Transition-Metal-Free Fluoroarylation of Diazoacetamides: A Complementary Approach to 3-Fluorooxindoles

Article abstract of DOI:10.1021/acs.joc.6b01286

An efficient transition-metal-free fluoroarylation reaction of N-aryl diazoacetamides with NFSI (N-fluorobenzenesulfonimide) is described. This reaction directly provides 3-fluorooxindole derivatives in yields of 67-93% with high selectivity via a carbene

Full text of DOI:10.1021/acs.joc.6b01286

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Note
Transition Metal-Free Fluoroarylation of Diazoacetamides:
A Complementary Approach to 3-Fluorooxindoles
Kuiyong Dong, Bin Yan, Sailan Chang, Yongjian Chi, Lihua Qiu, and Xinfang Xu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01286 • Publication Date (Web): 01 Jul 2016
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Transition Metal-Free Fluoroarylation of Diazoacetamides: A
Complementary Approach to 3-Fluorooxindoles
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Kuiyong Dong,† Bin Yan, ‡ Sailan Chang,† Yongjian Chi,† Lihua Qiu,*,† and Xinfang
Xu*,†
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† Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science, Soochow University, Suzhou 215123, China
Email: xinfangxu@suda.edu.cn; qiulihua@suda.edu.cn
‡ Jinghua Anti-cancer Pharmaceutical Engineering Center, Nantong 226407, China
F
R1
O
No cat.
R2 NFSI, Base
DCE, 80 oC
R1
N
R
O
N
N2 Ar
R2
1
2
Mild conditions
T ransition-Metal-free
Carbene-free pathway
Broad substrate scope
ABSTRACT: An efficient transition metal-free fluoroarylation reaction of N-aryl
diazoacetamides with NFSI (N-Fluorobenzenesulfonimide) is described. This reaction
directly provides 3-fluorooxindole derivatives in yields of 67%~93% with high
selectivity via a carbene-free process under mild reaction conditions.
Incorporation of fluorous functionalities into molecules is useful to modify the
physical, chemical, and biological properties, which are pervasive in pharmaceuticals,
agrochemicals, and material sciences.1 Consequently, various efficient and direct
fluorination approaches have been reported,2 including palladium-catalyzed
alkylaminofluorination disclosed by Hartwig;3 alkene difunctionalization reported by
Li and Rueping individually, such as aminofluorination,4 phosphonofluorination,5
azidofluorination,6 and carbofluorination;7 and more recently, a DBU-mediated
deoxyfluorination of alcohols reported by Doyle and co-workers.8 Among these
fluorination methods, access to substituted oxindolefluorides, which are prevalent
motifs in natural products and bio-active molecules, have attracted much attention;9
and it was also found that fluorine atom at the 3-position of the oxindole ring played a
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key role for enhancing the bioactivity (Figure 1).10 For example, compound A (BMS
204352) is a promising agent for the treatment of stroke;11a compound B was reported
as a potent and selective EP3 receptor antagonist;11b compound C was tested as
inhibitor of caspases-3 and -7 in apoptosis;11c and compound D showed potent
therapeutic effect to CB2-mediated disorders.11d
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F
Cl
F
MeO
O
F
N
O
S
N
Cl
F
O
F3C
H
S
Cl
A
B
O
N
O
H
O
tBu
O
F
F
O
S
N
O
S
O
N
NMe2
N
O
Pr
MeO
C
D
F
Figure 1. Examples of bioactive 3-fluorooxindole derivatives.
The reported works for the synthesis of these 3-fluorooxindole frameworks mostly
rely on the further decoration of the existing 3-substituted oxindoles via a nucleophilic
addition with fluoride reagent. Clearly, the diversity of these methods would be
restricted to the existing oxindole derivatives (Scheme 1a).12 Recently, attention has
been attracted to the fluorination transformation with diazo compounds, which are
versatile intermediates in organic synthesis and have commonly been employed as
carbene precursors in transition-metal-catalyzed reactions.13 In this context, the
research groups of Hu,14 Davies15 and others16 have intensively investigated the
diverse fluorination reactions with different diazo compounds (Scheme 1b). It is
known that the diazo compounds are amphiphilic reagents as the carbon atom bearing
the diazo group is thus nucleophilic.17 Based on this knowledge and inspired by these
works, herein we wish to report a novel fluorination process of N-aryl
diazoacetamides with NFSI (N-Fluorobenzenesulfonimide) under catalyst-free
conditions to give the 3-fluorooxindoles in high to excellent yields via a carbene-free
pathway (Scheme 1c).
Scheme 1. Approaches for the 3-Fluorooxindoles
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Initially, the reaction of diazoacetamide (1a) with NFSI was carried out in DCE
at 80 ℃ (Table 1). Interestingly, when the reaction was carried out in the absence of
the catalyst, it gave the fluorinated product in 53% yield (entry 1) although long
reaction time was needed. When Na2CO3 (1.5 eq) was applied, we envisioned that the
base could promote the transformation,18 and fortunately, the yield of 2a was
significantly improved to 72% (entry 2). With this result in hand, several bases were
investigated, and NaOAc was determined to be the best with DCE as the solvent
(entries 3-6). Various solvents were screened (entries 7-13), and only inferior results
were obtained. The fluorine source was also crucial for this transformation, as using
SelectFluor instead of NFSI only gave 32% yield (entry 14). Under the optimized
conditions, the reaction could be carried out on gram-scale and the desired product 2a
was obtained in good yield (entry 15, 74% yields). Control reactions in the presence
of Cu(hfacac)2 or Rh2(OAc)4 were carried out, intramolecular aromatic substitution
product 3 was obtained via carbene reaction in 63% and 81% yields respectively, and
only 18% of desired product 2a was obtained in the case of copper catalyst (entry 17).
Table 1. Optimization of Reaction Conditionsa
entrybase
solvent time (h) 2a (%)b
-
1
2
3
4
DCE
16
4
3
53
72
57
53
Na2CO3 DCE
K2CO3 DCE
NaHCO3DCE
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K3PO4 DCE
NaOAc DCE
NaOAc Toluene 4
NaOAc DCM
NaOAc CHCl3
8
5
65
81
49
73
65
41
74
69
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32
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10 NaOAc THF
11 NaOAc TBME
12 NaOAc PhCl
13 NaOAc Dioxane 5
14c NaOAc DCE
15 d NaOAc DCE
DCE
12
5
5
1
16e
17f
-
-
DCE
aTo the reaction mixture of the base（0.3 mmol）and NFSI (0.3 mmol) in 1.0 mL of
solvent, the solution of 1a (0.2 mmol) in 1.0 mL of solvent was added via a syringe in
30 min. Isolated yield after chromatography. cUsing SelectFluor as the fluorine source.
b
dThe reaction was carried out on 6.0 mmol scale. eCu(hfacac)2 (5.0 mol%) was used as
the catalyst and the major product is 3. fRh2(OAc)4 (1.0 mol%) was used as the catalyst.
With the optimized reaction conditions established, we evaluated the substrate
scope of this protocol. As depicted in Scheme 2, the reaction exhibited a broad
substrate generality, readily affording a variety of different 3-fluorooxindoles in good
to high yields. Diazo compounds with electron-rich and deficient substitutions were
uniformly fluorinated in 76-84% yield within a few hours (2a-2e). The
diazoacetamides with para- or meta- and ortho-position substitutions on the aryl
group had little effect, and all led to the corresponding products in comparable yields
(2e-2g). Moreover, to extensively explore the substrates scope, diazoacetamides 1
with various R2 groups were investigated and they all gave high yields (2g-2r,
72~93% yields). It should be noted that the reaction was highly selective，and
diversified substitutions or functional groups were tolerated under this catalyst-free
conditions. Compounds with benzyl (2i-2o, > 75% yields), propargyl (2p, 82% yield),
ether (2q, 88% yield) and allyl groups (2r, 72% yield), were all untouched in this
process. -Substituted diazoacetamides 1 also performed well under these conditions,
and the reaction of substrate 1s can even occur at room temperature (2s, 67% yield)
while higher reaction temperature was required to acquire 3-fluorooxindoles 2t and
2u.
Scheme 2. Substrate Scope
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N2 R2
F
R3
NFSI (1.5 equiv)
NaOAc (1.5 equiv)
N
R3
R1
O
O
R1
N
R2
DCE 80 oC
O
7
1
2a
8
9
F
F
F
MeO
F3C
O
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O
N
N
N
Me
2a, 5 h, 81%
Me
Me
2b, 3 h, 80%
2c, 5 h, 80%
F
F
F
Br
Cl
O
O
O
O
N
N
N
Me
Br
2f, 4 h, 84%
Me
Me
2d, 5 h, 84%
2e, 4 h, 76%
F
F
F
O
N
O
N
N
Br
R2
Me
X
2h, R2 = Et, 3 h, 92%
2i, R2 = Ph, 3 h, 93%
2j, R2 = Bn, 6 h, 81% 2m
2k, X=Br, 5 h, 75%
2l, X=Cl, 4h, 78%
2g, 5h, 77%
, X=NO2, 7 h, 84%
F
F
F
O
N
O
O
N
N
O
O
2p, 3 h,82%
2o, 4 h, 86%
2n, 5 h, 89%
R3
F
F
F
O
N
O
O
N
N
Me
2s, R3 = Me, 8 h, 67%c
2t, R3 = Ts, 12 h, 81%d
2u, R3 = Ph, 12 h, 86%d
MeO
Ph
2q, 3 h, 88%
2r, 6 h, 72%
aReactions were carried out on a 0.2 mmol scale in 2.0 mL DCE at 80 oC. bTo
the reaction mixture of the NaOAc (0.3 mmol) and NFSI (0.3 mmol) in 1.0 mL
DCE, 1a (0.2 mmol) in 1.0 mL DCE was added via a syringe in 30 min.
cReaction was carried out at rt. dReaction was carried out at 90 o
C
To gain insight into the mechanism details, few control reactions were carried out.
Reaction pathway of carbene intermediate was first excluded, cause no metal catalyst
was used in this reaction, and the carbene transformation would prefer leading to the
non-fluorinated product (Table 1, entries 16 and 17); the other control reaction in the
absence of NFSI turned out slowly decomposition of the material to give 3a (Eq 1).
The possibility via intermediate 3 could be ruled out, no fluorination product was
detected under the standard conditions with 3 (Eq 2). Photolysis was also not the case
since it gave the same results when the reaction was carried out in dark under the
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same condition (Eq 3). It was also not the pathway to form the 3-halogenated
oxindoles via -halogenation of diazoacetamides 1 and followed by aromatic
substitution, since all the ,-disubstitute diazoacetamides (1s-1u), which couldn’t go
through this pathway all performed well under these conditions. Another Based on
these observations, we proposed our reaction pathway (Scheme 1C). Initially, the
nucleophilic carbon on the diazo group17 was attacked by the F electrophile, followed
by intramolecular addition with the aryl group, and releasing a molecule of N2
synchronously to give the final ring-closed products.
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In summary, we have developed a novel catalyst-free fluorination reaction for the
synthesis of 3-fluorooxindoles with diazo compounds and NFSI under mild
conditions.27 The reaction showed high selectivity and broad substrate scope to give a
variety of 3-fluorooxindoles in moderate to good yields. The mechanistic studies
suggested that a carbene-free process fluorination pathway was involved. Under these
conditions, many functional groups are all untouched in this process.
EXPERIMENTAL SECTION
General. All reactions were carried out under an atmosphere of nitrogen using
oven-dried glassware. DCM, DCE and toluene were distilled prior to use and kept
over activated 4 Å molecular sieves. TBME (tert-butyl methyl ether) and CHCl3 were
purchased from chemical company and used without further treatment. 1H NMR (400
MHz), 19F (376 M Hz) and 13C NMR (100 MHz) were recorded on a NMR
spectrometer with CDCl3 as solvent. Chemical shifts of 1H, 19F and 13C NMR spectra
were reported in ppm with the solvent signals as reference, and F NMR spectra were
not proton decoupled. All coupling constants (J values) were reported in Hertz (Hz).
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The peak information is described as: singlet(s), doublet (d), doublet of doublets (dd),
triplet (t), quartet (q), multiplet (m) and composite (comp, for the overlapped signals).
Column chromatography was performed on silica gel 300-400 mesh. High-resolution
mass spectra (HRMS) were recorded on a LC-TOF spectrometer using electrospray
ionization (ESI) techniques.
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General Procedure for the Preparation of Diazoacetamides 1 (1a~1r).20 To a
50-mL oven-dried flask with a magnetic stirring bar, substituted amines (3.8 mmol)
and DIPEA (N,N-Diisopropylethylamine, 0.66 mL, 3.8 mmol) were dissolved in dry
DCM (20.0 mL), and bromoacetyl bromide (0.34 mL, 3.8 mmol) was added slowly at
o
0 C, then the reaction mixture was stirred at room temperature for 2-12 h. After the
reaction was completed, DCM was removed under reduced pressure. The obtained
crude 2-bromo-acetamides were directly used for the next step without further
purification. The crude 2-bromo-acetamides and N,N'-ditosylhydrazine (3.2 g, 9.5
mmol) were dissolved in THF (20.0 mL), DBU (1,8-Diazabicyclo[5.4.0]undec-7-ene,
o
2.7 mL, 18.0 mmol) was added slowly over 5 min at 0 C, and the reaction mixture
was stirred for 10-60 minutes until no more gas was generated from the reaction
mixture. The reaction was quenched with saturated NaHCO3 solution (30.0 mL), and
the aqueous phase was extracted with ethyl acetate (20.0 mL×3). The combined
organic phase was dried with anhydrous Na2SO4, the crude product was purified by
column chromatography on silica gel (petroleum ether : ethyl acetate = 10:1 to 2:1) to
give the pure diazoacetamides 1.
Diazoacetamides 1s,21 1t22 and 1u23 were prepared according to the reported
references, and the characteristic data are consistent with the reported references.
General Procedure for the Synthesis of 2. To a 10-mL oven-dried vial with a
magnetic stirring bar, NaOAc (24.6 mg, 0.3 mmol), NFSI (94.6 mg, 0.3 mol) and
anhydrous DCE (1.0 mL), diazoacetamides 1 (0.2 mmol) in anhydrous DCE (1.0 mL)
was added to the mixture under argon at 80 oC over 30 min via a syringe pump. After
the diazo compound was consumed (monitored by thin layer chromatography), the
resulting mixture was cooled to room temperature, and the crude reaction mixture was
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purified by flash column chromatography on silica gel (petroleum ether : ethyl acetate
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= 20:1 to 10:1) to give the pure products 2 in moderate to high yields.
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3-Fluoro-1-methylindolin-2-one (2a).24 White solid, 26.7 mg, 81% yield (in 6.0 mmol
scale: 732.6 mg, 74% yield); mp 63.2-64.3 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm)
7.46 (dd, J = 7.3, 0.7 Hz, 1H), 7.40 (t, J = 7.8 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H), 6.83
(d, J = 7.9 Hz, 1H), 5.66 (d, JH-F = 51.0 Hz, 1H), 3.19 (s, 3H); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 171.2 (d, J = 18.2 Hz), 144.8 (d, J = 5.3 Hz), 131.6 (d, J = 3.3 Hz),
126.1 (d, J = 1.2 Hz), 123.4 (d, J = 2.9 Hz), 122.8 (d, J = 16.2 Hz), 108.9 (d, J = 1.3
Hz), 85.6 (d, J = 188.2 Hz), 26.3; 19F NMR (376 MHz, CDCl3) (δ, ppm) -194.0 (d,
JH-F = 51.0 Hz) HRMS (ESI) calculated for C9H8FNNaO [M+Na]+: 188.0488, found
188.0488.
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3-Fluoro-5-methoxy-1-methylindolin-2-one (2b). White solid, 31.1 mg, 80% yield; mp
81.9-83.3 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.08 (t, J = 1.8 Hz, 1H), 6.92 (dt,
J = 8.5, 2.2 Hz, 1H), 6.74 (dd, J = 8.5, 1.1 Hz, 1H), 5.64 (d, JH-F = 50.9 Hz, 1H), 3.80
(s, 3H), 3.17 (s, 3H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 170.9 (d, J = 18.2 Hz),
156.5 (d, J = 3.0 Hz), 138.1 (d, J = 5.2 Hz), 123.9 (d, J = 16.0 Hz), 116.0 (d, J = 3.2
Hz), 113.1 (d, J = 1.0 Hz), 109.4 (d, J = 1.2 Hz), 85.8 (d, J = 188.9 Hz), 56.0, 26.4;
19F NMR (376 MHz, CDCl3) (δ, ppm) -193.5 (d, JH-F = 50.9 Hz). HRMS (ESI)
calculated for C10H10FNNaO2 [M+Na]+: 218.0593, found 218.0585.
3-Fluoro-1-methyl-5-(trifluoromethyl)indolin-2-one (2c). Yellow solid, 37.1 mg, 80%
yield; mp 105.5-106.7 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.73 - 7.65 (m, 2H),
6.93 (d, J = 8.1 Hz, 1H), 5.70 (d, JH-F = 50.7 Hz, 1H), 3.22 (s, 3H); 13C NMR (100
MHz, CDCl3) (δ, ppm) 171.0 (d, J = 18.1 Hz), 147.8 (d, J = 4.1 Hz), 129.4 - 129.1
(m,1C), 125.8 (qd, J = 33.2, 2.9 Hz), 124.0 (q, J = 271.6 Hz), 123.5 - 123.3 (m, 1C),
123.2, 108.8 (d, J = 1.0 Hz), 84.7 (d, J = 190.5 Hz), 26.6; 19F NMR (376 MHz, CDCl3)
(δ, ppm) -61.9 (s), -194.5 (d, JH-F = 50.7 Hz). HRMS (ESI) calculated for
C10H7F4NNaO [M+Na]+: 256.0361, found 256.0364.
5-Chloro-3-fluoro-1-methylindolin-2-one (2d). White solid, 33.5 mg, 84% yield; mp
1
114.7-115.2 oC; H NMR (400 MHz, CDCl3) (δ, ppm) 7.44 (s, 1H), 7.37 (dt, J = 8.3,
1.8 Hz, 1H), 6.76 (dd, J = 8.3, 1.1 Hz, 1H), 5.64 (d, JH-F = 50.7 Hz, 1H), 3.17 (s, 3H);
13C NMR (100 MHz, CDCl3) (δ, ppm) 170.7 (d, J = 18.1 Hz), 143.3 (d, J = 5.0 Hz),
131.5 (d, J = 3.1 Hz), 128.9 (d, J = 3.3 Hz), 126.6 (d, J = 1.1 Hz), 124.3 (d, J = 16.2
Hz), 109.9 (d, J = 1.2 Hz), 85.1 (d, J = 190.3 Hz), 26.5; 19F NMR (376 MHz, CDCl3)
(δ, ppm) -193.5 (d, JH-F = 50.7 Hz). HRMS (ESI) calculated for C9H7ClFNNaO
[M+Na]+: 222.0098, found 222.0089.
5-Bromo-3-fluoro-1-methylindolin-2-one (2e). White solid, 34.1 mg, 76% yield; mp
107.9-108.9 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.58 - 7.54 (m, 1H), 7.54 - 7.46
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(m, 1H), 6.71 (d, J = 8.3 Hz, 1H), 5.63 (d, JH-F = 50.7 Hz, 1H), 3.16 (s, 3H);13C NMR
(100 MHz, CDCl3) (δ, ppm) 170.5 (d, J = 18.1 Hz), 143.8 (d, J = 5.0 Hz), 134.3 (d, J
= 3.1 Hz), 129.3, 124.6 (d, J = 16.2 Hz), 115.9 (d, J = 3.3 Hz), 110.4, 85.0 (d, J =
190.4 Hz), 26.4; 19F NMR (376 MHz, CDCl3) (δ, ppm) -193.9 (d, JH-F = 50.7 Hz).
HRMS (ESI) calculated for C9H7BrFNNaO [M+Na]+: 265.9593, found 265.9590.
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7-Bromo-3-fluoro-1-methylindolin-2-one (2f). White solid, 37.6 mg, 84% yield; mp
110.3-111.4 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.54 - 7.47 (m, 1H), 7.45 - 7.35
(m, 1H), 7.03 - 6.93 (m, 1H), 5.63 (d, JH-F = 51.0 Hz, 1H), 3.57 (s, 3H); 13C NMR
(100 MHz, CDCl3) (δ, ppm) 171.5 (d, J = 17.5 Hz), 142.1 (d, J = 5.0 Hz), 137.1 (d, J
= 3.3 Hz), 125.8 (d, J = 16.0 Hz), 125.3 (d, J = 1.3 Hz), 124.6 (d, J = 2.9 Hz), 103.1
(d, J = 1.3 Hz), 84.8 (d, J = 188.7 Hz), 30.0; 19F NMR (376 MHz, CDCl3) (δ, ppm)
-192.2 (d, JH-F = 51.0 Hz); HRMS (ESI) calculated for C9H7BrFNNaO [M+Na]+:
265.9593, found 265.9588.
6-Bromo-3-fluoro-1-methylindolin-2-one (2g). Yellow solid, 34.5 mg, 77% yield; mp
113.3-115.1 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.32 (dd, J = 7.9, 1.3 Hz, 1H),
7.26 (d, J = 6.2 Hz, 1H), 7.00 (s, 1H), 5.61 (d, JH-F = 50.9 Hz, 1H), 3.18 (s, 3H); 13C
NMR (100 MHz, CDCl3) (δ, ppm) 171.0 (d, J = 18.1 Hz), 146.1 (d, J = 5.1 Hz), 127.4
(d, J = 1.0 Hz), 126.3 (d, J = 2.8 Hz), 125.5 (d, J = 4.0 Hz), 121.7 (d, J = 16.6 Hz),
112.6 (d, J = 1.3 Hz), 85.0 (d, J = 189.5 Hz), 26.5; 19F NMR (376 MHz, CDCl3) (δ,
ppm) -193.3 (d, JH-F = 50.9 Hz); HRMS (ESI) calculated for C9H7BrFNNaO [M+Na]+:
265.9593, found 265.9591.
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1-Ethyl-3-fluoroindolin-2-one (2h). Colorless oil, 33.1 mg, 92% yield; H NMR (400
MHz, CDCl3) (δ, ppm) 7.46 (dd, J = 7.4, 0.6 Hz, 1H), 7.38 (dd, J = 11.1, 4.5 Hz, 1H),
7.09 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 5.64 (d, JH-F = 51.1 Hz, 1H), 3.72
(qd, J = 7.2, 0.9 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H);13C NMR (100 MHz, CDCl3) (δ,
ppm) 170.3 (d, J = 18.0 Hz), 143.4 (d, J = 5.2 Hz), 130.9 (d, J = 3.3 Hz), 125.7 (d, J =
1.1 Hz), 122.6 (d, J = 2.8 Hz), 122.4, 108.4 (d, J = 1.3 Hz), 85.1 (d, J = 188.0 Hz),
34.3, 11.9; 19F NMR (376 MHz, CDCl3) (δ, ppm) -193.5 (d, JH-F = 51.1 Hz). HRMS
(ESI) calculated for C10H10FNNaO [M+Na]+: 202.0644, found 202.0642.
3-Fluoro-1-phenylindolin-2-one (2i). Yellow solid, 44.6 mg, 93% yield; mp
o
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106.5-108.4 C; H NMR (400 MHz, CDCl3) (δ, ppm) 7.59 - 7.50 (m, 3H), 7.47 –
7.38 (m, 3H), 7.33 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz,
1H), 5.84 (d, JH-F = 51.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.4 (d, J = 18.0
Hz), 144.9 (d, J = 5.0 Hz), 133.6, 131.5 (d, J = 3.3 Hz), 129.9, 128.6, 126.5 (d, J = 1.1
Hz), 126.4, 123.9 (d, J = 2.9 Hz), 122.7 (d, J = 16.2 Hz), 110.2 (d, J = 1.3 Hz), 85.7 (d,
J = 188.7 Hz);19F NMR (376 MHz, CDCl3) (δ, ppm) -191.7 (d, JH-F = 51.0 Hz);
HRMS (ESI) calculated for C14H10FNNaO [M+Na]+: 250.0644, found 250.0636.
1-Benzyl-3-fluoroindolin-2-one (2j). Colorless oil, 39.2 mg, 81% yield; 1H NMR (400
MHz, CDCl3) (δ, ppm) 7.47 (d, J = 7.2 Hz, 1H), 7.37 - 7.22 (comp, 6H), 7.07 (t, J =
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7.5 Hz, 1H), 6.72 (d, J = 7.9 Hz, 1H), 5.76 (d, JH-F = 51.0 Hz, 1H), 4.87 (q, J = 15.7
Hz, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 171.3 (d, J = 18.1 Hz), 144.0 (d, J =
5.1 Hz), 135.1, 131.5 (d, J = 3.3 Hz), 129.0, 128.0, 127.5, 126.3 (d, J = 1.1 Hz), 123.4
(d, J = 2.9 Hz), 122.9 (d, J = 16.3 Hz), 109.9 (d, J = 1.3 Hz), 85.6 (d, J = 188.4 Hz),
44.0; 19F NMR (376 MHz, CDCl3) (δ, ppm) -192.6 (d, JH-F = 51.0 Hz); HRMS (ESI)
calculated for C15H12FNNaO [M+Na]+: 264.0801, found 264.0793
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1-(4-Bromobenzyl)-3-fluoroindolin-2-one (2k). White solid, 46.3 mg, 75% yield; mp
83.9-85.1 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.52 - 7.40 (comp, 3H), 7.29 (t, J
= 7.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.10 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 7.9 Hz,
1H), 5.76 (d, JH-F = 51.0 Hz, 1H), 4.82 (dd, J = 16 Hz ,J = 1.2 Hz ,2H); 13C NMR (100
MHz, CDCl3) (δ, ppm) 171.3 (d, J = 18.1 Hz), 143.7 (d, J = 5.1 Hz), 134.1, 132.2,
131.6 (d, J = 3.3 Hz), 129.2, 126.4 (d, J = 1.1 Hz), 123.6 (d, J = 2.9 Hz), 122.9 (d, J =
16.4 Hz), 122.0, 109.7 (d, J = 1.3 Hz), 85.5 (d, J = 188.7 Hz), 43.4; 19F NMR (376
MHz, CDCl3) (δ, ppm) -192.4 (d, JH-F = 51.0 Hz). HRMS (ESI) calculated for
C15H11BrFNNaO [M+Na]+: 341.9906, found 341.9905.
1-(4-Chlorobenzyl)-3-fluoroindolin-2-one (2l). White solid, 42.8 mg, 78% yield; mp
o
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78.3-79.2 C; H NMR (400 MHz, CDCl3) (δ, ppm) 7.48 (dd, J = 7.4, 0.6 Hz, 1H),
7.33 - 7.22 (comp, 5H), 7.10 (t, J = 7.6 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 5.76 (d, JH-F
= 51.0 Hz, 1H), 4.84 (dd, J = 16.8, 0.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm)
171.3 (d, J = 18.1 Hz), 143.7 (d, J = 5.1 Hz), 134.0, 133.6, 131.6 (d, J = 3.4 Hz),
129.0 (d, J = 36.6 Hz), 126.4 (d, J = 1.2 Hz), 123.6 (d, J = 2.9 Hz), 122.9 (d, J = 16.4
Hz), 122.8, 109.8 (d, J = 1.4 Hz), 85.5 (d, J = 188.7 Hz), 43.4; 19F NMR (376 MHz,
CDCl3) (δ, ppm) -192.5 (d, JH-F = 51.0 Hz); HRMS (ESI) calculated for
C15H11ClFNNaO [M+Na]+: 298.0411, found 298.0408.
3-Fluoro-1-(4-Nitrobenzyl)indolin-2-one (2m). Yellow solid, 47.8 mg, 84% yield; mp
157.0-157.4 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 8.17 (d, J = 8.7 Hz, 2H), 7.55 -
7.43 (comp, 3H), 7.30 (t, J = 7.8 Hz, 1H), 7.12 (t, J = 7.6 Hz, 1H), 6.67 (d, J = 7.9 Hz,
1H), 5.79 (d, JH-F = 50.9 Hz, 1H), 4.97 (s, 2H); 13C NMR (100 MHz, CDCl3) (δ, ppm)
171.3 (d, J = 18.2 Hz), 147.8, 143.3 (d, J = 5.1 Hz), 142.5, 131.7 (d, J = 3.3 Hz),
128.2, 126.6 (d, J = 1.1 Hz), 124.3, 123.9 (d, J = 2.9 Hz), 122.8 (d, J = 16.4 Hz),
109.5 (d, J = 1.3 Hz), 85.4 (d, J = 189.0 Hz), 43.3;19F NMR (376 MHz, CDCl3) (δ,
ppm) -192.1 (d, JH-F = 50.9 Hz); HRMS (ESI) calculated for C15H12FN2O3 [M+H]+:
287.0832, found 287.0830.
1-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-fluoroindolin-2-one (2n). White solid, 50.7 mg,
89% yield; mp 72.2-73.6 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.46 (dd, J = 7.4,
0.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.83 - 6.72 (comp, 4H),
5.93 (s, 2H), 5.74 (d, JH-F = 51.0 Hz, 1H), 4.77 (dd, J = 15.6, 7.2 Hz, 2H);13C NMR
(100 MHz, CDCl3) (δ, ppm) 171.3 (d, J = 18.0 Hz), 148.3, 147.5, 143.9 (d, J = 5.1
Hz), 131.5 (d, J = 3.3 Hz), 128.9, 126.3 (d, J = 1.1 Hz), 123.5 (d, J = 2.9 Hz), 122.9 (d,
J = 16.3 Hz), 121.1, 109.9 (d, J = 1.3 Hz), 108.6, 108.1, 101.3, 85.6 (d, J = 188.5 Hz),
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43.8; 19F NMR (376 MHz, CDCl3) (δ, ppm) -192.7 (d, JH-F = 51.0 Hz); HRMS (ESI)
calculated for C16H12FNNaO3 [M+Na]+: 308.0699, found 308.0696.
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1-Fluoro-3-(Naphthalen-2-ylmethyl)-1H-inden-2(3H)-one (2o). White solid, 50.1 mg,
o
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86% yield; mp 109.7-110.3 C; H NMR (400 MHz, CDCl3) (δ, ppm) 7.84 - 7.72
(comp, 4H), 7.51 - 7.36 (comp, 4H), 7.28 - 7.19 (m, 1H), 7.05 (t, J = 7.6 Hz, 1H),
6.75 (d, J = 7.9 Hz, 1H), 5.79 (d, JH-F = 51.0 Hz, 1H), 5.02 (dd, J = 15.7 Hz, 2H); 13C
NMR (100 MHz, CDCl3) (δ, ppm) 171.4 (d, J = 18.1 Hz), 144.0 (d, J = 5.1 Hz), 133.4,
133.0, 132.5, 131.5 (d, J = 3.3 Hz), 129.0, 127.9, 126.6, 126.4, 126.3, 126.3 (d, J =
1.1 Hz), 125.2, 123.5 (d, J = 2.9 Hz), 123.0, 122.8, 110.0 (d, J = 1.3 Hz), 85.7 (d, J =
188.5 Hz), 44.2;19F NMR (376 MHz, CDCl3) (δ, ppm) -192.4 (d, JH-F = 51.0 Hz).
HRMS (ESI) calculated for C19H14FNNaO [M+Na]+: 314.0957, found 314.0956.
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3-Fluoro-1-(prop-2-yn-1-yl)indolin-2-one (2p). Yellow oil, 31.2 mg, 82% yield;
1HNMR (400 MHz, CDCl3) (δ, ppm) 7.49 (dd, J = 7.4, 0.6 Hz, 1H), 7.43 (t, J = 7.8
Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 5.71 (d, JH-F = 50.9 Hz,
1H), 4.56 (dd, J = 17.7, 2.5 Hz, 1H), 4.40 (dd, J = 17.7, 2.5 Hz, 1H), 2.27 (t, J = 2.5
Hz, 1H); 13C NMR (100 MHz, CDCl3) (δ, ppm) 170.2 (d, J = 18.3 Hz), 142.9 (d, J =
5.1 Hz), 131.6 (d, J = 3.3 Hz), 126.3 (d, J = 1.1 Hz), 123.8 (d, J = 2.9 Hz), 122.8 (d, J
= 16.5 Hz), 110.0 (d, J = 1.4 Hz), 85.5 (d, J = 189.5 Hz), 76.2, 73.0, 29.5; 19F NMR
(376 MHz, CDCl3) (δ, ppm) -193.1 (d, JH-F = 50.9 Hz); HRMS (ESI) calculated for
C11H8FNNaO [M+Na]+: 212.0488, found 212.0479.
3-Fluoro-1-(2-Methoxyethyl)indolin-2-one (2q). Colorless oil, 37.1 mg, 88% yield; 1H
NMR (400 MHz, CDCl3) (δ, ppm) 7.44 (dd, J = 7.4, 0.6 Hz, 1H), 7.37 (t, J = 7.8 Hz,
1H), 7.09 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 5.66 (d, JH-F = 51.1 Hz, 1H),
3.97 – 3.86 (m, 1H), 3.84 - 3.73 (m, 1H), 3.66 – 3.56 (m, 2H), 3.32 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 171.4 (d, J = 18.0 Hz), 144.6 (d, J = 5.1 Hz), 131.5 (d, J = 3.3
Hz), 126.1 (d, J = 1.2 Hz), 123.2 (d, J = 2.9 Hz), 122.8 (d, J = 16.2 Hz), 109.8 (d, J =
1.4 Hz), 85.6 (d, J = 188.1 Hz), 70.0, 59.1, 40.4; 19F NMR (376 MHz, CDCl3) (δ, ppm)
-193.1 (d, JH-F = 51.1 Hz); HRMS (ESI) calculated for C11H12FNNaO2 [M+Na]+:
232.0750, found 232.0751.
1-Cinnamyl-3-fluoroindolin-2-one (2r). White solid, 36.9 mg, 72% yield; mp
o
1
95.0-95.8 C; H NMR (400 MHz, CDCl3) (δ, ppm) 7.49 (d, J = 7.2 Hz, 1H), 7.41 -
7.20 (comp, 6H), 7.11 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.64 (d, J = 15.9
Hz, 1H), 6.23 - 6.11 (m, 1H), 5.73 (d, JH-F = 51.0 Hz, 1H), 4.58 – 4.38 (m, 2H); 13C
NMR (100 MHz, CDCl3) (δ, ppm) 171.0 (d, J = 17.9 Hz), 144.1 (d, J = 5.1 Hz), 136.1,
133.8, 131.6 (d, J = 3.3 Hz), 128.8, 128.2, 126.6, 126.3 (d, J = 1.0 Hz), 123.4 (d, J =
2.9 Hz), 123.0 (d, J = 16.4 Hz), 122.2, 109.8, 85.6 (d, J = 188.6 Hz), 42.2;19F NMR
(376 MHz, CDCl3) (δ, ppm) -192.9 (d, JH-F = 51.0 Hz). HRMS (ESI) calculated for
C17H14FNNaO [M+Na]+: 290.0957, found 290.0952.
1
3-Fluoro-1,3-dimethylindolin-2-one (2s).25 Colorless oil, 24.0 mg, 67% yield; H
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NMR (400 MHz, CDCl3) (δ, ppm) 7.44 – 7.35 (m, 2H), 7.11 (t, J = 7.5 Hz, 1H), 6.84
(d, J = 7.8 Hz, 1H), 3.20 (s, 3H), 1.76 (d, JH-F = 22.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 173.3 (d, J = 21.7 Hz), 143.7 (d, J = 5.1 Hz), 131.2 (d, J = 2.9 Hz),
127.4 (d, J = 18.6 Hz), 124.2 (d, J = 0.8 Hz), 123.4 (d, J = 2.6 Hz), 108.8 (d, J = 1.0
Hz), 91.0 (d, J = 183.8 Hz), 26.3, 21.3 (d, J = 29.4 Hz); 19F NMR (376 MHz, CDCl3)
(δ, ppm) -152.7 (q, JH-F = 22.1 Hz); HRMS (ESI) calculated for C10H10FNNaO
[M+Na]+: 202.0644, found 202.0637.
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1-Fluoro-3-methyl-1-tosyl-1H-inden-2(3H)-one (2t). White solid, 49.5 mg, 81% yield;
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mp 179.9-180.5 C; H NMR (400 MHz, CDCl3) (δ, ppm) 7.86 (d, J = 8.1 Hz, 2H),
7.69 (d, J = 7.5 Hz, 1H), 7.55 – 7.47 (m, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.18 (t, J = 7.6
Hz, 1H), 6.90 (d, J = 7.9 Hz, 1H), 3.19 (s, 3H), 2.49 (s, 3H); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 166.2 (d, J = 20.6 Hz), 146.7, 145.8 (d, J = 5.1 Hz), 133.8 (d, J = 2.6
Hz), 131.4, 130.2, 129.6, 128.0, 123.8 (d, J = 2.3 Hz), 117.3 (d, J = 17.5 Hz), 109.3,
100.5 (d, J = 238.6 Hz), 26.9, 22.0;19F NMR (376 MHz, CDCl3) (δ, ppm) -157.7 (s).
HRMS (ESI) calculated for C16H15FNO3S [M+H] +: 320.0757, found 320.0757
3-Fluoro-1-methyl-3-phenylindolin-2-one (2u).26 Yellow solid, 41.5 mg, 86% yield;
mp 85.7-87.0 oC; 1H NMR (400 MHz, CDCl3) (δ, ppm) 7.49 - 7.32 (comp, 7H), 7.15
(t, J = 7.6 Hz, 1H), 6.93 (d, J = 7.9 Hz, 1H), 3.22 (s, 3H); 13C NMR (100 MHz,
CDCl3) (δ, ppm) 172.6 (d, J = 24.3 Hz), 144.9 (d, J = 5.4 Hz), 136.0 (d, J = 27.0 Hz),
131.7 (d, J = 3.0 Hz), 129.4 (d, J = 1.8 Hz), 128.7, 127.0 (d, J = 18.1 Hz), 126.3 (d, J
= 0.6 Hz), 126.1 (d, J = 6.1 Hz), 123.7 (d, J = 2.7 Hz), 109.0 (d, J = 1.0 Hz), 93.3 (d,
J = 187.7 Hz), 26.6; 19F NMR (376 MHz, CDCl3) (δ, ppm) -152.9 (s); HRMS (ESI)
calculated for C15H12FNNaO [M+Na]+: 264.0801, found 264.0803.
ASSOCIATED CONTENT
Supporting Information
1H, 13C and 19F NMR spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
Email: xinfangxu@suda.edu.cn; qiulihua@suda.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the grants from the Priority Academic Program Development of Jiangsu
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Higher Education Institutions (PAPD); and Natural Science Foundation of China
Jiangsu province (SBK20150315 and 15KJD150004).
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REFERENCES
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