Visible-light-induced photocatalytic formyloxylation reactions of 3-bromooxindoles with water and DMF: The scope and mechanism

Article abstract of DOI:10.1039/c4gc00647j

The formyloxylation reaction of 3-bromooxindoles with water and N,N-dimethylformamide (DMF) has been developed in the presence of the photoredox catalyst fac-Ir(ppy)₃ under irradiation of visible light at ambient temperature. The reaction provides a straightforward approach to pharmaceutically and synthetically useful 3-formyloxyoxindoles in high yields. The mechanism of this transformation was investigated by fluorescence quenching experiments, on-off switching of the light source, labeling experiments, mass spectral analyses and in situ IR experiments. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00647j

Green Chemistry
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Visible-light-induced photocatalytic
formyloxylation reactions of 3-bromooxindoles
with water and DMF: the scope and mechanism†
Cite this: Green Chem., 2014, 16,
3787
You-Quan Zou,a Wei Guo,a Feng-Lei Liu,a Liang-Qiu Lu,a Jia-Rong Chen*a and
Wen-Jing Xiao*a,b
The formyloxylation reaction of 3-bromooxindoles with water and N,N-dimethylformamide (DMF) has
been developed in the presence of the photoredox catalyst fac-Ir(ppy)3 under irradiation of visible light at
ambient temperature. The reaction provides a straightforward approach to pharmaceutically and syntheti-
cally useful 3-formyloxyoxindoles in high yields. The mechanism of this transformation was investigated
by fluorescence quenching experiments, “on–off” switching of the light source, labeling experiments,
mass spectral analyses and in situ IR experiments.
Received 10th April 2014,
Accepted 8th May 2014
DOI: 10.1039/c4gc00647j
www.rsc.org/greenchem
many new methods for the incorporation of DMF into small
molecules forming basic building blocks for elaboration into
Introduction
A major goal for the advancement of modern organic chem- biologically relevant molecules and pharmaceutically impor-
istry is the development of efficient, atom economical, sustain- tant compounds. For example, Chang et al. reported a highly
able and selective methodologies that allow the rapid regioselective palladium catalyzed cyanation of aryl C–H bonds
construction of structurally complex and functionally diverse by employing DMF as the “C” source and ammonia as the “N”
molecular architectures from readily available starting source of the –CN unit.11 In 2010, the group of Tsuji described
materials.1,2 In this regard, photoredox catalysis using visible an intermolecular hydroamidation of alkynes catalyzed by pal-
light has emerged as a novel and powerful strategy for mole- ladium using DMF as the reaction partner.12 Notably, Jiao and
cular bond activations to construct intricate molecules, and co-workers realized an alternative way for the direct cyanation
demonstrated great potential in the past several years.3 The of indole and benzofuran rings using DMF as the “CN” source,
asymmetric alkylation of aldehydes and the [2 + 2] cyclo- leading to valuable aryl nitriles with excellent selectivities.13
addition of enones constitute landmark achievements in this Recently, other interesting reactions involving DMF as a pre-
area,4,5 which enabled other elegant research studies.6–9 cursor were also conducted.14 The first example applying DMF
Despite these significant advances, visible light photoredox to visible light photoredox catalysis was reported by the
catalysis has not reached its full potential. The implemen- Stephenson group. They successfully converted alcohols to the
tation of clean and commercially available compounds in corresponding bromides and iodides via a Vilsmeier–Haack
visible light photoredox catalysis toward intricate molecules is intermediate under mild reaction conditions.15,16
highly desirable.
On the other hand, water has often been regarded as an
N,N-Dimethylformamide (DMF), which often serves as a ideal reagent as a result of its “green chemistry” features.17 We
polar reaction medium, is also widely used as a multipurpose envisioned that the development of new multicomponent reac-
feedstock in organic synthesis.10 Chemists have developed tions that assemble DMF, water and other reactants into valu-
able compounds under the irradiation of visible light should
be highly useful. As part of our ongoing research program
aKey Laboratory of Pesticide & Chemical Biology, Ministry of Education,
directed at the applications of visible light photoredox catalysis
College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan,
for organic synthesis,18 we disclose herein a novel and efficient
Hubei 430079, China. E-mail: wxiao@mail.ccnu.edu.cn; Fax: +86 27 67862041;
visible light induced radical addition/oxidation/hydrolysis
cascade which gives 3-formyloxyoxindoles from 3-bromooxin-
doles, DMF and water (Scheme 1). This transformation can
directly install a formyloxy group at the C3-position of oxi-
ndoles using DMF as the “H, C, O” source and H2O as the “O”
source, and the corresponding products can be used in the
Tel: +86 27 67862041
bState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
†Electronic supplementary information (ESI) available: Experimental procedures
and compound characterisation data, including X-ray crystal data for 2a.
CCDC 937531. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4gc00647j
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analysis. Control experiments showed that a trace amount of
product, or no product at all, was obtained in the absence of
either the photocatalyst or the light source, which indicated
that this transformation proceeded via a visible light catalytic
pathway (entries 2 and 3). Encouraged by these preliminary
results, we then embarked on optimizing the reaction con-
ditions to improve the yield of 2a. Firstly, an extensive screen-
ing of photocatalysts was conducted and it was found that fac-
Ir(ppy)3 was still the best choice (entry 1 vs. entries 4–9). Sub-
sequent investigation of the light source such as 3 W blue
LEDs gave comparable results with somewhat prolonged reac-
tion time (entry 10). When H2O (5.0 equiv.) was added to the
reaction mixture, the model reaction was completed within 4 h
and the yield was increased to 70% (entry 11). Finally, dou-
bling the water equivalent further reduced the reaction time to
2.5 h and increased the yield of 2a to 79%.
Scheme 1 Concept of the visible-light-induced photocatalytic formyl-
oxylation reactions of 3-bromooxindoles with water and DMF.
synthesis of natural alkaloids and pharmaceuticals.19–21
Mechanism studies have been performed by fluorescence
quenching experiments, “on–off” switching of the light source,
labeling experiments, mass spectral analyses and in situ IR
experiments.
Results and discussion
Reaction optimization
Substrate scope
We commenced our investigation of the visible light photo-
redox three-component reaction using 3,5-dibromo-1,3-dimethyl-
indolin-2-one 1a and DMF, along with 2 mol% photocatalyst
fac-Ir(ppy)3, and an 18 W fluorescent household light bulb.
This initial experiment gave the desired product 2a in 62%
isolated yield after workup (Table 1, entry 1), and the structure
of 2a was unambiguously established by X-ray crystallographic
The generality of the visible light induced assembly of 3-bromo-
oxindoles, DMF and water was investigated under the
optimal reaction conditions using 2 mol% fac-Ir(ppy)3. As
shown in Table 2, this reaction tolerates a wide range of 3-bro-
mooxindoles and various 3-formyloxyoxindoles were obtained
in moderate to excellent yields upon isolation. For example,
electron-withdrawing, electron-neutral and electron-donating
substitution patterns on the aromatic rings all performed well,
furnishing the corresponding products in 42–87% yields
(Table 2, entries 1–8). It is noteworthy that halogen substitu-
ents such as F, Cl, and Br on the benzene ring were compatible
with the photoredox process. Products 2a, 2c–2f might be
further modified at the halogenated positions using tran-
sition-metal catalyzed cross-coupling reactions.22 Meanwhile,
we have also tested the C-4-Br substituted substrate; unfortu-
nately, we could not detect the desired product. It was also
found that the group at the C-3 position of the oxindole skele-
ton might be extended to ethyl, isopropyl, butyl as well as
longer-chain octyl groups. These substrates reacted smoothly
to give the desired products in good yields (93–96% yields,
entries 9–12). Cyclic substituents such as cyclopentyl and
cyclohexyl are also suitable for this transformation and give
good results (entries 13 and 14). In addition, the feasibility of
this methodology could also be realized for 3-bromooxindoles
bearing an allyl or a phenyl group at the C-3 position with
somewhat lower yields (entries 15 and 16). Structural variation
in the nitrogen protected groups did not affect the reaction
efficiency and compounds containing N-H, Bn, 4-Me-Bn and
allyl groups in 1q–1t gave the products in 83–91% yields
(entries 17–20), while the presence of an acylated group gave a
complex mixture (entry 21).
Table 1 Results of the experiments on optimization of reaction
conditionsa
Entry Photocatalystb
H2O (x) Time (h) Yieldc (%)
1
fac-Ir(ppy)3
—
fac-Ir(ppy)3
[Ru(bpy)3Cl2]·6H2O
Ir(ppy)2(dtbbpy)PF6
Ir(ppy)2(bpy)PF6
[Ir(dF(CF3)ppy)2(dtbbpy)](PF6)
Ru(bpm)3(BArF)2
Eosin Y
—
—
—
—
—
—
—
—
—
—
5
7
24
24
24
24
24
24
24
24
8
62
Trace
0
Trace
44
31
2
3d
4
5
6
7
8
9
Trace
Trace
62
70
79
9
10e
11
12
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
4
2.5
10
Insight into the catalytic mechanism of the visible light
induced formyloxylation reaction
a The reactions were carried out on a 0.2 mmol scale of 1a with 2 mol% While a precise reaction mechanism awaits further study, we
of photocatalyst and H2O (x equiv.) in DMF (2.0 mL). b See the ESI
now propose a possible catalytic cycle to explain the generation
of 3-formyloxyoxindoles. As illustrated in Scheme 2, the photo-
for the detailed structures of the photocatalysts. c Isolated yields.
d Reaction was carried out in the dark. e 3 W blue LEDs were used as
the light source. DMF: N,N-dimethylformamide.
catalyst fac-Ir(ppy)3 was first excited to the highly active species
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Table 2 Substrate scopea
Table 2 (Contd.)
Yieldb (%)
79
Entry
13
1
Time (h)
3
2
Yieldb (%)
80
Entry
1c
1
Time (h)
2.5
2
2
3
4
5
6
3
79
68
84
83
42
14
15
3
88
78
6
3.5
2.5
2.5
3.5
16
17
18
19
11.5
2.5
2.5
3
40
83
89
86
7
2.5
10
3
87
83
96
93
8
9
20
21
3
91
10
3
—
—
N.D.
a Reactions were carried out on a 0.4 mmol scale of 1 with 2 mol% of
fac-Ir(ppy)3 and H2O (10 equiv.) in DMF (2.0 mL). b Isolated yields.
c The reactions were carried out on a 0.2 mmol scale of 1a. DMF:
N,N-dimethylformamide; N.D.: not determined.
11
12
4
8
93
93
fac-*Ir(ppy)3 by the irradiation of visible light, which was then
reacted with alkyl bromide 1b, resulting in the formation of
the radical intermediate I with the release of bromide ions and
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Scheme 2 Possible mechanism for the visible light induced three-
component assembly of 3-bromooxindoles, DMF and water.
+
fac-Ir(ppy)3 by an oxidative quenching cycle. Subsequently,
radical addition reaction between the intermediate I and N,N-
dimethylformamide took place, giving the radical intermediate
II. The next step may involve the oxidation of intermediate II
to the iminium ion III by two possible pathways: (a) the inter-
+
mediate II is oxidized by fac-Ir(ppy)3 regenerating the ground
state fac-Ir(ppy)3 to complete the catalytic cycle (path A);
(b) the intermediate II is oxidized by another molecule 1b,
affording the iminium ion III and the radical intermediate I
through a chain-propagation mechanism (path B). Finally,
hydrolysis of III gave the terminal product 2b accompanying
dimethylaminehydrobromide 3 as the byproduct. It is worth
mentioning that an extra base is not needed to neutralize HBr,
because the dimethylamine derived from DMF could serve as a
base to capture the acid HBr.
In order to shed some light on the above mechanism, a series
of experiments including fluorescence quenching experiments,
“on–off” switching of the light source and labeling experiments,
MS analyses as well as in situ IR studies were carried out.
(1) Fluorescence quenching experiments. To gain some
insight into the proposed catalytic mechanism in which elec-
tron transfer from excited state fac-*Ir(ppy)3 to the substrate 1b
would occur, fluorescence quenching experiments (Stern–
Volmer studies) of fac-Ir(ppy)3 were carried out. We were
pleased to observe that the fluorescence intensity decreased
with increasing concentration of 1b (Fig. 1a).23 The maximum
emission wavelength (λem) for fac-Ir(ppy)3 was about 520 nm,
and the data at this wavelength were selected for the Stern–
Volmer plot (Fig. 1b). As shown in Fig. 1, a linear relationship
between I0/I and the concentration of 1b was observed at low
concentrations (I0 and I are the fluorescence intensities before
and after the addition of 1b, Fig. 1d). At high concentrations,
the Stern–Volmer plot exhibited an upward curvature, concave
Fig. 1 Fluorescence quenching (Stern–Volmer) studies between fac-
Ir(ppy)3 and 1b.
toward the y-axis (Fig. 1c). These results strongly indicate that ble for this visible light induced transformation (Scheme 2,
the photoexcited state fac-*Ir(ppy)3 was quenched by 1b via path B). In order to gain some information about this reaction
electron transfer, and static and dynamic quenching might pathway, we performed the experiment on the on–off switching
occur simultaneously in this reaction system.24
of the light source in the reaction of 1b, DMF and water. We
(2) “On–off” switching of the light source. As depicted in initially removed the light source after 20 minutes when the
Scheme 2, a radical-chain propagation process was also possi- yield of 1b was approximately 13% under the standard con-
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Scheme 4 Results of C-13 labeling experiments.
Fig. 2 Time profile of the visible light induced assembly of 1b, DMF and
water.
Scheme 5 Results of O-18 labeling experiments.
ditions (GC yield, using n-tetradecane as the internal stan-
dard).23 It was found that no further progress was observed
after stirring in the dark for 10 minutes (Fig. 2). Importantly,
the reintroduction of the visible light source for 20 minutes
led to the further conversion of 1b to the desired product 2b in
34% yield (GC yield). The “on–off” cycle could be repeated
many times until the full consumption of 1b took place. This
phenomenon demonstrated that the visible light induced
three-component reactions required continuous irradiation
with visible light, although the radical chain mechanism
cannot be ruled out in this reaction system.25
(3) Labeling experiments and ESI-MS analyses. To better
understand the “C, H, O” source of the formyloxy group, we
performed a series of labeling experiments. Treatment of 1b
with 10 equivalents of deuterium oxide under the optimal
reaction conditions resulted in no deuterium product
(Scheme 3a). Interestingly, when N,N-dimethylformamide-d1
(98 atom% D) was used as the reaction partner, almost com-
plete isotope incorporation occurred into the final product 2b
in 85% yield (Scheme 3b). Thus, the hydrogen atom of the for-
myloxy group unambiguously originated from N,N-dimethyl-
formamide (DMF). The deuterium product was further
confirmed by HRMS analysis.23
DMF is an efficient carbon source of “OCHO” in the present
protocol. Meanwhile, mass spectrometric data were also
recorded and integrated with the NMR spectroscopic analy-
sis.23 These results further support our proposed mechanism.
To better understand the source for the two oxygen atoms,
we carried out O-18 labeling experiments (Scheme 5). Using
water-18O (97% atom) as the reaction partner, the O-18 label-
ing product was obtained in 81% isolated yield under the opti-
mized reaction conditions. However, we cannot identify which
oxygen atom was labeled at this stage. So the O-18 labeling
product was further hydrolyzed to the corresponding
3-hydroxyl oxindole 4 under basic conditions, and the O-18
labeling hydrolyzed product was not observed based on HRMS
analysis. These results revealed that Oa was from DMF, and Ob
originated from water.23
(4) Possible byproduct. As depicted in Scheme 2, the possi-
ble byproduct is dimethylaminehydrobromide 3, which might
be a salt dissolved in the aqueous phase during the workup
process. To validate this proposal, we carefully studied the
reaction of 1b (Table 2, entry 2). After the reaction was com-
plete (monitored by TLC), D2O was added into the flask, then
extracted with ethyl ether, and the aqueous phase was used
for the NMR experiment directly. As shown in Fig. 3, besides
DMF, only one signal (δ = 2.67 ppm) was observed (Fig. 3c).
Next, in order to confirm that the “C” of the formyloxy
group at the C3-oxindole position also arose from DMF, we
conducted the following C-13 labeling experiment. It was
found that the carbon of the formyloxy group was wholly from
DMF (Scheme 4), which implied that the carbonyl moiety of
Scheme 3 Results of deuterium experiments.
Fig. 3 Results of the byproduct studies.
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Conclusions
In summary, we have developed a visible light induced three
component assembly of 3-formyloxyoxindoles from 3-bromo-
oxindoles, DMF and water. Two green and sustainable natural
resources, visible light and water, were combined into one
reaction system which opened new opportunities to visible
light photoredox catalysis. The mild reaction conditions, broad
scope of substrates, excellent functional group tolerance and
high reaction efficiencies made this new protocol attractive,
and a variety of 3-formyloxyoxindole derivatives can be con-
structed in a highly concise fashion. Moreover, the detailed
mechanism of this transformation was investigated based on
fluorescence quenching experiments, “on–off” switching of
the light source study, labeling experiments, MS studies and
in situ IR experiments. The application of this strategy to the
synthesis of some promising candidates for drug discovery
and the biological evaluation of these 3-formyloxyoxindoles
are currently ongoing in our laboratory.
Experimental section
General information
Unless otherwise noted, materials were purchased from com-
mercial suppliers and used without further purification. All
the solvents were treated according to general methods.
Organic solutions were concentrated under reduced pressure
on a Büchi rotary evaporator. Flash column chromatography
(FC) was performed using 200–300 mesh silica gel. 1H NMR
spectra were recorded on Varian Mercury 600 (600 MHz) spec-
trophotometers. Chemical shifts (δ) are reported in ppm from
the solvent resonance as the internal standard (CDCl3:
7.26 ppm). Data are reported as follows: chemical shift, multi-
plicity (s = singlet, d = doublet, t = triplet, m = multiplet), coup-
ling constants (Hz) and integration. 13C NMR spectra were
recorded on Varian Mercury 400 (100 MHz) spectropho-
tometers (CDCl3: 77.0 ppm) with complete proton decoupling.
IR spectra were recorded on a BRUKER TENSOR 27 FT-IR
spectrometer and are reported in terms of the frequency of
absorption (cm−1). GC-MS was performed using a Thermo
DSQ II 2000. High resolution mass spectra were obtained from
the Shanghai Mass Spectrometry Center (Shanghai Institute of
Organic Chemistry). Melting points were measured using a
Büchi Melting Point B-545. Fluorescence spectra were collected
on a Cary Eclipse Fluorescence spectrophotometer. For the
ReactIR kinetic experiments, the reaction spectra were
recorded using an IC 15 from Mettler-Toledo AutoChem.
Fig. 4 (a) Overall three-dimensional Fourier transform IR (3D-FTIR)
profile of the three-component reaction. (b) Kinetic profile for the
three-component reaction.
This signal could be assigned to the two methyl protons of
dimethylaminehydrobromide when compared with dimethyl-
aminehydrobromide (δ = 2.68 ppm). On the other hand,
dimethylaminehydrobromide 3 might be unstable at high
temperatures and released dimethylamine and hydrobromide,
which were detected by GC-MS.23 These results provide com-
pelling evidence that dimethylaminehydrobromide 3 indeed
existed in this process.
(5) In situ IR experiments. In order to gain some insight
into the kinetic behaviors of this transformation, the reaction
of 1b with DMF and water was monitored via in situ FTIR. It
was very clear that from the 3D-FTIR spectrum (Fig. 4a), the
product 2b was formed with the consumption of 1b. From the
kinetic profile of this reaction (Fig. 4b), a linear relationship
General procedure for visible light induced formyloxylation
between the concentration of 2b and the reaction time was A 10 mL Schlenk tube equipped with a magnetic stir bar and
observed at the beginning of this reaction, which indicated rubber septum was charged with 3,5-dibromo-1,3-dimethylin-
that the reaction rate is independent of 1b. However, a plot of dolin-2-one 1a (0.20 mmol, 1.0 equiv.), tris-(2-phenylpyridi-
2b formation vs. time became a curved line with the pro- nato-C2,N)iridium(III) ( fac-Ir(ppy)3) (0.004 mmol, 0.02 equiv.),
gress of this reaction, which might result from the catalyst water (2.0 mmol, 10.0 equiv.), and DMF (2.0 mL). The mixture
deactivation.23,26
was degassed via the freeze–pump–thaw method and placed at
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a distance of ∼5 cm from the 18 W household light bulb. After
the reaction was complete (2.5 h, monitored by TLC analysis),
H2O (5.0 mL) was added to the reaction mixture. Then, the
mixture was extracted with Et2O and the combined organic
layers were dried over Na2SO4 and concentrated in vacuo. The
residue was purified by FC (silica gel, PE : EtOAc = 10 : 1–5 : 1)
to give the desired product 5-bromo-1,3-dimethyl-2-oxoindolin-
3-yl formate 2a (44.8 mg, 79% yield) as a white solid.
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Acknowledgements
We are grateful to the National Science Foundation of China
(no. 21002036, 21072069, 21232003 and 21202053), the
National Basic Research Program of China (2011CB808600),
the Program for Changjiang Scholars and Innovative Research
Team in University (IRT0953) and the Excellent Doctorial
Dissertation Cultivation Grant from Central China Normal
University (CCNU13T04094, 2013YBZD22) for support of this
research. We thank Prof. Guosheng Liu of Shanghai Institute
of Organic Chemistry for helping with HRMS analysis. We also
thank Mr Hong Yi and Prof. Ai-Wen Lei of Wuhan University
for their help with in situ IR experiments, as well as Dr Xiang-
Gao Meng and Xiao-Peng Liu of Central China Normal Univer-
sity for their help with X-ray diffraction and NMR analysis.
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see: (a) D. Gust, T. A. Moore and A. L. Moore, Acc. Chem.
Res., 1993, 26, 198; (b) D. Ravelli, D. Dondi, M. Fagnoni and
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2011, 3, 140. Formate ester was also observed with the
increased steric hindrance of the cyclic alcohol, but DMF is
the source of “C, H” of the formate unit. The other part of
the ester product is from the alcohol, and bromide was
sacrificed.
(p) P. Wu, C. He, J. Wang, X. Peng, X. Li, Y. An and 16 (a) M. D. Konieczynska, C. Dai and C. R. Stephenson, Org.
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9 For visible light initiated multicomponent reactions, see:
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423; (b) Y. Yasu, T. Koike and M. Akita, Angew. Chem., Int. 20 For selected reviews, see: (a) G. S. Singh and Z. Y. Desta,
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5356; (n) Z.-K. Xiao, H.-Y. Yin and L.-X. Shao, Org. Lett., 23 Please see the ESI† for details.
2013, 15, 1254.
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235.
21 Representative work from our group on the oxindoles:
(a) J.-R. Chen, X.-P. Liu, X.-Y. Zhu, L. Li, Y.-F. Qiao,
J.-M. Zhang and W.-J. Xiao, Tetrahedron, 2007, 63, 10437;
(b) S.-W. Duan, J. An, J.-R. Chen and W.-J. Xiao, Org. Lett., 25 (a) Y. Miyake, K. Nakajima and Y. Nishibayashi, J. Am.
2011, 13, 2290; (c) S.-W. Duan, Y. Li, Y.-Y. Liu, Y.-Q. Zou,
D.-Q. Shi and W.-J. Xiao, Chem. Commun., 2012, 48, 5160.
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J. D. Nguyen, P. Finkbeiner and C. R. Stephenson, J. Am.
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Y. Yang, X. Zhang, Z. Zeng and A. Lei, Chem. – Eur. J., 2013,
19, 5120.
1440; (e) N. Kambe, T. Iwasaki and J. Terao, Chem. Soc. 26 We also investigated the influence of light intensity on the
Rev., 2011, 40, 4937.
reaction efficiencies, please see the ESI† for details.
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