Silver-Catalyzed Decarboxylative Radical Addition/Cyclization of α,α-Difluoroarylacetic Acids with Acrylamides To Synthesize Difluorinated Oxindoles

Article abstract of DOI:10.1002/ejoc.201701248

A facile silver-catalyzed decarboxylative radical addition/cyclization reaction of α,α-difluoroarylacetic acids and acrylamides has been disclosed. The method provides a highly attractive approach to synthesize a series of difluorinated oxindoles that contain various functional groups in moderate to good yields under mild conditions. Moreover, experimental studies reveal that the CF₂ group of the α,α-difluoroarylacetic acids plays a vital role in the transformation.

Full text of DOI:10.1002/ejoc.201701248

A Journal of
Accepted Article
Title: Silver-Catalyzed Decarboxylative Radical Addition/Cyclization
of α,α-Difluoroarylacetic Acids with Acrylamides to Synthesize
Difluorinated Oxindoles
Authors: Jun Deng, Yin-Long Li, Ji-Bo Wang, Xue-Lin Wang, and Yang
Cao
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701248
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701248
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10.1002/ejoc.201701248
European Journal of Organic Chemistry
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Silver-Catalyzed Decarboxylative Radical Addition/Cyclization of
α,α-Difluoroarylacetic Acids with Acrylamides to Synthesize
Difluorinated Oxindoles
Yin-Long Li,[a,b] Ji-Bo Wang,[b] Xue-Lin Wang,[b] Yang Cao,[b] Jun Deng *[a,b]
Abstract:
A
facile silver-catalyzed decarboxylative radical
addition/cyclization of α,α-difluoroarylacetic acids with acrylamides
has been disclosed. The methodology provides a highly attractive
approach to synthesize a series of difluorinated oxindoles with
various functional groups in moderate to good yields under mild
conditions. Moreover, experimental studies revealed that the CF2
group of α,α-difluoroarylacetic acids played a vital role in this
transformation.
Introduction
As one of the “magic elements”, fluorine atom(s) incorporated
into organic molecules often provides some additional benefits
on their physical and biological properties. Therefore, fluorine
chemistry is widely exploited in pharmaceuticals, agrochemicals,
and material sciences.[1] In particular, the difluoromethyl group
(CF2), which has emerged as bioisosteres of hydroxy and thiol
units, can act as a more lipophilic hydrogen bond donor than OH
and NH.[2] As a result, it is of the high value to the construction of
difluorinated molecules and confers the advantageous effects in
structural library design and drug discovery.[3] Traditionally, the
synthesis of difluoromethylated organic compounds mainly relies
on the deoxyfluorination of aldehydes or ketones by using DAST,
Deoxofluor and other derivatives as the fluorinating reagents.[4]
Alternatively, the transition-metal-catalyzed (or -mediated)
difluoromethylenation processes also received more attention in
recent years, such as the palladium and nickel-catalyzed
difluoroalkylation reactions.[5] Despite these advances, it is still
high desirable to develop a practical and mild synthesis method
of CF2 group containing scaffolds.
Figure 1. Transformations of α,α-difluoroarylacetic acids/salts
reaction of aliphatic carboxylic acids.[7] Following this report,
aliphatic carboxylic acids were widely utilized as reaction
precursors
for
fluorination,[8]
alkynylation,[9]
trifluoromethylthiolation,[10] allylation,[11] and other related
reactions.[12] Recently, α,α-difluoroarylacetic acids were used as
synthons to access various difluoromethylated aryl motifs
(Figure 1).[13]
Oxindole derivatives exist in a wide range of natural products
and pharmaceuticals and an increasing number of methods for
constructing oxindole scaffolds have been developed.[14] Among
these methods, the difunctionalization of acrylamides through a
tandem process for synthesizing 3,3-disubstituted oxindoles was
extensively explored.[15] Hence, we attempted to develop a facile
silver-catalyzed decarboxylative radical addition/cyclization
cascade of α,α-difluoroarylacetic acids with acrylamides and
synthesize a series of difluorinated oxindoles with various
functional groups.
Since carboxylic acids are widely available and inexpensive,
and can be easily stored and handled, they are utilized as
pivotal synthetic sources in organic chemistry.[6] Among the
numerous utilizations of carboxylic acids, silver-catalyzed
decarboxylative functionalization has been proved to be a
powerful tool for constructing new chemical bonds. Li and co-
workers originally reported the silver-catalyzed Hunsdiecker
[a]
[b]
Chongqing Key Laboratory of Natural Product Synthesis and Drug
Research, School of Pharmaceutical Sciences, Chongqing
University, Chongqing 401331, China
Results and Discussion
E-mail: jdeng@cqu.edu.cn
School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
Initially, we chose acrylamide 1a and α,α- difluoroarylacetic acid
2a as the model substrates to validate the feasibility of the
proposed transformation. To our delight, when the reaction was
conducted with AgNO3 (0.2 equiv) and K2S2O8 (1.5 equiv) in the
DMSO/H2O (1/1, v/v) at 55 oC, the desired product 3a was
obtained in 47% yield (Table 1, entry 1). Other mixed solvent
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201701248
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Table 1. Optimization Studies[a]
Scheme 1. Scope of Acrylamides[a]
Entry
1
[Ag]
Oxidant
(equiv)
K2S2O8
(1.5)
K2S2O8
(1.5)
K2S2O8
(1.5)
K2S2O8
(1.5)
Solvent
Yield (%)[b]
47
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
--
DMSO/H2O
(1/1)
CH2Cl2/H2O
(1/1)
acetone/H2O
(1/1)
DMSO
2
15
3
10
4
30
5
K2S2O8
(1.5)
K2S2O8 (3)
H2O
15
6
DMSO/H2O
(1/1)
DMSO/H2O
(1/1)
DMSO/H2O
(1/1)
DMSO/H2O
(1/2)
DMSO/H2O
(1/2)
DMSO/H2O
(1/2)
DMSO/H2O
(1/2)
DMSO/H2O
(1/2)
69
7
PIDA (3)
TBHP (3)
NR
NR
72
8
9
K2S2O8(3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
10[c]
11
12
13
14
15[d]
16[e]
35
20
AgF
65
Ag2O
64
AgOAc
AgNO3
AgNO3
DMSO/H2O
(1/2)
DMSO/H2O
(1/2)
DMSO/H2O
(1/2)
67
70
53
[a] Conditions: 1a (0.15 mmol), 2a (1.5 equiv), AgNO3 (0.2
equiv), oxidant (3.0 equiv), solvent (3.0 mL), 55 oC under N2
atmosphere for 3 h. [b] Isolated yield. [c] Reaction temperature
[a] Conditions: 1 (0.15 mmol), 2a (1.5 equiv), AgNO3 (0.2 equiv),
oxidant (3.0 equiv), DMSO/H2O (1/1, 3.0 mL), 55 C under N2
atmosphere, isolated yield.
o
o
was 30 C. [d] 1.0 equiv of Na2CO3 was added. [e] 1.0 equiv of
Et3N was added. PIDA = Iodobenzene diacetate. TBHP= tert-
Butyl hydroperoxide.
optimized conditions, but they did not increase the isolated yield
(Table 1, entries 15 and 16).
Under the optimal reaction conditions, the acrylamides with
various substituents were investigated in order to expand the
structural diversity of difluorinated oxindoles. As shown in
Scheme 1, the phenyl and benzyl groups on the nitrogen atom
were compatible with each other and the corresponding
products were obtained in 64% and 59% yields (scheme 1, 3b
and 3c). However, the unprotected N-phenylmethacrylamide 1d
did not work at all. The methyl substituent on the different
positions on phenyl ring could successfully deliver the desired
products in the yields of 39%~51%. The meta-substituted
substrate provided a mixture of the products in the moderate
yield and regioselectivity (3f and 3f', 49%, 2:1). Nevertheless,
the substrates with various halogen groups (F, Cl, Br, and I),
which enable following modifications, uneventfully gave the
difluorinated oxindoles 3h-3k in moderate to good yields.
Unfortunately, the substrates bearing strong electron-
withdrawing substituents (e.g. NO2 and CF3) showed the poor
reactivity and the starting material were recovered after 8 h (data
not shown). Next, several substituents at the 2-position of the
systems, such as CH2Cl2/H2O (1/1, v/v) and acetone/H2O (1/1,
v/v), resulted in poor yields (Table 1, entries 2 and 3). When
DMSO or H2O was used as the sole solvent, the yield of 3a was
decreased to 30% or 15% (Table 1, entries 4 and 5). As
expected, an increased load of K2S2O8 (3.0 equiv) afforded the
difluorinated product 3a in 69% yield (Table 1, entry 6). In
comparison, no product was detected in the presence of other
oxidants such as PIDA and TBHP (Table 1, entries 7 and 8).
Gratifyingly, switching the ratio of DMSO and H2O to 1/2 gave
the difluorinated product 3a in the satisfied yield (72%, Table 1,
entry 9). Moreover, lowering the reaction temperature to 35 oC or
removing the silver catalyst could significantly decrease the yield
to 35% or 20% (Table 1, entries 10 and 11). Additionally, other
silver (I) salts were also evaluated and the evaluation results
indicated that AgF, Ag2O, and AgOAc could produce the desired
product 3a in 64-67% yields (Table 1, entries 12, 13, and 14).
K2CO3 and Et3N were employed as the additives under the
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10.1002/ejoc.201701248
European Journal of Organic Chemistry
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acrylamide moieties were evaluated. The acrylamides containing
aryl groups at the 2-positions were applicable and gave the
products 3l-3o in 33-50% yields. Conversely, the mono-
substituted olefin (R2 = H) did not promote the cyclization even
after 12 h. Noteworthy, the acrylamide 1q was also suitable for
this transformation and tricyclic oxindole 3q was obtained in 50%
yield after 5 h.
Scheme 3. Large-scale reaction
In order to demonstrate the synthetic applicability of this
protocol, the scope of α,α-difluoroarylacetic acids was also
tested (Scheme 2). The reactions of substituted α,α-
difluoroarylacetic acids with electron-donating groups were
amenable to the optimized conditions, which furnished 4a-4e in
the yields of 45%~80%. It was found that the hydrolyzed by-
product 4d' also isolated in 25% yield. However, the phenyl ring
of α,α-difluoroarylacetic acids with electron-withdrawing groups
was detrimental and failed to generate the products. The
reaction of α,α-difluoro-2-naphthylacetic acid took place
smoothly to generate 4f in 60% yield. Moreover, the heterocyclic
substrates were tolerated and the thiophene-substituted
difluorinated oxindole 4g was formed in 35% yield after 5 h.
We further interrogated the developed process by enlarging
the scale of substrate 1a to 1.5 mmol. Under the optimal
conditions, we were delighted to obtain 63% yield of 3a which
showed the practicality of this protocol (Scheme 3).
Scheme 4. KIE Studies of Acrylamides
Scheme 2. Scope of α,α-Difluoroarylacetic Acids[a]
Scheme 5. Control Experiments
To gain further insights into the mechanism of this process,
some control experiments were carried out (Schemes 4 and 5).
First, the intra- and inter-molecular competing kinetic isotope
effect (KIE) experiments were conducted under the standard
conditions (see the Supporting Information for details) and no
kinetic isotopic effect (kH/kD = 1.0) were observed (Scheme 4,
Eqs. a and b). It revealed that C−H bond cleavage was not the
rate-determining step. Next, the reaction was found to be
completely inhibited by 3.0 equiv of BHT (2,6-di-tert-butyl-4-
methylphenol) (Scheme 5, Eq. a). When TEMPO was subjected
to the standard conditions, the yield of 3a significantly dropped
[a] Conditions: 1 (0.15 mmol), 2a (1.5 equiv), AgNO3 (0.2 equiv), oxidant (3.0
equiv), DMSO/H2O (1/1, 3.0 mL), 55 oC under N2 atmosphere, isolated yield
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10.1002/ejoc.201701248
European Journal of Organic Chemistry
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using a Laboratory Devices MEL-TEMP and were uncorrected/calibrated. TLC
analysis was performed using glass-backed plates (60 Å, 250 m) and visualized
using UV and KMnO4 stains. High-resolution mass spectra were obtained using
a Q-TOF micro spectrometer. All spectral data obtained for new compounds are
reported here.
to 18%. Unfortunately, the direct trap for the CF2 radical adduct
with TEMPO was unsuccessful due to its instability. However,
the hydrolyzed intermediate 5 of CF2 species was generated in
20% yield (Scheme 5, Eq. b). These results implied a free
radical intermediate was involved in the catalytic cycle.
Furthermore, the non- or mono-fluoroarylacetic acids 6 and 7
were used under the optimized reaction conditions and
corresponding oxindoles were not obtained. This phenomenon
indicated that the CF2 group of α,α-difluoroarylacetic acids
played a vital role in this transformation (Scheme 5, Eq. c).
General procedure for the silver-catalyzed synthesis of difluorinated
oxindoles: To
a Schlenck tube containing a magnetic stirrer bar was
successively added acrylamide 1 (0.15 mmol), α,α-difluoroaryl acetic acid 2
(0.23 mmol, 1.5 equiv), AgNO3 (5.1 mg, 0.03 mmol, 0.2 equiv) and K2S2O8
(121.5 mg, 0.45 mmol, 3.0 equiv). The tube was degassed by alternating vacuum
evacuation and backfilled with N2 for three times. Then DMSO (1.0 mL) and
Based on these observations and literature survey,[15]
a
o
H2O (2.0 mL) were added and the resulting mixture was stirred at 55 C for the
plausible catalytic cycle is depicted in Scheme 6. Initially, the
Ag(I) was oxidized by K2S2O8 to generate the Ag(II) complex,
which initiates the α,α-difluoroarylacetic acids in an SET process
reported time. The mixture was diluted with H2O (1.0 mL) and extracted with
EtOAc (3×3 mL), the combined organic layers were dried over Na2SO4, filtered
and concentrated under reduced pressure. The crude product was purified by
flash column chromatography (SiO2; gradient eluent: petroleum ether to 5%
EtOAc in petroleum ether or 5% acetone in petroleum ether) to provide the
desired product.
to afford the α,α-difluoroary radical
Subsequently, the radical addition of
I
and release CO2.
I with acrylamides
generated the intermediate II and the following intramolecular
radical cyclization gave the radical III. Further oxidation of
radical III by K2S2O8 or Ag(II) provided the species IV. Finally,
dehydrogenation of the resulting species IV could furnish the
product 3.
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-1,3-dimethylindolin-2-one (3a).
Reaction time: 3 h; yield: 41 mg, 72%, light yellow oil; Rf = 0.38 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.36 (s, 3H), 2.73 –
2.80 (m, 1H), 2.92 (s, 3H), 2.96 – 3.08 (m, 1H), 6.71 (d, J = 7.8 Hz, 1H), 7.02
(td, J = 0.6, 7.8 Hz, 1H), 7.10 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 7.2 Hz, 1H), 7.24
– 7.27 (m, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.43 – 7.45 (m, 4H), 7.53 – 7.54 (m,
2H); 19F NMR (564 MHz, CDCl3) δ -86.5 (ddd, J = 9.0, 18.0, 246.5 Hz, 1F), -
92.6 (dt, J = 18.0, 247.0 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 26.1, 26.4, 45.1
(d, J = 4.2 Hz), 45.7 (t, J = 27.9 Hz), 108.0, 121.6 (t, J = 242.1 Hz), 122.2, 124.1,
Scheme 6. Plausible Mechanism
125.7 (t, J = 5.9 Hz), 126.5, 127.1, 127.8, 128.0, 128.9, 131.7, 134.8 (t, J = 26.1
~
Hz), 140.3, 142.5, 143.0, 179.1. IR (KBr) ν = 3486, 1715, 1614, 1493, 1125,
843, 747 cm-1; HRMS (ESI): m/z calcd for C24H21F2NNaO (M+Na)+ 400.1489,
found 400.1488.
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-3-methyl-1-phenylindolin-2-
one (3b). Reaction time: 3 h; yield: 42 mg, 64%, light yellow oil; Rf = 0.42 (10%
acetone/petroleum Ether); 1H NMR (600 MHz, CDCl3) δ 1.50 (s, 3H), 2.80 –
2.88 (m, 1H), 3.13 – 3.21 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 7.03 (t, J = 7.2 Hz,
1H), 7.18 (t, J = 7.8 Hz, 1H), 7.21 – 7.26 (m, 5H), 7.33 – 7.38 (m, 2H), 7.40 –
7.48 (m, 6H), 7.53 (d, J = 7.2 Hz, 2H); 19F NMR (564 MHz, CDCl3) δ -88.7
(ddd, J = 11.3, 19.4, 247.6 Hz, 1F), -91.0 (dt, J = 16.9, 247.0 Hz, 1F); 13C NMR
(150 MHz, CDCl3) δ 27.0, 45.4, 46.1 (t, J = 27.8 Hz), 109.3, 121.8 (t, J = 243.0
Hz), 122.7, 124.3, 125.6 (t, J = 5.7 Hz), 126.5, 126.9, 127.2, 127.80, 127.82,
127.9, 128.9, 129.5, 131.6, 134.5, 135.3 (t, J = 25.8 Hz), 140.2, 142.7, 142.9,
~
178.7. IR (KBr) ν = 3647, 1721, 1613, 1476, 1033, 843, 764 cm-1; HRMS
(ESI): m/z calcd for C29H23F2NNaO (M+Na)+ 462.1645, found 462.1646.
Conclusions
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-1-benzyl-3-methylindolin-2-one
(3c). Reaction time: 3 h; yield: 40 mg, 59%, light yellow oil; Rf = 0.41 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.43 (s, 3H), 2.75 –
2.83 (m, 1H), 3.05 – 3.13 (m, 1H), 4.57 (d, J = 15.6 Hz, 1H), 4.82 (d, J = 15.6
Hz, 1H), 6.63 (d, J = 7.8 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.8 Hz,
1H), 7.16 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 2H), 7.22 – 7.30 (m, 5H), 7.37
– 7.39 (m, 1H), 7.44 – 7.47 (m, 4H), 7.55 (d, J = 7.2 Hz, 2H); 19F NMR (564
MHz, CDCl3) δ -90.4 (ddd, J = 11.8, 19.2, 245.9 Hz, 1F), -91.1 (dt, J = 15.5,
245.9 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 26.7, 43.8, 45.3, 45.8 (t, J = 27.6
Hz), 109.1, 121.7 (t, J = 245.7 Hz), 122.3, 124.0, 125.5 (t, J = 6.0 Hz), 126.7,
In conclusion, we have demonstrated a facile silver-catalyzed
decarboxylative
radical
addition/cyclization
of
α,α-
difluoroarylacetic acids with acrylamides, and a series of
difluorinated oxindoles with various functional groups were
synthesized in moderate to good yields under mild conditions.
The mechanism studies revealed that the CF2 group of α,α-
difluoroarylacetic acids played a vital role in this transformation
involving a free-radical pathway.
127.2, 127.3, 127.5, 127.8, 128.7, 128.9, 131.9, 135.3 (t, J = 26.9 Hz), 136.0,
~
140.3, 142.1, 142.6, 179.4. IR (KBr) ν = 3461, 1715, 1614, 1489, 1184, 843,
737 cm-1; HRMS (ESI): m/z calcd for C30H25F2NNaO (M+Na)+ 476.1802, found
476.1806.
Experimental Section
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-1,3,7-trimethylindolin-2-one
(3e). Reaction time: 3 h; yield: 30 mg, 51%, light yellow oil; Rf = 0.39 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.33 (s, 3H), 2.48 (s,
3H), 2.70 – 2.78 (m, 1H), 2.99 – 3.08 (m, 1H), 3.18 (s, 3H), 6.91 (t, J = 7.2 Hz,
1H), 6.98 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 7.11 (d, J = 7.8 Hz, 2H),
7.36 – 7.39 (m, 1H), 7.44 – 7.47 (m, 4H), 7.55 (d, J = 7.8 Hz, 2H); 19F NMR
(564 MHz, CDCl3) δ -85.6 (ddd, J = 8.5, 18.0, 246.5 Hz, 1F), -92.5 (dt, J = 18.0,
246.5 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 19.1, 26.7, 29.4, 44.4 (d, J = 4.4
Hz), 46.0 (t, J = 28.4 Hz), 119.5, 121.6 (t, J = 243.9 Hz), 122.0, 122.1, 125.8 (t,
General information: All reactions were performed in flame-dried glassware
under N2 unless otherwise noted. Solvents were distilled prior to use. Reagents
were used as purchased without further purification. Chromatographic
separations were performed using 48-75 Å SiO2. The 1H NMR spectra were
recorded at 600 MHz, 13C NMR spectra were recorded at 150 MHz, and 19F
NMR spectra were recorded at 564 MHz using CDCl3 or with TMS or residual
solvent as standard unless otherwise noted. Melting points were determined
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10.1002/ejoc.201701248
European Journal of Organic Chemistry
FULL PAPER
J = 6.0 Hz), 126.4, 127.1, 127.8, 128.9, 131.6, 132.2, 134.7 (t, J = 26.1 Hz),
Hz, 1F), -90.6 (dt, J = 16.9, 248.7 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 26.2,
26.3, 45.3, 45.7 (t, J = 28.4 Hz), 109.4, 115.0, 121.4 (t, J = 242.7 Hz), 125.5 (t, J
~
140.2, 140.8, 142.5, 179.8. IR (KBr) ν = 3471, 2361, 1710, 1639, 1402, 1075,
768 cm-1; HRMS (ESI): m/z calcd for C25H23F2NNaO (M+Na)+ 414.1645, found
414.1647.
= 6.0 Hz), 126.7, 127.2, 127.4, 127.8, 128.9, 130.8, 133.7, 134.7 (t, J = 24.5 Hz),
~
140.2, 142.1, 142.8, 178.5. IR (KBr) ν = 3455, 1711, 1608, 1491, 1120, 844,
767 cm-1; HRMS (ESI): m/z calcd for C24H20BrF2NNaO (M+Na)+ 478.0594,
found 478.0598.
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-1,3,4-trimethylindolin-2-one
(3f) ＆ 3-(2-([1,1'-biphenyl]-4-yl)-2,2-difluoroethyl)-1,3,6-trimethylindolin-2-
one (3f'). Reaction time: 3 h; yield: 28 mg, 49% (a mixture couldn’t be separated,
isomer ratio = 2:1), light yellow oil; Rf = 0.38 (10% acetone/petroleum ether); 1H
NMR (600 MHz, CDCl3) δ 1.34 (s, 3H), 1.40 (s, 6H), 2.38 (s, 9H), 2.70 – 2.78
(m, 1H), 2.85 (s, 6H), 2.92 (s, 3H), 2.96 – 3.12 (m, 5H), 6.56 (d, J = 8.4 Hz, 3H),
6.82 (d, J = 7.8 Hz, 2H), 6.84 (d, J = 7.8 Hz, 1H), 7.08 – 7.10 (m, 5H), 7.14 (d, J
= 7.8 Hz, 2H), 7.19 (t, J = 7.8 Hz, 2H), 7.37 (t, J = 7.2 Hz, 3H), 7.44 – 7.46 (m,
12H), 7.55 (d, J = 7.8 Hz, 6H); 19F NMR (564 MHz, CDCl3) δ -86.6 (ddd, J =
8.5, 17.5, 247.0 Hz, 2F), -86.9 (ddd, J = 9.0, 18.6, 246.5 Hz, 1F), -92.9 (dt, J =
18.0, 245.9 Hz, 1F), -96.0 (dt, J = 18.6, 247.0 Hz, 1F); 13C NMR (150 MHz,
CDCl3) δ 18.5, 21.8, 23.8, 26.07, 26.12, 26.4, 44.8 (t, J = 27.9 Hz), 45.6 (d, J =
4.8 Hz), 45.7, 105.7, 108.9, 119.5, 121.6 (t, J = 241.5 Hz), 122.8, 123.8, 124.9,
125.7 (t, J = 6.2 Hz), 125.8 (t, J = 5.9 Hz), 126.46, 126.53, 127.1, 127.76, 127.78,
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-7-iodo-1,3-dimethylindolin-2-
one (3k). Reaction time: 3 h; yield: 45 mg, 60%, light yellow oil; Rf = 0.38 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.33 (s, 3H), 2.71 –
2.78 (m, 1H), 3.01 – 3.10 (m, 1H), 3.24 (s, 3H), 6.73 (t, J = 7.8 Hz, 1H), 7.07 (d,
J = 7.8 Hz, 2H), 7.16 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.45 – 7.50 (m,
4H), 7.59 (d, J = 7.2 Hz, 2H), 7.67 (d, J = 7.8 Hz, 1H); 19F NMR (564 MHz,
CDCl3) δ -84.5 (ddd, J = 7.9, 16.4, 247.0 Hz, 1F), -92.3 (dt, J = 18.6, 247.6 Hz,
1F); 13C NMR (150 MHz, CDCl3) δ 26.7, 30.0, 44.6 (d, J = 5.1 Hz), 45.9 (t, J =
29.9 Hz), 71.5, 121.4 (t, J = 243.5 Hz), 123.9, 124.0, 125.8 (t, J = 5.7 Hz), 126.6,
127.2, 127.8, 128.9, 134.1 (t, J = 25.8 Hz), 134.6, 140.1, 140.6, 142.7, 143.3,
~
179.7. IR (KBr) ν = 3452, 2070, 1712, 1639, 1454, 1124, 768 cm-1; HRMS
(ESI): m/z calcd for C24H20F2INNaO (M+Na)+ 526.0455, found 526.0454.
127.9, 128.85, 128.89, 128.91, 134.5 (t, J = 26.1 Hz), 135.3, 138.1, 140.3, 142.5,
~
143.1, 143.3, 179.0, 179.4. IR (KBr) ν = 3646, 3119, 1715, 1609, 1470, 1065,
844, 765 cm-1; HRMS (ESI): m/z calcd for C25H23F2NNaO (M+Na)+ 414.1645,
found 414.1648.
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-1-methyl-3-phenylindolin-2-
one (3l). Reaction time: 5 h; yield: 35 mg, 50%, light yellow oil; Rf = 0.38 (10%
EtOAc/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 2.90 (s, 3H), 3.12 – 3.19
(m, 1H), 3.57 – 3.66 (m, 1H), 6.77 (d, J = 7.8 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H),
7.15 (d, J = 7.8 Hz, 2H), 7.22 – 7.28 (m, 3H), 7.32 – 7.39 (m, 5H), 7.44 – 7.47
(m, 4H), 7.55 (d, J = 7.2 Hz, 2H); 19F NMR (564 MHz, CDCl3) δ -85.1 (ddd, J =
9.0, 18.0, 247.0 Hz, 1F), -91.9 (dt, J = 17.5, 247.6 Hz, 1F); 13C NMR (150 MHz,
CDCl3) δ 26.4, 46.1 (t, J = 27.9 Hz), 52.8 (d, J = 4.2 Hz), 108.3, 121.5 (t, J =
244.1 Hz), 122.2, 125.8 (t, J = 5.9 Hz), 126.5, 126.6, 126.8, 127.1, 127.6, 127.8,
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-1,3,5-trimethylindolin-2-one
(3g). Reaction time: 3 h; yield: 23 mg, 39%, light yellow oil; Rf = 0.37 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.34 (s, 3H), 2.26 (s,
3H), 2.71 – 2.78 (m, 1H), 2.94 (s, 3H), 3.00 – 3.08 (m, 1H), 6.61 (t, J = 7.8 Hz,
1H), 6.93 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 7.10 (d, J = 7.8 Hz, 2H), 7.38 (t, J =
7.8 Hz, 1H), 7.42 – 7.46 (m, 4H), 7.54 (d, J = 7.2 Hz, 2H); 19F NMR (564 MHz,
CDCl3) δ -88.7 (ddd, J = 12.4, 15.8, 247.0 Hz, 1F), -90.5 (dt, J = 16.4, 247.0 Hz,
1F); 13C NMR (150 MHz, CDCl3) δ 21.1, 26.2, 26.4, 45.1, 45.7 (t, J = 28.2 Hz),
107.6, 121.6 (t, J = 242.7 Hz), 124.9, 125.6 (t, J = 6.0 Hz), 126.5, 127.1, 127.8,
128.6, 128.7, 128.9, 129.4, 134.8 (t, J = 26.6 Hz), 140.2, 140.3, 142.6, 144.1,
~
177.1. IR (KBr) ν = 3626, 2360, 1714, 1613, 1403, 1265, 1098, 739 cm-1;
HRMS (ESI): m/z calcd for C29H23F2NNaO (M+Na)+ 462.1645, found 462.1647.
128.1, 128.9, 131.6, 131.7, 134.9 (t, J = 26.4 Hz), 140.2, 140.7, 142.4, 179.0. IR
~
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-1-methyl-3-(p-tolyl)indolin-2-
one (3m). Reaction time: 5 h; yield: 31 mg, 45%, light yellow oil; Rf = 0.35
(10% EtOAc/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 2.27 (s, 3H), 2.88
(s, 3H), 3.10 – 3.17 (m, 1H), 3.55 – 3.64 (m, 1H), 6.76 (d, J = 7.8 Hz, 1H), 7.06
– 7.10 (m, 3H), 7.14 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.30 – 7.39 (m,
3H), 7.44 – 7.47 (m, 4H), 7.55 (d, J = 7.2 Hz, 2H); 19F NMR (564 MHz, CDCl3)
(KBr) ν = 3458, 1710, 1402, 1116, 804, 765 cm-1; HRMS (ESI): m/z calcd for
C25H23F2NNaO (M+Na)+ 414.1645, found 414.1655.
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-5-fluoro-1,3-dimethylindolin-2-
one (3h). Reaction time: 3 h; yield: 36 mg, 61%, light yellow oil; Rf = 0.35 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.36 (s, 3H), 2.72 –
2.75 (m, 1H), 2.95 (s, 3H), 2.97 – 3.05 (m, 1H), 6.64 (dd, J = 3.6, 7.8 Hz, 1H),
6.94 – 6.98 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 7.44 –
7.47 (m, 4H), 7.54 (d, J = 7.2 Hz, 2H); 19F NMR (564 MHz, CDCl3) δ -87.7
(ddd, J = 10.2, 18.6, 247.0 Hz, 1F), -92.4 (dt, J = 17.5, 247.0 Hz, 1F), -121.1 (s,
1F); 13C NMR (150 MHz, CDCl3) δ 26.2, 26.3, 45.6, 45.7 (t, J = 28.2 Hz), 108.3
(d, J = 8.0 Hz), 112.3 (d, J = 24.6 Hz), 114.2 (d, J = 23.6 Hz), 121.5 (t, J = 242.4
Hz), 125.6 (t, J = 6.3 Hz), 126.7, 127.2, 127.8, 128.9, 133.4 (d, J = 8.0 Hz),
δ -85.0 (ddd, J = 8.5, 17.5, 247.0 Hz, 1F), -91.9 (dt, J = 18.0, 247.0 Hz, 1F); 13
C
NMR (150 MHz, CDCl3) δ 20.9, 26.3, 46.0 (t, J = 29.1 Hz), 52.5, 108.2, 121.6 (t,
J = 244.2 Hz), 122.1, 125.8 (t, J = 5.9 Hz), 126.3, 126.6, 126.8, 127.1, 127.8,
128.5, 128.9, 129.4, 129.6, 134.8 (t, J = 26.4 Hz), 137.3, 137.4, 140.3, 142.5,
~
144.0, 177.3. IR (KBr) ν = 3056, 1715, 1612, 1494, 1096, 843, 741 cm-1; HRMS
(ESI): m/z calcd for C30H25F2NNaO (M+Na)+ 476.1802, found 476.1818.
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-3-(4-bromophenyl)-1-
134.7 (t, J = 26.1 Hz), 139.0, 140.2, 142.7, 159.2 (t, J = 239.1 Hz), 178.7. IR
~
methylindolin-2-one (3n). Reaction time: 5 h; yield: 26 mg, 33%, light yellow
oil; Rf = 0.36 (10% EtOAc/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 2.89
(s, 3H), 3.07 – 3.14 (m, 1H), 3.50 – 3.59 (m, 1H), 6.78 (d, J = 7.8 Hz, 1H), 7.10
– 7.14 (m, 3H), 7.20 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 7.8 Hz, 1H), 7.35 – 7.39 (m,
4H), 7.44 – 7.48 (m, 4H), 7.55 (d, J = 7.8 Hz, 2H); 19F NMR (564 MHz, CDCl3)
(KBr) ν = 3460, 1715, 1625, 1495, 1274, 1116, 738 cm-1; HRMS (ESI): m/z
calcd for C24H20F3NNaO (M+Na)+ 418.1395, found 418.1406.
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-5-chloro-1,3-dimethylindolin-
2-one (3i). Reaction time: 3 h; yield: 43 mg, 71%, white solid, mp: 139-142 oC;
Rf = 0.38 (10% acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.36 (s,
3H), 2.70 – 2.77 (m, 1H), 2.97 (s, 3H), 3.02 – 3.08 (m, 1H), 6.65 (d, J = 8.4 Hz,
1H), 7.11 (d, J = 1.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.22 (dd, J = 1.8, 8.4 Hz,
1H), 7.38 (t, J = 7.2 Hz, 1H), 7.44 – 7.47 (m, 4H), 7.54 – 7.56 (m, 2H); 19F
NMR (564 MHz, CDCl3) δ -89.1 (ddd, J = 11.3, 16.9, 247.6 Hz, 1F), -90.9 (dt, J
= 16.4, 247.6 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 26.2, 26.3, 45.3, 45.7 (t, J
= 28.4 Hz), 108.9, 121.4 (t, J = 243.0 Hz), 124.5, 125.6 (t, J = 6.2 Hz), 126.7,
δ -85.3 (ddd, J = 8.5, 18.0, 247.6 Hz, 1F), -91.9 (dt, J = 17.5, 247.0 Hz, 1F); 13
C
NMR (150 MHz, CDCl3) δ 26.4, 46.0 (t, J = 37.2 Hz), 52.4 (d, J = 4.2 Hz),
108.4, 121.4 (t, J = 243.0 Hz), 121.9, 122.3, 125.7 (t, J = 6.0 Hz), 126.6, 126.8,
127.1, 127.8, 128.3, 128.76, 128.82, 128.9, 131.7, 134.6 (t, J = 26.0 Hz), 139.2,
~
140.1, 142.6, 144.0, 176.7. IR (KBr) ν = 3457, 1717, 1614, 1489, 1402, 1096
cm-1; HRMS (ESI): m/z calcd for C29H22BrF2NNaO (M+Na)+ 540.0751, found
540.0766.
127.2, 127.7, 127.8, 127.9, 128.9, 133.4, 134.7 (t, J = 26.1 Hz), 140.2, 141.6,
~
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-7-methoxy-1-methyl-3-
142.8, 178.6. IR (KBr) ν = 3064, 1710, 1611, 1492, 1039, 845, 765 cm-1; HRMS
(ESI): m/z calcd for C24H20ClF2NNaO (M+Na)+ 434.1099, found 434.1114.
phenylindolin-2-one (3o). Reaction time: 5 h; yield: 30 mg, 43%, light yellow
oil; Rf = 0.37 (10% EtOAc/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 3.08
– 3.15 (m, 1H), 3.20 (s, 3H), , 3.55 – 3.63 (m, 1H), 3.86 (s, 3H), 6.89 – 6.92 (m,
2H), 7.02 (t, J = 7.8 Hz, 1H), 7.20 – 7.23 (m, 3H), 7.24 – 7.31 (m, 6H), 7.38 (t, J
= 7.2 Hz, 1H), 7.44 – 7.49 (m, 4H), 7.55 – 7.56 (m, 2H); 19F NMR (564 MHz,
CDCl3) δ -85.8 (ddd, J = 8.5, 18.6, 245.9 Hz, 1F), -91.7 (dt, J = 16.9, 246.5 Hz,
1F); 13C NMR (150 MHz, CDCl3) δ 29.7, 46.1 (t, J = 28.2 Hz), 52.8 (d, J = 4.2
Hz), 56.0, 112.1, 119.4, 121.6 (t, J = 244.8 Hz), 122.5, 125.8 (t, J = 6.2 Hz),
126.5, 126.6, 127.2, 127.5, 127.7, 128.6, 128.9, 131.1, 132.1, 135.0 (t, J = 26.0
3-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-5-bromo-1,3-dimethylindolin-
2-one (3j). Reaction time: 3 h; yield: 44 mg, 65%, light yellow oil; Rf = 0.34
(10% acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.36 (s, 3H), 2.69
– 2.77 (m, 1H), 2.97 (s, 3H), 3.00 – 3.11 (m, 1H), 6.61 (d, J = 8.4 Hz, 1H), 7.15
(d, J = 8.4 Hz, 2H), 7.24 (s, 1H), 7.35 – 7.39 (m, 2H), 7.44 – 7.45 (m, 4H), 7.55
– 7.56 (m, 2H); 19F NMR (564 MHz, CDCl3) δ -89.4 (ddd, J = 11.8, 17.5, 247.6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701248
European Journal of Organic Chemistry
FULL PAPER
~
~
Hz), 140.37, 140.42, 142.6, 145.4, 177.4. IR (KBr) ν = 3459, 1713, 1632, 1491,
1402, 1116, 842, 736 cm-1; HRMS (ESI): m/z calcd for C30H25F2NNaO2
(M+Na)+ 492.1751, found 492.1764
160.5, 179.1. IR (KBr) ν = 3473, 2360, 1713, 1614, 1494, 1253, 1125, 753 cm-1;
HRMS (ESI): m/z calcd for C19H19F2NNaO2 (M+Na)+ 354.1282, found 354.1284.
3-(2-(Benzo[d][1,3]dioxol-5-yl)-2,2-difluoroethyl)-1,3-dimethylindolin-2-one
(4e). Reaction time: 3 h; yield: 41 mg, 80%, light yellow oil; Rf = 0.35 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.34 (s, 3H), 2.64 –
2.72 (m, 1H), 3.86 – 2.97 (m, 1H), 3.05 (s, 3H), 5.93 (d, J = 5.4 Hz, 2H), 6.52 (d,
J = 1.2 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.67 (d, J = 8.4 Hz, 1H), 6.77 (d, J =
7.8 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.24 – 7.27 (m,
1H); 19F NMR (564 MHz, CDCl3) δ -87.0 (ddd, J = 10.7, 19.7, 244.8 Hz, 1F), -
90.8 (ddd, J = 15.8, 18.0, 244.8 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 26.2,
26.3, 45.1, 45.9 (t, J = 28.4 Hz), 101.4, 105.9 (t, J = 6.5 Hz), 107.6, 107.9, 119.2
1-(2-([1,1'-Biphenyl]-4-yl)-2,2-difluoroethyl)-1-methyl-5,6-dihydro-1H-
pyrrolo[3,2,1-ij]quinolin-2(4H)-one (3q). Reaction time: 5 h; yield: 30 mg,
50%, light yellow oil; Rf = 0.26 (10% EtOAc/petroleum ether); 1H NMR (600
MHz, CDCl3) δ 1.37 (s, 3H), 1.83 – 1.86 (m, 2H), 2.64 – 2.80 (m, 3H), 2.97 –
3.08 (m, 1H), 3.22 – 3.26 (m, 1H), 3.54 – 3.58 (m, 1H), 6.92 (t, J = 7.8 Hz, 1H),
7.01 (d, J = 7.2 Hz, 1H), 7.07 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 8.4 Hz, 2H), 7.37
(t, J = 7.2 Hz, 1H), 7.45 (t, J = 8.4 Hz, 4H), 7.54 (d, J = 7.2 Hz, 2H); 19F NMR
(564 MHz, CDCl3) δ -85.5 (ddd, J = 8.5, 18.6, 246.4 Hz, 1F), -93.0 (dt, J = 18.6,
246.5 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 20.1, 24.6, 26.1, 38.7, 45.5 (t, J =
27.6 Hz), 46.4 (d, J = 4.5 Hz), 119.9, 121.6 (t, J = 254.6 Hz), 121.7, 122.0, 125.8
(t, J = 6.9 Hz), 121.4 (t, J = 243.5 Hz), 122.2, 123.9, 127.9, 130.2 (t, J = 26.3
~
Hz), 131.9, 143.0, 147.2, 148.5, 179.1. IR (KBr) ν = 3458, 1713, 1611, 1491,
1120, 808, 754 cm-1; HRMS (ESI): m/z calcd for C19H17F2NNaO3 (M+Na)+
368.1074, found 368.1077.
(t, J = 6.0 Hz), 126.55, 126.62, 127.1, 127.8, 128.9, 130.4, 134.9 (t, J = 25.8 Hz),
~
138.7, 140.2, 142.4, 178.1. IR (KBr) ν = 3459, 3150, 2069, 1710, 1629, 1402,
1117, 767 cm-1; HRMS (ESI): m/z calcd for C26H23F2NNaO (M+Na)+ 426.1645,
found 426.1648.
3-(2,2-Difluoro-2-(naphthalen-1-yl)ethyl)-1,3-dimethylindolin-2-one
(4f).
Reaction time: 3 h; yield: 32 mg, 60%, light yellow solid, mp: 118-120 oC; Rf =
0.39 (10% acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.35 (s, 3H),
2.86 – 2.94 (m, 1H), 3.07 (s, 3H), 3.24 – 3.35 (m, 1H), 6.78 (d, J = 7.8 Hz, 1H),
6.97 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.22 –
7.27 (m, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.60 (t, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8
Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 8.19 (d, J = 9.0 Hz, 1H); 19F NMR (564 MHz,
CDCl3) δ -87.8 – -88.8 (m, 2F); 13C NMR (150 MHz, CDCl3) δ 26.2, 26.3, 45.3,
45.4 (t, J = 26.3 Hz), 108.0, 122.2, 122.3 (t, J = 244.2 Hz), 123.6, 123.8 (t, J =
3-(2,2-Difluoro-2-(2-methoxyphenyl)ethyl)-1,3-dimethylindolin-2-one (4a).
Reaction time: 2 h; yield: 22 mg, 45%, light yellow solid, mp: 80-82 oC; Rf =
0.33 (10% acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.33 (s, 3H),
2.83 – 2.91 (m, 1H), 2.86 (s, 3H), 3.18 – 3.27 (m, 1H), 3.88 (s, 3H), 6.62 – 6.68
(m, 3H), 6.81 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 8.4 Hz, 1H), 7.15 – 7.20 (m, 2H),
7.24 (td, J = 1.2, 8.4 Hz, 1H); 19F NMR (564 MHz, CDCl3) δ -86.2 (dt, J = 13.0,
251.0 Hz, 1F), -89.8 (ddd, J = 15.8, 20.9, 251.0 Hz, 1F); 13C NMR (150 MHz,
CDCl3) δ 26.0, 26.3, 43.1 (t, J = 27.0 Hz), 45.7 (d, J = 5.9 Hz), 55.7, 107.7,
111.2, 119.5, 120.8 (t, J = 242.4 Hz), 121.9, 123.4 (t, J = 24.8 Hz), 123.9 (t, J =
9.6 Hz), 124.2, 124.7 (t, J = 3.5 Hz), 125.9, 127.0, 127.9, 128.8, 129.3, 130.9,
~
131.8 (t, J = 24.0 Hz), 132.0, 133.9, 143.0, 179.1. IR (KBr) ν = 3502, 1714,
1614, 1494, 1253, 1125, 754 cm-1; HRMS (ESI): m/z calcd for C22H19F2NNaO
(M+Na)+ 374.1332, found 374.1334.
3.0 Hz), 126.2 (t, J = 7.7 Hz), 127.7, 131.3, 132.0, 142.9, 157.0, 178.9. IR (KBr)
~
ν = 3472, 2971, 1717, 1614, 1494, 1254, 1040, 754 cm-1; HRMS (ESI): m/z
calcd for C19H19F2NNaO2 (M+Na)+ 354.1282, found 354.1280.
3-(2,2-Difluoro-2-(thiophen-2-yl)ethyl)-1,3-dimethylindolin-2-one
(4g).
3-(2,2-Difluoro-2-(3-methoxyphenyl)ethyl)-1,3-dimethylindolin-2-one (4b).
Reaction time: 2 h; yield: 23 mg, 46%, light yellow oil; Rf = 0.35 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.35 (s, 3H), 2.68 –
2.75 (m, 1H), 2.93 – 3.03 (m, 1H), 2.99 (s, 3H), 3.72 (s, 3H), 6.55 (s, 1H), 6.72
(d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 6.84 (dd, J = 1.8, 7.8 Hz, 1H), 7.03
(t, J = 7.8 Hz, 1H), 7.17 (t, J = 8.4 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.25 – 7.27
(m, 1H); 19F NMR (564 MHz, CDCl3) δ -87.3 (ddd, J = 9.6, 19.7, 245.9 Hz, 1F),
-93.0 (dt, J = 18.6, 245.9 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 26.1, 26.3,
45.1 (d, J = 3.8 Hz), 45.6 (t, J = 27.8 Hz), 55.2, 107.9, 110.0 (t, J = 13.5 Hz),
Reaction time: 5 h; yield: 16 mg, 35%, light yellow oil; Rf = 0.39 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.39 (s, 3H), 2.78 –
2.85 (m, 1H), 3.01 – 3.09 (m, 1H), 3.10 (s, 3H), 6.79 (d, J = 7.8 Hz, 1H), 6.89 –
6.92 (m, 2H), 7.03 (td, J = 1.2, 7.2 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.25 – 7.28
(m, 2H); 19F NMR (564 MHz, CDCl3) δ -78.4 (ddd, J = 10.2, 20.9, 260.6 Hz,
1F), -81.5 (ddd, J = 12.4, 19.7, 254.4 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ
26.0, 26.3, 45.2, 45.9 (t, J = 27.2 Hz), 108.0, 119.9 (t, J = 240.8 Hz), 122.3,
123.9, 126.4 (t, J = 5.7 Hz), 126.6, 127.0, 128.0, 131.8, 138.6 (t, J = 30.8 Hz),
~
143.0, 179.2. IR (KBr) ν = 3119, 1716, 1614, 1401, 1169, 1126, 753 cm-1;
HRMS (ESI): m/z calcd for C16H15F2NNaOS (M+Na)+ 330.0740, found
330.0740.
115.9, 117.5 (t, J = 6.3 Hz), 121.4 (t, J = 242.6 Hz), 122.2, 124.0, 127.9, 129.1,
~
131.8, 137.5 (t, J = 23.7 Hz), 143.0, 159.1, 179.1. IR (KBr) ν = 3472, 3141,
2068, 1715, 1614, 1493, 1125, 753 cm-1; HRMS (ESI): m/z calcd for
C19H19F2NNaO2 (M+Na)+ 354.1282, found 354.1282.
Acknowledgements
3-(2-(2,4-Dimethoxyphenyl)-2,2-difluoroethyl)-1,3-dimethylindolin-2-one
(4c). Reaction time: 2 h; yield: 30 mg, 56%, light yellow solid, mp: 100-102 oC;
Rf = 0.37 (10% acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.32 (s,
3H), 2.82 – 2.87 (m, 1H), 2.89 (s, 3H), 3.15 – 3.23 (m, 1H), 3.76 (s, 3H), 3.84 (s,
3H), 6.14 (dd, J = 2.4, 9.0 Hz, 1H), 6.34 (s, 1H), 6.57 (d, J = 9.0 Hz, 1H), 6.63
(d, J = 7.2 Hz, 1H), 6.97 (t, J = 7.2 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 7.19 (d, J
= 7.8 Hz, 1H); 19F NMR (564 MHz, CDCl3) δ -84.7 (dt, J = 13.0, 249.3 Hz, 1F),
-92.0 (ddd, J = 16.4, 20.3, 249.3 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 26.0,
26.2, 43.3 (t, J = 27.9 Hz), 45.2 (d, J = 3.9 Hz), 55.4, 55.6, 98.6, 103.4, 107.7,
This work is financially supported by the Scientific Research
Foundation for the Returned Overseas Chinese Scholars, State
Education Ministry, and the National Natural Science Foundation
of China (Grant No. 21572154).
116.2 (t, J = 25.2 Hz), 120.9 (t, J = 242.1 Hz), 121.9, 123.9, 127.2 (dd, J = 7.8,
Keywords:
Silver-catalyzed
•
decarboxylative
radical
~
9.6 Hz), 127.7, 132.1, 142.9, 158.3, 162.1, 178.9. IR (KBr) ν = 3459, 2967,
1714, 1614, 1494, 1145, 767 cm-1; HRMS (ESI): m/z calcd for C20H21F2NNaO3
(M+Na)+ 384.1387, found 384.13890.
addition/cyclization •α,α-difluoroarylacetic acids • difluorinated
oxindoles
3-(2,2-Difluoro-2-(4-methoxyphenyl)ethyl)-1,3-dimethylindolin-2-one (4d).
Reaction time: 2 h; yield: 24 mg, 48%, light yellow oil; Rf = 0.34 (10%
acetone/petroleum ether); 1H NMR (600 MHz, CDCl3) δ 1.34 (s, 3H), 2.67 –
2.75 (m, 1H), 2.98 – 3.01 (m, 4H), 3.78 (s, 3H), 6.73 – 6.75 (m, 3H), 6.99 (d, J =
8.4 Hz, 2H), 7.04 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.25 – 7.27 (m,
1H); 19F NMR (564 MHz, CDCl3) δ -85.0 (ddd, J = 8.5, 19.2, 245.3 Hz, 1F), -
92.0 (dt, J = 18.6, 245.3 Hz, 1F); 13C NMR (150 MHz, CDCl3) δ 26.1, 26.3, 45.1
(d, J = 4.1 Hz), 45.8 (t, J = 29.0 Hz), 55.3, 107.9, 113.2, 121.7 (t, J = 242.1 Hz),
122.2, 124.1, 126.7 (t, J = 6.0 Hz), 127.9, 128.3 (t, J = 26.6 Hz), 131.9, 143.0,
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Entry for the Table of Contents (Please choose one layout)
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Difluorinated oxindoles*
Yin-Long Li, Ji-Bo Wang, Xue-Lin Wang,
Yang Cao, Jun Deng *
Page No. – Page No.
Silver-Catalyzed
Decarboxylative
Text for Table of Contents
Radical Addition/Cyclization of α,α-
Difluoroarylacetic
Acrylamides
Acids
with
to
Synthesize
Difluorinated Oxindoles
A series of difluorinated oxindoles with various functional groups has been synthesized by silver-catalyzed decarboxylative
radical addition/cyclization of α,α-difluoroarylacetic acids with acrylamides. The mechanism studies revealed that a free-
radical pathway was involed in this transformation and CF2 group of α,α-difluoroarylacetic acids played a vital role.
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