To a 10 mL volumetric flask were added N-
arylacrylamide 1 (0.4 M) and FeSO4·7H2O (1 mol %), and the
volume was completed with formamide. Nitrogen gas was
bubbled over 5 min, and then H2SO4 (0.4 M) was added.
Solution 2: To a 10 mL volumetric flask was added aqueous
H2O2 (30 wt % in H2O; 0.8 M), and the volume was
completed with formamide. Nitrogen gas was bubbled over 5
min.
Note: Because of the solubility of some starting materials, it
was necessary to decrease their concentrations in solution 1
(1e, 0.04 M; 1f and 1i, 0.136 M; 1h, 0.2 M). Also, tert-butanol
was used as a cosolvent (2% v/v).
Figure 4. Control experiments and possible mechanism.
obtained on a Bruker Daltonics MicroToF spectrometer using
electrospray ionization−time of flight (ESI-TOF) techniques.
a
Scheme 2. Synthesis of New Spiro Compounds
a
Reaction conditions: (a) continuous photo-Fenton process in formamide, tR = 10 min (3g, 77%; 3h, 97%); (b) RuCl3 (3.5 mol %), NaIO4, ACN/
H2O, rt, 2 h; (c) Dean−Stark, toluene, 4 h; (d) I2, THF, H2O, 1.5 h, 0 °C; (e) TBHP (70% aqueous solution), SeO2, reflux, 96 h.
E
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Operational Conditions for the Photochemical Flow
Reactor. Considering two syringes and the reactor volume (1
mL), the injection flow rate was 50 μL/min for a residence
time of 10 min. For reactor equilibration, both solutions were
infused for 3 times the desired residence time, and the reaction
effluent was discharged. After the reactor equilibration, the
reaction effluent was collected in a single flask. The isolated
yield was measured after continuous production of the desired
oxindole for 1.5 h. For example, the reaction effluent (7 mL)
was collected in a single flask, and this crude material was
purified by flash column chromatography as described below.
Each reaction was monitored, and every 10 min one sample
of the reaction effluent was collected for analysis by TLC and
GC/MS. This protocol was repeated three times. For sample
extraction, a saturated aqueous solution of sodium bicarbonate
(0.5 mL) and CHCl3 (2 mL) were added to the flask. The
resulting mixture was stirred, and the organic layer was
removed. In the same flask, the aqueous layer was washed with
CHCl3 (2 mL). The combined organic layers were dried over
MgSO4, filtered, and analyzed by TLC and GC/MS.
9 Hz, J = 2 Hz), 7.39 (d, 1H, J = 2 Hz) ppm; 13C NMR
(DMSO-d6, 75 MHz) δ 24.1, 26.2, 41.9, 45.3, 109.3, 122.7,
125.6, 127.1, 135.9, 142.6, 170.5, 179.3 ppm; IR (KBr) νmax
3370, 3191, 2965, 1702, 1681, 1612, 1495, 1081, 1054 cm−1;
MS (EI+) m/z (relative intensity) 252 (M+, 42), 194 (100).
2-(7-Phenyl-1,3-dimethyl-2-oxoindolin-3-yl)acetamide
(3e).14 Yield = 60%, 0.026 g (from 4.3 mL of output solution,
1
0.02 M); Rf = 0.39 (9:1 CHCl3/MeOH); H NMR (CDCl3,
500 MHz) δ 1.50 (s, 3H), 2.74 (d, 1H, J = 15 Hz), 2.76 (s,
3H), 2.87 (d, 1H, J = 15 Hz), 5.32 (br s, 1H), 6.53 (br s, 1H),
7.08−7.12 (m, 2H), 7.34−7.41 (m, 6H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 24.0, 30.6, 43.9, 45.4, 121.8, 122.4,
125.9, 127.8, 128.8, 130.0, 131.4, 134.4, 138.9, 139.8, 171.5,
181.8 ppm; IR (ATR) νmax 3339, 3201, 2963, 1699, 1679,
1613, 1458 cm−1; MS (EI+) m/z (relative intensity) 294 (M+,
46), 236 (100).
2-(3-Benzyl-1-methyl-2-oxoindolin-3-yl)acetamide (3f).
Yield = 82%, 0.169 g (from 7 mL of output solution, 0.068
1
M); Rf = 0.31 (9:1 CHCl3/MeOH); H NMR (CDCl3, 500
MHz) δ 2.79 (d, 1H, J = 15 Hz), 2.96 (s, 3H), 2.98 (d, 1H, J =
15 Hz), 3.09 (d, 1H, J = 15 Hz), 3.15 (d, 1H, J = 15 Hz), 5.36
(br s, 1H), 6.30 (br s, 1H), 6.58 (d, 1H, J = 10 Hz), 6.78 (d,
2H, J = 10 Hz), 7.02−7.09 (m, 4H), 7.18 (dd, 1H, J = 10 Hz, J
= 1 Hz), 7.21 (d, 1H, J = 5 Hz) ppm; 13C NMR (CDCl3, 125
MHz) δ 26.1, 42.3, 43.7, 52.1, 108.2, 122.6, 123.8, 126.9,
127.6, 128.5, 130.0, 130.3, 135.0, 143.6, 171.3, 179.2 ppm; IR
(ATR) νmax 3391, 3198, 2936, 1714, 1682, 1670, 1613, 1495
cm−1; MS (EI+) m/z (relative intensity) 294 (M+, 46), 160
(100).
Typical Procedure for Purification of Oxindoles 3a−j.
The reaction effluent (7 mL) was used without quenching to
load a glass chromatography column (silica gel; diameter = 4
cm, length = 20 cm). This glass column was very efficient for
separation of the oxindole and formamide. A 9:1 CHCl3/
MeOH mixture was used as the eluent.
To recycle formamide, prior to chromatography a simple
vacuum distillation was used.
2-(1,3-Dimethyl-2-oxoindolin-3-yl)acetamide (3a).14 Yield
1
2-(3-Allyl-1-methyl-2-oxoindolin-3-yl)acetamide (3g).19
= 99%, 0.303 g; Rf = 0.39 (9:1 CHCl3/MeOH); H NMR
1
Yield = 77%, 0.263 g; Rf = 0.35 (9:1 CHCl3/MeOH); H
(CDCl3, 500 MHz) δ 1.45 (s, 3H), 2.68 (d, 1H, J = 15 Hz),
2.82 (d, 1H, J = 15 Hz), 3.24 (s, 3H), 5.35 (br s, 1H), 6.42 (br
s, 1H), 6.86 (d, 1H, J = 5 Hz), 7.07−7.10 (m, 1H), 7.27−7.30
(m, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ 23.7, 26.5,
43.4, 46.1, 108.5, 122.8, 123.0, 128.3, 133.4, 142.9, 171.6,
180.7 ppm; IR (ATR) νmax 3383, 3202, 2967, 1713, 1699,
1680, 1614, 1495 cm−1; MS (EI+) m/z (relative intensity) 218
(M+, 40), 160 (100).
NMR (CDCl3, 500 MHz) δ 2.55−2.64 (m, 2H), 2.72 (d, 1H, J
= 15 Hz), 2.86 (d, 1H, J = 15 Hz), 3.23 (s, 3H), 4.95−5.03 (m,
2H), 5.17 (br s, 1H), 5.38−5.46 (m, 1H), 6.26 (br s, 1H), 6.85
(d, 1H, J = 10 Hz), 7.08 (td, 1H, J = 8 Hz, J = 1 Hz), 7.25−
7.27 (m, 1H), 7.29 (td, 1H, J = 8 Hz, J = 1.5 Hz) ppm; 13C
NMR (CDCl3, 125 MHz) δ 26.4, 41.7, 42.3, 50.3, 108.4, 119.7,
122.8, 123.4, 128.5, 131.0, 131.6, 143.6, 171.3, 179.5 ppm; IR
(ATR) νmax 3405, 3203, 2963, 1717, 1681, 1667, 1631, 1613,
1495 cm−1; MS (EI+) m/z (relative intensity) 244 (M+, 40),
160 (100).
2-(5-Methyl-1,3-dimethyl-2-oxoindolin-3-yl)acetamide
(3b).14 Yield = 47%, 0.110 g (from 5 mL of output solution);
Rf = 0.39 (9:1 CHCl3/MeOH); 1H NMR (CDCl3, 500 MHz)
δ 1.45 (s, 3H), 2.34 (s, 3H), 2.68 (d, 1H, J = 15 Hz), 2.80 (d,
1H, J = 15 Hz), 3.22 (s, 3H), 5.21 (br s, 1H), 6.55 (br s, 1H),
6.75 (d, 1H, J = 10 Hz), 7.07−7.09 (m, 2H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 21.3, 23.6, 26.6, 43.6, 46.1, 108.3, 123.7,
128.7, 132.7, 133.4, 140.5, 171.6, 180.7 ppm; IR (ATR) νmax
3381, 3189, 2963, 1707, 1695, 1683, 1606, 1502 cm−1; MS
(EI+) m/z (relative intensity) 232 (M+, 38), 174 (100).
2-(5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)acetamide
(3c).14 Yield = 74%, 0.258 g; Rf = 0.28 (9:1 CHCl3/MeOH);
1H NMR (CDCl3, 500 MHz) δ 1.45 (s, 3H), 2.68 (d, 1H, J =
15 Hz), 2.79 (d, 1H, J = 15 Hz), 3.22 (s, 3H), 3.79 (s, 3H),
5.30 (br s, 1H), 6.58 (br s, 1H), 6.76 (d, 1H, J = 10 Hz), 6.81
(dd, 1H, J = 10 Hz, J = 2.5 Hz), 6.90 (d, 1H, J = 2.5 Hz) ppm;
13C NMR (CDCl3, 125 MHz) δ 23.5, 26.6, 43.6, 46.4, 55.9,
108.8, 110.5, 112.6, 134.8, 136.3, 156.5, 171.5, 180.4 ppm; MS
(EI+) m/z (relative intensity) 248 (M+, 82), 190 (100).
2-(5-Chloro-1,3-dimethyl-2-oxoindolin-3-yl)acetamide
(3d).14 Yield = 86%, 0.306 g; Rf = 0.49 (9:1 CHCl3/MeOH);
1H NMR (DMSO-d6, 300 MHz) δ 1.20 (s, 3H), 2.61 (d, 1H, J
= 15 Hz), 2.80 (d, 1H, J = 15 Hz), 3.09 (s, 3H), 6.59 (br s,
1H), 6.97 (d, 1H, J = 9 Hz), 7.22 (br s, 1H), 7.26 (dd, 1H, J =
2-(3-Allyl-1-benzyl-2-oxoindolin-3-yl)acetamide (3h).
Yield = 97%, 0.218 g (from 7 mL of output solution, 0.1
1
M); Rf = 0.38 (9:1 CHCl3/MeOH); H NMR (CDCl3, 500
MHz) δ 2.60−2.69 (m, 2H), 2.77 (d, 1H, J = 15 Hz), 2.92 (d,
1H, J = 15 Hz), 4.86 (d, 1H, J = 15 Hz), 4.96−5.07 (m, 3H),
5.13 (br s, 1H), 5.39−5.47 (m, 1H), 6.14 (br s, 1H), 6.72 (d,
1H, J = 8 Hz), 7.05 (td, 1H, J = 8 Hz, J = 1 Hz), 7.17 (td, 1H, J
= 8 Hz, J = 1 Hz), 7.23−7.33 (m, 6H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 42.0, 42.4, 44.1, 50.3, 109.4, 119.9,
122.8, 123.4, 127.4, 127.7, 128.4, 128.8, 130.9, 131.6, 135.9,
142.8, 171.2, 179.6 ppm; MS (EI+) m/z (relative intensity)
320 (M+, 10), 91 (100); HRMS (ESI-TOF) calcd for
C20H21N2O2 [M + H]+ 321.1603, found (M + 1) 321.1601.
2-(1-Benzyl-3-methyl-2-oxoindolin-3-yl)acetamide (3i).
Yield = 90%, 0.127 g (from 5 mL of output solution, 0.068
1
M); Rf = 0.39 (9:1 CHCl3/MeOH); H NMR (CDCl3, 500
MHz) δ 1.49 (s, 3H), 2.75 (d, 1H, J = 15 Hz), 2.89 (d, 1H, J =
15 Hz), 4.94 (s, 2H), 5.36 (br s, 1H), 6.28 (br s, 1H), 6.73 (d,
1H, J = 8 Hz), 7.04 (td, 1H, J = 8 Hz, J = 1 Hz), 7.16 (td, 1H, J
= 8 Hz, J = 1.5 Hz), 7.24−7.28 (m, 2H), 7.30−7.34 (m, 4H)
ppm; 13C NMR (CDCl3, 125 MHz) δ 24.2, 43.4, 44.0, 46.2,
109.6, 122.9, 123.1, 127.3, 127.8, 128.3, 128.9, 133.3, 135.9,
F
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142.1, 171.4, 180.8 ppm; IR (ATR) νmax 3398, 3196, 2965,
1707, 1681, 1612, 1491 cm−1; MS (EI+) m/z (relative
intensity) 294 (M+, 18), 91 (100).
νmax 3328, 2960, 1707, 1684, 1650, 1599, 1498, 1294, 1041
cm−1; MS (EI+) m/z (relative intensity) 262 (M+, 95), 190
(100).
2-(6-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)acetamide
(3j). Yield = 81%, 0.280 g; Rf = 0.39 (9:1 CHCl3/MeOH).
Major isomer: 1H NMR (CDCl3, 500 MHz) δ 1.45 (s, 3H),
2.92 (d, 1H, J = 15 Hz), 2.96 (d, 1H, J = 15 Hz), 3.21 (s, 3H),
3.86 (s, 3H), 5.39 (br s, 1H), 6.15 (br s, 1H), 6.52 (d, 1H, J =
2-(3-Benzyl-1-methyl-2-oxoindolin-3-yl)-N-methylaceta-
mide (3n). Yield = 58%, 0.041 g (from 3.4 mL of output
solution, 0.068 M); Rf = 0.47 (95:5 CHCl3/MeOH); 1H NMR
(CDCl3, 500 MHz) δ 2.69 (d, 3H, J = 5 Hz), 2.77 (d, 1H, J =
15 Hz), 2.95 (d, 1H, J = 15 Hz), 2.97 (s, 3H), 3.12 (d, 2H, J =
5 Hz), 6.21 (br s, 1H), 6.58 (d, 1H, J = 8 Hz), 6.77−6.79 (m,
2H), 7.01−7.06 (m, 4H), 7.16−7.21 (m, 2H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 26.1, 26.4, 42.7, 43.6, 52.1, 108.1, 122.4,
123.8, 126.8, 127.6, 128.4, 130.1, 130.6, 135.1, 143.6, 169.7,
179.4 ppm; MS (EI+) m/z (relative intensity) 308 (M+, 12),
160 (100).
8 Hz), 6.62 (d, 1H, J = 8 Hz), 7.23 (t, 1H, J = 8 Hz) ppm; 13
C
NMR (CDCl3, 125 MHz) δ 21.7, 26.7, 41.5, 46.5, 55.6, 101.9,
106.1, 123.5, 129.5, 144.5, 155.9, 172.1, 180.8 ppm.
Minor isomer: 1H NMR (CDCl3, 500 MHz) δ 1.40 (s, 3H),
2.66 (d, 1H, J = 15 Hz), 2.76 (d, 1H, J = 15 Hz), 3.21 (s, 3H),
3.82 (s, 3H), 5.48 (br s, 1H), 6.36 (br s, 1H), 6.44 (d, 1H, J =
2 Hz), 6.57 (dd, 1H, J = 8 Hz, J = 2 Hz), 7.16 (d, 1H, J = 8
Hz) ppm; 13C NMR (CDCl3, 125 MHz) δ 23.8, 26.5, 43.6,
45.7, 55.6, 96.6, 106.7, 118.5, 125.2, 144.2, 160.3, 171.7, 181.2
ppm.
Synthesis of Spiro[oxindole-3,4-dihydropyridin-2-
one] 4 via Oxidative Cleavage of the CC Bond. Step
1: An aqueous solution of RuCl3 (500 μL, 0.035 mmol, 3.5
mol %) was added to a solution of oxindole 3g (122.1 mg, 0.5
mmol) in 6:1 acetonitrile/water (3.5 mL). Then NaIO4 (213.9
mg, 1.0 mmol) was added portionwise over a period of 5 min
at room temperature. The resulting mixture was stirred for 2 h.
The reaction was quenched with a saturated aqueous solution
of Na2S2O3 (10 mL) and extracted with EtOAc (3 × 10 mL).
The combined organic layers were washed with water (20 mL)
and brine (20 mL), dried over MgSO4, and concentrated
under reduced pressure. The crude material containing the
desired compound int-4 was used in the next reaction without
further purification. Step 2: The crude material containing
compound int-4 (0.5 mmol) was dissolved in toluene. The
resulting mixture was stirred in a Dean−Stark apparatus and
monitored by TLC. After 4 h, the solvent was removed under
reduced pressure. The crude mixture was purified by flash
column chromatography on silica gel (9:1 CHCl3/MeOH).
1-Methyl-1′H-spiro[indoline-3,4′-pyridine]-2,2′(3′H)-
IR (ATR) νmax 3400, 3206, 2966, 1701, 1665, 1627, 1608,
1475, 1260, 1071 cm−1; MS (EI+) m/z (relative intensity) 248
(M+, 43), 190 (100); HRMS (ESI-TOF) calcd for
C13H17N2O3 [M + H]+ 249.1239, found (M + 1) 249.1233.
Typical Procedure for the Purification of Oxindoles
3k−n. The reaction effluent (7 mL) was quenched with a
saturated aqueous solution of NaHCO3 to pH 7. Also, 2 equiv
of Na2SO3 was added. The resulting mixture was filtered
through a short pad of silica gel (MeOH), and then methanol
and N-methylformamide were removed by reduced-pressure
distillation. The resulting crude mixture was dissolved using
chloroform and filtered to remove any insoluble material. The
solvent was removed under reduced pressure, and the crude
mixture was used to load a glass chromatography column
(silica gel; diameter = 4 cm, length = 20 cm). A 95:5 CHCl3/
MeOH mixture was used as the eluent.
2-(1,3-Dimethyl-2-oxoindolin-3-yl)-N-methylacetamide
(3k).14 Yield = 89%, 0.289 g; Rf = 0.45 (95:5 CHCl3/MeOH);
1H NMR (CDCl3, 500 MHz) δ 1.42 (s, 3H), 2.66 (d, 1H, J =
15 Hz), 2.67 (d, 3H, J = 5 Hz), 2.78 (d, 1H, J = 15 Hz), 3.25
(s, 3H), 6.36 (br s, 1H), 6.86 (d, 1H, J = 8 Hz), 7.07 (td, 1H, J
= 8 Hz, J = 1 Hz), 7.25−7.29 (m, 2H) ppm; 13C NMR
(CDCl3, 125 MHz) δ 23.7, 26.3, 26.5, 43.7, 46.2, 108.4, 122.8,
122.9, 128.2, 133.6, 143.0, 169.9, 180.9 ppm; IR (ATR) νmax
3323, 2965, 1713, 1656, 1613, 1495 cm−1; MS (EI+) m/z
(relative intensity) 232 (M+, 40), 160 (100).
N-Methyl-2-(1,3,5-trimethyl-2-oxoindolin-3-yl)-N-methyl-
acetamide (3l).14 Yield = 42%, 0.143 g; Rf = 0.45 (95:5
CHCl3/MeOH); 1H NMR (CDCl3, 500 MHz) δ 1.41 (s, 3H),
2.34 (s, 3H), 2.64 (d, 1H, J = 15 Hz), 2.72 (d, 3H, J = 5 Hz),
2.75 (d, 1H, J = 15 Hz), 3.22 (s, 3H), 6.45 (br s, 1H), 6.75 (d,
1H, J = 8 Hz), 7.06−7.08 (m, 2H) ppm; 13C NMR (CDCl3,
125 MHz) δ 21.3, 23.6, 26.3, 26.5, 43.8, 46.2, 108.2, 123.7,
128.5, 132.5, 133.7, 140.4, 169.9, 180.8 ppm; IR (ATR) νmax
3327, 2963, 1714, 1687, 1649, 1602, 1501 cm−1; MS (EI+) m/
z (relative intensity) 246 (M+, 55), 174 (100).
2-(5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)-N-methyla-
cetamide (3m).14 Yield = 59%, 0.154 g (from 5 mL of output
solution); Rf = 0.39 (95:5 CHCl3/MeOH); 1H NMR (CDCl3,
500 MHz) δ 1.42 (s, 3H), 2.64 (d, 1H, J = 15 Hz), 2.72 (d,
3H, J = 5 Hz), 2.76 (d, 1H, J = 15 Hz), 3.22 (s, 3H), 3.79 (s,
3H), 6.47 (br s, 1H), 6.76 (d, 1H, J = 8.5 Hz), 6.80 (dd, 1H, J
= 8.5 Hz, J = 2.5 Hz), 6.89 (d, 1H, J = 2.5 Hz) ppm; 13C NMR
(CDCl3, 125 MHz) δ 23.6, 26.3, 26.5, 43.6, 46.5, 55.9, 108.7,
110.4, 112.3, 135.0, 136.4, 156.3, 169.8, 180.5 ppm; IR (ATR)
1
dione (4). Yield = 83%; Rf = 0.40 (9:1 CHCl3/MeOH); H
NMR (CDCl3, 500 MHz) δ 2.62 (d, 1H, J = 16.4 Hz), 3.03 (d,
1H, J = 16.4 Hz), 3.23 (s, 3H), 4.88 (d, 1H, J = 7.7 Hz), 6.42
(dd, 1H, J = 7.7 Hz, J = 1.2 Hz), 6.86 (d, 1H, J = 7.8 Hz), 7.07
(td, 1H, J = 7.6 Hz, J = 1 Hz), 7.15 (br s, 1H), 7.27 (d, 1H, J =
7.7 Hz), 7.32 (td, 1H, J = 7.7 Hz, J = 1.2 Hz); 13C NMR
(CDCl3, 125 MHz) δ 26.6, 38.7, 48.3, 105.1, 108.5, 123.3,
123.4, 127.7, 129.0, 132.1, 142.4, 168.5, 177.7 ppm; IR (KBr)
νmax 3272, 1711, 1656, 1611, 1470, 1349, 1090, 697 cm−1; MS
(EI+) m/z (relative intensity) 130 (25), 199 (52), 213 (8), 227
(50, M+), 228 (100, M+), 229 (M+, 15); HRMS calcd for
C13H12N2O2 [M + Na]+ 251.0796, found (M + 23) 251.0795.
Synthesis of Spiro[oxindole-δ-lactone] 5 via Iodolac-
tonization. I2 (380.7 mg, 1.5 mmol) was added portionwise
over a period of 10 min to a solution of oxindole 3g (122.1 mg,
0.5 mmol) in 1:1 tetrahydrofuran/water (4 mL) cooled to 0
°C. After 1.5 h at 0 °C, the reaction was quenched with a
saturated aqueous solution of Na2S2O3 (10 mL). The mixture
was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine (20 mL), dried over
MgSO4, and concentrated under reduced pressure. The
mixture was purified by flash column chromatography on
silica gel (1:1 EtOAc/hexane).
2′-(Iodomethyl)-1-methyl-2′,3′-dihydrospiro[indoline-
3,4′-pyran]-2,6′(5′H)-dione (5). Yield = 40%; Rf = 0.51 (1:1
1
EtOAc/hexane); H NMR (CDCl3, 500 MHz) δ 2.06−2.02
(m, 1H), 2.17−2.23 (m, 1H), 2.53 (dd, 1H, J = 17.4 Hz, J =
2.3 Hz), 2.95 (d, 1H, J = 17.4 Hz), 3.26 (s, 3H), 3.39−3.46
(m, 2H), 4.68−4.74 (m, 1H), 6.94 (d, 1H, J = 7.8 Hz), 7.12 (t,
G
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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1H, J = 7.6 Hz), 7.24 (d, 1H, J = 7.2 Hz), 7.38 (td, 1H, J = 7.8
Hz, J = 1 Hz); 13C NMR (CDCl3, 125 MHz) δ 7.0, 26.7, 36.1,
36.2, 45.5, 75.7, 109.1, 123.3, 123.4, 129.4, 130.5, 142.8, 168.0,
176.8 ppm; IR (KBr) νmax 1747, 1712, 1612, 1494, 1470, 1376,
1354, 754 cm−1; MS (EI+) m/z (relative intensity) 130 (35),
160 (100), 244 (45), 371 (11, M+), 372 (M+, 2); HRMS calcd
for C13H12N2O2 [M + Na]+ 393.9916, found (M + 23)
393.9915.
1H, J = 17.4 Hz), 4.71 (d, 1H, J = 15.6 Hz) 5.00 (d, 1H, J =
7.0 Hz), 5.05 (d, 1H, J = 15.6 Hz), 5.17 (d, 1H, J = 6.8 Hz),
5.20−5.17 (m, 2H), 5.83−5.90 (m, 1H), 6.75 (d, 1H, J = 7.9
Hz), 7.11 (td, 1H, J = 7.6 Hz, J = 1.0 Hz), 7.24 (d, 1H, J = 7.8
Hz), 7.26−7.32 (m, 5H); 13C NMR (CDCl3, 125 MHz) δ
38.3, 43.9, 54.5, 86.2, 109.7, 120.6, 122.6, 123.3, 126.9, 127.5,
127.9, 128.8, 129.6, 130.5, 136.3, 143.1, 173.2, 175.3 ppm; MS
(EI+) m/z (relative intensity) 319 (M+, 3), 91 (100).
Synthesis of Spiro[oxindole-γ-lactones] 6a and 6b via
Allylic Oxidation and Lactonization. TBHP (70% aqueous
solution; 3.9 mmol) and SeO2 (1.6 mmol) were added to a
solution of the oxindole (3g or 3h) (0.8 mmol) in CH2Cl2 (25
mL). The resulting mixture was stirred under reflux for 96 h.
The reaction was quenched with a 1 M aqueous solution of
HCl (10 mL). The mixture was extracted with CHCl3 (3 × 10
mL). The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The crude material was
purified by flash column chromatography on silica gel (7:3
hexanes/EtOAc). The diastereoisomers were separated and
fully characterized.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00057.
■
sı
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Leandro H. Andrade − Institute of Chemistry, University of Sao
Paulo, 05300-080 Sao Paulo, SP, Brazil; orcid.org/0000-
0001-5975-4980; Email: leandroh@iq.usp.br
̃
̃
1′-Methyl-2-vinyl-2H-spiro[furan-3,3′-indoline]-2′,5(4H)-
dione (6a). Yield = 55%. Spectral data for the isolated
diastereomers:
Authors
Marialy N. Sanabria − Institute of Chemistry, University of Sao
Paulo, 05300-080 Sao Paulo, SP, Brazil
Milene M. Hornink − Institute of Chemistry, University of Sao
Paulo, 05300-080 Sao Paulo, SP, Brazil
Valquíria G. Correia − Institute of Chemistry, University of Sao
Paulo, 05300-080 Sao Paulo, SP, Brazil
1
Major diastereomer: Rf = 0.34 (7:3 hexanes/EtOAc); H
̃
NMR (CDCl3, 500 MHz) δ 2.69 (d, 1H, J = 17.1 Hz), 3.25 (s,
3H), 3.32 (d, 1H, J = 17.1 Hz), 5.11 (d, 1H, J = 9.7 Hz), 5.15
(m, 1H), 5.34 (dd, 1H, J = 17.5 Hz, J = 1.8 Hz), 5.37−5.44
(m, 1H), 6.89 (d, 1H, J = 7.9 Hz), 7.11 (td, 1H, J = 7.6 Hz, J =
0.9 Hz), 7.24 (d, 1H, J = 7.4 Hz), 7.36 (td, 1H, J = 7.8 Hz, J =
1.2 Hz); 13C NMR (CDCl3, 125 MHz) δ 39.6, 44.2, 55.6, 85.6,
108.8, 120.5, 123.3, 123.8, 127.8, 129.5, 130.4, 142.9, 173.7,
174.2 ppm; IR (KBr) νmax 1790, 1715, 1614, 1495, 1472 1378,
1354, 755 cm−1; MS (EI+) m/z (relative intensity) 130 (44),
159 (100), 187 (18), 243 (M+, 5); HRMS calcd for
C14H13NO3 [M + H]+ 244.0974, found (M + 1) 244.0961.
̃
̃
̃
̃
̃
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00057
Notes
The authors declare no competing financial interest.
1
Minor diastereomer: Rf = 0.29 (7:3 hexanes/EtOAc); H
ACKNOWLEDGMENTS
■
NMR (CDCl3, 500 MHz) δ 2.92 (d, 1H, J = 17.4 Hz), 3.01 (d,
1H, J = 17.4 Hz), 3.19 (s, 3H), 4.97 (d, 1H, J = 7.0 Hz), 5.15−
5.21 (m, 2H), 5.86−5.89 (m, 1H), 6.86 (d, 1H, J = 7.8 Hz),
7.15 (td, 1H, J = 7.6 Hz, J = 0.9 Hz), 7.33 (d, 1H, J = 7.4 Hz),
7.36 (td, 1H, J = 7.8 Hz, J = 1.1 Hz) ppm; 13C NMR (CDCl3,
125 MHz) δ 25.3, 37.1, 53.4, 85.1, 107.6, 121.5, 119.4, 122.3,
126.2, 128.7, 129.3, 142.9, 172.3, 174.0 ppm; MS (EI+) m/z
(relative intensity) 130 (44), 159 (100), 187 (18), 243 (M+,
5).
We thank the National Council for Scientific and Techno-
logical Development (CNPq) (Grants 312751/2018-4 and
141672/2015-3), Coordination for the Improvement of
Higher Education Personnel (CAPES), and the Sao Paulo
Research Foundation (FAPESP) (Grants 2017/02854-8 and
̃
2019/10762-1) for financial support.
REFERENCES
■
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diastereomers:
1
Major diastereomer: Rf = 0.57 (7:3 hexanes/EtOAc); H
NMR (CDCl3, 500 MHz) δ 2.73 (d, 1H, J = 17.0 Hz), 3.39 (d,
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(dd, 1H, J = 17.2 Hz, J = 1.9 Hz), 5.39−5.46 (m, 1H), 6.78 (d,
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7.24 (m, 2H), 7.27−7.32 (m, 5H); 13C NMR (CDCl3, 125
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Minor diastereomer: Rf = 0.44 (7:3 hexanes/EtOAc); H
NMR (CDCl3, 500 MHz) δ 2.98 (d, 1H, J = 17.4 Hz), 3.05 (d,
H
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Heterogeneous Fenton Catalytic Reactivity: A Review. Appl. Catal., B
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