Solvent Effects: Syntheses of 3,3-Difluorooxindoles and 3-Fluorooxindoles from Hydrazonoindolin-2-one by Selectfluor

Article abstract of DOI:10.1021/acs.joc.8b00737

Efficient syntheses of 3,3-difluorooxindoles and 3-fluorooxindoles via fluorination of hydrazonoindolin-2-one with Selectfluor are reported. Under different solvent conditions, this method produced 3,3-difluorooxindoles and 3-fluorooxindoles selectively. The broad substrate scope and mild reaction conditions make this transformation a valuable method in drug discovery and development.

Full text of DOI:10.1021/acs.joc.8b00737

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Note
Solvent Effects: Syntheses of 3,3-Difluorooxindoles and 3-
Fluorooxindoles from Hydrazonoindolin-2-one by Selectfluor
Qiong Yang, Guo-Li Dai, Yu-Ming Yang, Zhuangzhu Luo, and Zhen-Yu Tang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 16 May 2018
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Solvent Effects: Syntheses of 3,3-Difluorooxindoles and 3-Fluorooxindoles from
Hydrazonoindolin-2-one by Selectfluor
*
,
*,
Qiong Yang†, Guo-Li Dai†, Yu-Ming Yang†, Zhuangzhu Luo ‡ and Zhen-Yu Tang †, ‡
† Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South
University, Changsha 410083, China
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‡
School of Chemical Engineering and Technology, Sun Yat-sen University, Guangzhou 510275, China
Supporting Information
ABSTRACT: Efficient syntheses of 3,3-difluorooxindoles and 3-fluorooxindoles via fluorination of hydrazonoindolin-2-one with
Selectfluor are reported. Under different solvent conditions, this method produced 3,3-difluorooxindoles and 3-fluorooxindoles
selectively. The broad substrate scope and mild reaction conditions make this transformation a valuable method in drug
discovery and development.
3-Fluorooxindole derivatives are biologically active
indole derivatives, such as nucleophilic fluorination of isatin
1
9
compounds, which have attracted considerable attention as
with thermally unstable diethylaminosulfur trifluoride (DAST)
2
10
promising agents for treatments of stroke (Figure 1, A),
and electrophilic fluorination of indole with NSFI.
b)
together with other activities, such as corticotropin-releasing
ring-closure strategies to construct pyrole ring of indoles,
including transition-metal or photo-catalyzed intramolecular
3
factor (CRF) receptor antagonists (Figure 1, B), and potential
1
1
-
agents for the treatment of abnormal cell growth (Figure 1,
cyclization of halodifluoroacetamides and intermolecular
4
12
C). Introduction of fluorides into the 3-position of indoles
difluoroalkylation/amidation of anilines. While significant
represents an important strategy in preparing these
progresses have been made in these syntheses, there are still
many limitations, such as instability of the fluorinating
reagents, poor functional-group tolerance and lengthy
synthetic
5
compounds.
Scheme 1. Different Protocols for Construction of
fluoro-2-oxindoles
Previous works:
R1
N
N2
F
NFSI, NaH ref.7
NFSI,NaOAc ref.8
R3
O
O
N
O
1
N
1
R
R
=
B
o
c
R1
F
O
F
R1
R3
BrCF2COOEt ref.12
DAST ref.9
N
O
O
R2
R2
N
R1
R2
N
R1
Figure1. Representative examples of bioactive
H
3
-fluorooxindole derivatives
CF2I
R2
N
O
N
R1
R2
Preparation of functionalized 3-fluorooxindoles has
R1
received considerable synthetic interests over the last few
H
H
6
CF2Cl
O
CF2Br
O
decades. Primarily, 3-fluoroinated oxindole was synthesized
R2
N
R1
R2
N
by nucleophilic addition of fluoride from N-fluorobenzene-
R1
sulfonimide (NFSI) under the strong basic condition of sodium
7
hydride (Scheme1).
Alternatively, an NSFI-initiated
fluoroarylation and ring-cylization of diazoacetamides offered
8
another pathway. However, these methods employed strong
base and normally produced moderate yields. In the
meanwhile, various methods for the syntheses of
routes. Clearly, a new method that allows the generation of
3
,3-difluorooxindoles have been developed. These methods
3-fluoro-2-oxindole derivatives under mild conditions is still
generally fall into two categories: a) direct fluorination of
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urgently needed.
report our progress.
Selective incorporation of different numbers of fluorine
into the 3-position of oxindoles represents another challenge.
None of the previous examples produced both
Our initial studies commenced with the model reaction
between isatin hydrazone 1a and Selectfluor (Table 1). We
found that simply mixing isatin hydrazone with Selectfluor at
o
3-fluorooxindole and 3,3-difluorooxindole under the same
70
C in cyclohexane for 15 hours, afforded 17%
strategy. Based on our previous experience in decarboxylative
3-fluorooxindole 2a and 23% 3,3-difluorooxindole 3a with
lithium acetate (LiOAc) as base (entry 1). This initial result
promoted us to improve both yield and selectivity towards
either 3-fluorooxindole or 3,3-difluorooxindole. Various
hydrophilic and hydrophobic solvents were screened.
Dichloroethane (DCE) was demonstrated as the best solvent to
afford 3-fluorooxindole with 46% yield and acetonitrile (MeCN)
as the best solvent to produce 3,3-difluorooxindole with 49%
yield (entries 1 to 8). Further optimization with different bases
in DCE, revealed LiOAc as the best base. No fluorinating
product was detected in DCE without base (entry 14). After
further optimizations of the reagent ratio, concentration and
temperature, the reaction of 1a with Selectfluor (2 equiv)/
13
fluorination of carboxylic acids, we set out to develop a
general method to synthesize both compounds from
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commercially available and cost-effective
a
Table 1. Optimization of Reaction Conditions
o
b
b
LiOAc (6 equiv) at 70 C in a dilute solution produced 2a in 68%
entry
Solvent
Cyclohexane
Benzene
Ethyl acetate
MTBE
THF
base
2a (%)
17
16
38
36
35
23
0
3a (%)
23
29
11
0
yield with high selectivity (entry 16). No product 2a or 3a was
formed when Selectfluor was replaced with the other
fluorinating reagents, such as NSFI, 1-fluoropyridium
tetrafluoroborate (NFPY), tetranbuylammonium fluoride (TBAF)
and DAST (entry 19). On the other hand, the product 3a was
selectively obtained with 60% yield in MeCN without a base at
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9
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
o
15
5
70 C (entry 20). Reactions with MeCN as solvent at different
temperatures were also tested. Room temperature was
proved to be the best temperature for the selective formation
of 3,3-difluoroxindole 3a (entries 21-23). At last, the other
isatin hydrazone analogs, such as phenyl-, tosyl-, and oxime-
hydrazones were also tested. None of them afforded
fluorinated product (inlet of Table 1).
Dioxane
MeCN
DCE
49
3
46
38
33
11
0
DCE
Li
2
CO
3
18
10
2
1
1
0
1
DCE
NaHCO
NaOAc
NaOH
3
3-Fluorooxindoles are interesting synthetic synthons and
1
4
DCE
tools for elucidating biological processes.
Under the
optimized condition, the substrate scope of 3-fluorooxindoles
formation with different combination of concentration and
temperature was investigated. As summarized in Scheme 2, a
wide range of N-substituted isatin hydrazones successfully
12
DCE
0
13
14
15
DCE
Et
3
N
0
0
DCE
None
LiOAc
LiOAc
LiOAc
LiOAc
LiOAc
None
None
None
None
0
0
o
c
underwent fluorination with Selectfluor at 80 C in DCE with
DCE
53
68
42
51
0
6
satisfactory yields. As the size and steric hindrance of the
protecting groups increased, the yields also improved (2l, 2m
versus 2b, 2c). Sensitive functional groups, such as olefin (2f),
alkyne (2g) and chloride (2m) were tolerated and thus
permitted further functionalization. To minimize 3,
c,d
c,d,e
c,d,f
g
16
DCE
6
1
1
1
7
8
9
DCE
3
DCE
12
0
DCE
3-difluorooxindole formation, the reactions of unprotected
20
MeCN
MeCN
MeCN
MeCN
0
60
68
76
75
isatin hydrazone derivatives were carried out at the lower
o
h
concentration and slightly lower temperature (70 C). The
2
2
1
2
3
0
5-subistituted isatin hydrazones with both electron-rich (2p)
and electron-deficient functional groups (2n and 2o) afforded
moderate yields. Reactions of 7-subtituted isatin hydrazones
(2q, 2r, and 2t) resulted in slightly higher yields than those of
5-subistituted counterparts. The bis-substituted istatin
hydrazones, such as 5,6-difluoro-3-hydrazonoindolin-2-one,
also formed the corresponding 3-fluorooxindole 2s in 51%
yield. Overall, low concentration and optimal temperature
were the keys to generate 3-fluorooxindoles selectively.
i
0
j
2
0
a
Standard conditions: 1a 0.5 mmol, Selectfluor 1 mmol, base 2
o
mmol, 3 mL solvent, 70 C, 15 hours. Yield determined by F NMR
c
spectroscopy using fluorobenzene as an internal standard. base 6
d
equiv. DCE 13 mL. 60 C. 80 C. Other fluorinating reagent
h
NSFI, NFPY, DAST or TBAF. 50 C. r.t. ice-bath.
b
19
e
o
f
o
g
o
i
j
starting material, isatin, through fine tuning of reaction
conditions, such as solvent, base and temperature. Herein, we
Replacement of the keto carbonyl (C=O) group of isatins
with the bioisoteric analogue moiety difluoromethylene (CF2)
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leads to 3,3-difluoro-2-oxindoles, which are of biological
temperature. For N-substituted isatin hydrazones, the yields
improved along with the increase in the size and steric
hindrance of the protecting groups (3l, 3m versus 3b, 3c).
Sensitive functional groups, such as allyl, propargryl and
15
significance in the development of medicinally active agents.
a,b
Scheme 2. Synthesis of 3-fluorooxindoles
1-chloroethyl, were tolerated (3f, 3g and 3m). The
aryl-substituted isatin hydrazones, bearing a broad range of
functional groups, were also compatible in this transformation.
The isatin hydrazones 1 with electron-donating substituents
gave higher yields (66%-97%) (3n, 3o, 3q-3w) than those of 1
with electron-deficient substituents (3p, 3x). High temperature
was required for 5-nitro-3,3-difluoroindolin-2-one 3u, due to
the poor solubility of 1u.
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To gain mechanistic insight into the reaction, several
control experiments were carried out. No deutrated product
2 4 2 4 2
was observed with D O or 1,2-dichloroathane-d (C D Cl ) as
solvent under our standard condition. In Murphy’s synthesis of
aryldihalomethanes by denitrogenative dihalogenation of
benzaldehyde hydrazones, diazo intermediate was proposed
16
to be the reaction intermediate.
However, when
3-diazoindolin-2-one was subjected to the standard conditions,
the desired products was not obtained (scheme 4). Thus, the
possibility of involving 3-diazoindolin-2-one as intermediate
could be ruled out. No germinal difluorinated product 3a
formed when mono-fluorooxindole 2a were subjected to the
standard condition of scheme 2 or scheme 3. This result
implies that 3a does not come from the further fluorination of
2a.
Scheme 4. Control Experiments and Plausible Mechanism
a
Standard conditions:
o
.0 mmol, 3 mL DCE, 80 C.
1 0.5 mmol, Selectfluor 1.0 mmol, LiOAc
b
Isolated yield after column
3
c
chromatography. 13 mL DCE, 70 C.
o
Here we describe
hydrazones under our optimized condition to synthesize
,3-difluorooxindole. As shown in Scheme 3, the reaction
a direct fluorination of isatin
3
demonstrated a broad substrate scope readily forming a
variety of 3,3-difluorooxindoles in satisfactory yields. A range
of isatin hydrazones gave 3, 3-difluoro-2- oxindoles (3a-3x) as
the exclusive products in 25-97% yields in MeCN at room
a,b
Scheme 3. Synthesis of 3,3-Difluoroxindole
A plausible mechanism is proposed in Scheme 4. An
oxidation and electrophilic substitution of isatin hydrazone by
Selectfluor occurred to generate intermediate 4. In a solvent
such as acetonitrile, intermediate
4 was converted to
3
,3-difluorooxindole by oxidation and denitrogenative
3
16
fluorination. On the other hand, in DCE, with a weak base as
LiOAc, dehydrogenation of 4 afforded intermediate 5. Final
denitrogentaion and hydrogen abstraction from HOAc
produced 3-fluorooxindole 2.
a
Standard conditions: 1 0.5 mmol, Selectfluor 1.0 mmol, 3 mL
In conclusion, we have successfully developed an efficient
b
MeCN, r.t. Isolated yield after column chromatography. 50 C
c
o
strategy to synthesize
2
a range of 3-CHF/CF -containing
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indolin-2-one with Selectflour under mild conditions. This
General procedure C for the syntheses of 3, 3-difluoro-
oxindoles (3a-3t, 3v-3w). To a 25 mL round-bottle flask with a
magnetic stirring bar were added 3-hydrazono-2-oxindoles (0.5
mmol, 1.0 equiv.), and Selectfluor (354 mg, 1 mmol). Then
acetonitrile (3 mL) was added. The reaction mixture was
stirred at room temperature for 12 hours. After hydrazone was
consumed (monitored by thin layer chromatography), the
resulting mixture was concentrated and purified by flash
column chromatography on silica gel (n-hexane: EA=9:1) to
give the pure products 3.
method has advantage over other methods due to high
selectivity and broad substrate scope. A plausible mechanism
based on behavior of Selectfluor in different solvents was
proposed. The high functional group tolerance and mild
reaction conditions make this transformation applicable in
drug discovery and development.
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■
EXPERIMENTAL SECTION
General Information. All reactions were carried out using
oven-dried glassware. All reagents were used as received from
commercial sources unless specified otherwise or prepared as
described in the literature. NMR spectra were recorded on
General procedure D for the syntheses of 3, 3-difluoro-
oxindoles (3u). To a 25 mL round-bottle flask with a magnetic
stirring bar were added 3-hydrazono-2-oxindoles (0.5 mmol,
1
13
Bruker Avance 400 (400 MHz for H, 100 MHz for C and 376
1.0 equiv.), and Selectfluor (354 mg, 1 mmol). Then
1
9
1
MHz for F) or Bruker Avance 500 (500 MHz for H, 125 MHz
acetonitrile (3 mL) was added. The reaction mixture was heat
1
3
o
for C acquisition) with CDCl
3
or DMSO-d
6
as solvent. Chemical
to 50 C in oil bath and stirred for 12 hours. After the
shifts (δ) are reported in ppm, and coupling constants (J) are in
Hertz (Hz). 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
hydrazones was consumed (monitored by thin layer
chromatography), the resulting mixture was cooled,
concentrated and purified by flash column chromatography on
silica gel (n-hexane: EA=9:1) to give the pure products 3u.
1
9
17
signals). NMR yield was determined by F NMR using
fluorobenzene as an internal standard. Column
3-Fluoro-2-oxindole (2a) (General Procedure A) White solid,
1
50.1 mg, 68% yield. H NMR (400 MHz, DMSO-d
6
) δ 10.65 (s,
chromatography was performed on silica gel 300-400 mesh.
High-resolution mass spectra were obtained on Thermo Fisher
LCQ Orbitrap Velos Pro mass spectrometer at Hunan
University Mass Spectrometry Facilities.
1H), 7.45 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.04 (t, J =
7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 5.88 (d, JH-F = 50.8 Hz, 1H).
13
6
C NMR (100 MHz, DMSO-d ) δ 172.9 (d, J = 18.0 Hz), 143.8 (d,
J = 6.0 Hz), 131.8 (d, J = 3.0 Hz), 126.6, 123.8 (d, J = 16.0 Hz),
122.7 (d, J = 2.0 Hz), 110.8 (d, J = 1.0 Hz), 86.5 (d, J = 181.0 Hz).
General procedure for the preparation of 3-hydrazono
1
9
-2-oxindoles(1a-1x). General procedure for the syntheses of
F NMR (376 MHz, DMSO-d
6
) δ -192.1 (d, JH-F = 50.8 Hz).
1
4c
the 3-hydrazono-2-oxindoles 1a-1x: Isatin (1.0 g, 6.06 mmol, 1
equiv.) was dissolved in methanol (20 mL) and stirred
vigorously. To this solution was added hydrazine hydrate
(reagent grade 80%, 0.73 mL, 2.0 equiv.) in one portion and
the solution was heated to reflux. After consumption of isatin
as determined by TLC, the solution was allowed to cool to
room temperature. Precipitations formed at this stage was
isolated by filtration and washed with a small quantity of cold
methanol. Additional portion of product was isolated and
purified by column chromatography after concentration.
3-Fluoro-1-methylindolin-2-one (2b) (General Procedure B)
1
3
White solid, 40.5 mg, 49% yield. H NMR (400 MHz, CDCl ) δ
7.40 (d, J = 7.2 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 7.05 (t, J = 7.4 Hz,
1H), 6.77 (d, J = 8.0 Hz, 1H), 5.60 (d, JH-F = 50.8 Hz, 1H), 3.13 (s,
1
3
3H). C NMR (100 MHz, CDCl
3
) δ 171.1 (d, J = 18.0 Hz), 144.8
(d, J = 5.0 Hz), 131.5 (d, J = 4.0 Hz), 126.0, 123.3 (d, J = 3.0 Hz),
1
9
122.8 (d, J = 17.0 Hz), 108.8, 85.5 (d, J = 187.0 Hz), 26.2.
NMR (376 MHz, CDCl ) δ -193.4 (d, JH-F = 50.8 Hz).
3-Fluoro-1-ethylindolin-2-one (2c)
F
3
1
4c
(General Procedure B)
White solid, 62.6 mg, 70% yield. H NMR (500 MHz, CDCl ) δ
1
3
General procedure A for the synthesis of 3-fluorooxiindoles
7.47 (d, J = 7.0 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.5 Hz,
1H), 6.86 (d, J = 7.5 Hz, 1H), 5.66 (d, JH-F = 51.0 Hz, 1H), 3.74 (q,
(2a, and 2n-2t). To a 100 mL round-bottle flask with a
13
magnetic stirring bar were added 3-hydrazono-2-oxindoles (0.5
mmol, 1.0 equiv.), Selectfluor (354 mg, 1 mmol) and LiOAc
J = 7.5 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H). C NMR (100 MHz,
3
CDCl ) δ 170.7 (d, J = 17.8 Hz), 143.8 (d, J = 5.1 Hz), 131.4 (d, J =
(
198 mg, 3 mmol). Then DCE (13 mL) was added. The reaction
3.3 Hz), 126.2 (d, J = 1 Hz), 123.1 (d, J = 2.9 Hz), 123.0 (d, J =
16.1 Hz), 108.9 (d, J = 1.1 Hz), 85.6 (d, J = 186.8 Hz), 34.8, 12.4.
o
mixture was heated to 70 C in oil bath and stirred for 18 hours.
After hydrazone was consumed (monitored by thin layer
chromatography), the resulting mixture was cooled,
concentrated and purified by flash column chromatography on
silica gel (n-hexane: EA=9:1) to give the pure products 2.
1
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3
F NMR (376 MHz, CDCl ) δ -193.4 (d, JH-F = 50.8 Hz).
3-Fluoro-1-propylindolin-2-one (2d) (General Procedure B)
1
White solid, 66.7 mg, 69% yield, mp 40-42 °C. H NMR (400
MHz, CDCl
7.09 (t, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 5.66 (d, JH-F
50.8 Hz, 1H), 3.58-3.69 (m, 2H), 1.66-1.75 (m, 2H), 0.97 (t, J =
3
) δ 7.45 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H),
General procedure B for the syntheses of 3fluorooxindoles
(2b-2m). To a 25 mL round-bottle flask with a magnetic stirring
bar were added 3-hydrazono-2-oxindoles (0.5 mmol, 1.0
equiv.), Selectfluor (354.3 mg, 1 mmol) and LiOAc (198 mg, 3
mmol). Then DCE (3 mL) was added. The reaction mixture was
=
1
3
3
7.6 Hz, 3H). C NMR (100 MHz, CDCl ) δ 171.1 (d, J = 17.7 Hz),
144.2 (d, J = 5.0 Hz), 131.4 (d, J = 3.3 Hz), 126.2, 123.1 (d, J =
2.7 Hz), 122.9 (d, J = 16.0 Hz), 109.1, 85.5 (d, J = 186.8 Hz), 41.7,
o
19
heat to 80 C in oil bath and stirred for 16 hours. After the
3
20.8, 11.3. F NMR (376 MHz, CDCl ) δ -193.1 (d, JH-F = 50.8
+
hydrazones was consumed (monitored by thin layer
chromatography), the resulting mixture was cooled,
concentrated and purified by flash column chromatography on
silica gel (n-hexane: EA=9:1) to give the pure products 2.
Hz). HRMS (ESI-TOF) m/z: [M + H] Calcd for C11H13FNO
194.0976, Found 194.0974.
3-Fluoro-1-isopropylindolin-2-one (2e) (General Procedure B)
1
White solid, 68.6 mg, 71% yield, mp 37-38 °C. H NMR (400
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MHz, CDCl
3
) δ 7.46 (d, J = 7.2 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H),
3
187.0Hz), 40.1, 27.2, 22.5, 14.0. F NMR (376 MHz, CDCl ) δ
+
7.09 (t, J = 7.6 Hz, 1H), 6.99 (d, J = 8.0 Hz, 1H), 5.60 (d, JH-F
=
C
-193.2 (d, JH-F = 50.8 Hz). HRMS (ESI-TOF) m/z: [M + H] Calcd
1
3
51.2 Hz, 1H), 4.50-4.60 (m, 2H), 1.48 (q, J = 7.0 Hz, 6H).
for C14H19FNO 236.1445, Found 236.1442.
1
4c
NMR (125 MHz, CDCl
3
) δ 170.8 (d, J = 17.5 Hz), 143.5 (d, J = 5.1
3-Fluoro-1-phenylindolin-2-one (2k) (General Procedure B)
1
Hz), 131.2 (d, J = 3.3 Hz), 126.3, 123.2 (d, J = 16.0 Hz), 122.7 (d,
3
White solid, 63.6 mg, 56% yield. H NMR (400 MHz, CDCl ) δ
1
9
J = 2.7 Hz), 110.4, 85.5 (d, J = 186.3 Hz), 44.2, 19.2. F NMR
376 MHz, CDCl ) δ -192.9 (d, JH-F = 51.2 Hz). HRMS (ESI-TOF)
7.54 (d, J = 7.6 Hz, 3H), 7.40-7.46 (m, 3H), 7.33 (t, J = 7.8 Hz,
(
3
+
1H), 7.16 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 5.85 (d, JH-F
13
m/z: [M + H] Calcd for C11H13FNO 194.0976, Found
3
= 51.2 Hz, 1H). C NMR (100 MHz, CDCl ) δ 170.4 (d, J = 18.0
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
194.0973.
Hz), 144.9 (d, J = 5.0 Hz), 133.5, 131.4 (d, J = 4.0 Hz), 126.3,
3-Fluoro-1-allylindolin-2-one (2f) (General Procedure B) White
123.8 (d, J = 3.0Hz), 122.6 (d, J = 17.0 Hz), 110.1 (d, J = 1.0 Hz),
1
19
solid, 69.8 mg, 73% yield, mp 52-53 °C. H NMR (500 MHz,
CDCl3) δ 7.48 (d, J = 7.0 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.11 (t,
J = 7.5 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.79-5.86 (m, 1H), 5.71
(d, JH-F = 51.0 Hz, 1H), 5.27 (t, J = 9.3 Hz, 2H), 4.26-4.37 (m, 2H).
3
85.5 (d, J = 187.0Hz). F NMR (376 MHz, CDCl ) δ -191.7 (d, JH-F
= 51.2 Hz).
1
4c
3-Fluoro-1-benzylindolin-2-one (2l)
(General Procedure B)
1
White solid, 100.1 mg, 83% yield. H NMR (400 MHz, CDCl ) δ
3
13C NMR (125 MHz, CDCl
3
) δ 170.8 (d, J = 18.7 Hz), 144.0 (d, J
7.48 (d, J = 8.0 Hz, 1H), 7.28-7.36 (m, 6H), 7.08 (t, J = 7.6 Hz,
1H), 6.73 (d, J = 7.6 Hz, 1H), 5.77 (d, JH-F = 51.2 Hz, 1H), 4.88 (q,
= 5.0 Hz), 131.4 (d, J = 3.7 Hz), 130.7, 126.1, 123.3 (d, J = 2.5
Hz), 122.7 (d, J = 16.3 Hz), 118.2, 109.7, 85.5 (d, J = 187.5 Hz),
13
3
J = 24.8 Hz, 2H). C NMR (100 MHz, CDCl ) δ 171.2 (d, J = 18.0
42.4. 19F NMR (376 MHz, CDCl
3
) δ -192.8 (d, JH-F = 51.0 Hz).
Hz), 143.9 (d, J = 5.0 Hz), 135.0, 131.4 (d, J = 3.0 Hz), 128.9,
127.9, 127.4, 126.2, 123.3 (d, J = 3.0Hz), 122.8 (d, J = 16.0 Hz),
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C11H11FNO 192.0819,
Found 192.0816.
1
9
109.8, 85.5 (d, J = 188.0Hz), 43.9. F NMR (376 MHz, CDCl
3
) δ
1
4c
3-Fluoro-1-propargylindolin-2-one (2g) (General Procedure B)
-192.6 (d, JH-F = 51.2 Hz).
1
White solid, 71.9 mg, 76% yield. H NMR (400 MHz, CDCl
3
) δ
3-Fluoro-1-chloroethylindolin-2-one (2m) (General Procedure B)
1
7
5
.49 (s, 1H), 7.43 (s, 1H), 7.16 (s, 1H), 7.08 (s, 1H), 5.72 (d, JH-F
=
White solid, 86.5 mg, 81% yield, mp 70-72 °C. H NMR (400
13
1.2 Hz, 1H), 4.38-4.59 (m, 2H), 2.71 (s, 1H). C NMR (100
) δ 170.1 (d, J = 18.0 Hz), 142.8 (d, J = 5.0 Hz), 131.5
d, J = 4.0 Hz), 126.2 (d, J = 1.0 Hz), 123.7 (d, J = 3.0 Hz), 122.6
d, J = 17.0 Hz), 109.9 (d, J = 2 Hz), 85.4 (d, J = 188.0), 76.1, 72.9,
3
MHz, CDCl ) δ 7.49 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H),
MHz, CDCl
3
7.14 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 8 Hz, 1H), 5.70 (d, JH-F = 50.8
13
(
Hz, 1H), 3.93-4.12 (m, 2H), 3.76 (t, J = 6.4 Hz, 2H). C NMR
(
3
(100 MHz, CDCl ) δ 171.3 (d, J = 18.0 Hz), 143.7 (d, J = 5.0 Hz),
1
9
29.4. F NMR (376 MHz, CDCl
3
) δ -193.1 (d, JH-F = 51.2 Hz).
131.5 (d, J = 3.0 Hz), 126.4 (d, J = 1.0 Hz), 123.6 (d, J = 2.0 Hz),
3-Fluoro-1-butylindolin-2-one (2h) (General Procedure B)
122.7 (d, J = 16.0 Hz), 109.1 (d, J = 1.0 Hz), 86.2 (d, J = 188.0Hz),
1
19
White solid, 72.5 mg, 70% yield, mp 41-43 °C. H NMR (400
MHz, CDCl ) δ 7.38-7.48 (m, 2H), 7.08-7.12 (m, 1H), 6.86 (t, J =
8.8 Hz, 1H), 5.68 (d, JH-F = 51.2 Hz, 1H), 3.66-3.69 (m, 2H),
3
42.0, 40.3. F NMR (376 MHz, CDCl ) δ -192.9 (d, JH-F = 50.8
+
3
Hz). HRMS (ESI-TOF) m/z: [M + H] Calcd for C10H10ClFNO
214.0429, Found 214.0428.
1
3
1.66-1.67 (m, 2H), 1.39-1.42 (m, 2H), 0.94-0.99 (m, 3H).
NMR (100 MHz, CDCl ) δ 171.0 (d, J = 17.9 Hz), 144.3 (d, J = 5.2
Hz), 133.4 (d, J = 3.2 Hz), 126.2, 123.1 (d, J = 2.8 Hz), 122.9 (d, J
C
5-Chloro-3-fluoro-indolin-2-one (2n) (General Procedure A)
1
3
White solid, 43.6mg, 47% yield, mp 120-123 °C. H NMR (500
MHz, DMSO-d
1H), 6.88 (d, J = 8.5 Hz, 1H), 5.89 (d, JH-F = 50.0 Hz, 1H).
NMR (125 MHz, DMSO-d ) δ 172.5 (d, J = 17.5 Hz), 142.7 (d, J =
6.3 Hz), 131.6 (d, J = 3.8 Hz), 126.8, 126.6 (d, J = 2.5 Hz), 125.7
6
) δ 10.77 (s, 1H), 7.56 (s, 1H), 7.41 (d, J = 8.5 Hz,
1
3
C
=
2
16.2 Hz), 109.1 (d, J = 1.3 Hz), 85.5 (d, J = 186.8), 39.9, 29.3,
1
9
0.1, 13.7. F NMR (376 MHz, CDCl
3
+
) δ -193.2 (d, JH-F = 51.2
6
Hz). HRMS (ESI-TOF) m/z: [M + H] Calcd for C12H15FNO
1
9
208.1132, Found 208.1130.
(d, J = 16.3 Hz), 112.3, 86.2 (d, J = 182.5Hz). F NMR (376 MHz,
DMSO-d ) δ -192.8 (d, JH-F = 50.0 Hz). HRMS (ESI-TOF) m/z: [M
3-Fluoro-1-amylindolin-2-one (2i) (General Procedure B) White
6
1
+
solid, 74.1 mg, 67% yield, mp 39-41 °C. H NMR (400 MHz,
+ H] Calcd for C8H6ClFNO 186.0116, Found 186.0115.
CDCl
3
) δ 7.47 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.10 (t,
5-Bromo-3-fluoro-indolin-2-one (2o) (General Procedure A)
1
J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.65 (d, JH-F = 51.2 Hz,
White solid, 51.7mg, 45% yield, mp 151-152 °C. H NMR (400
1
0
=
H), 3.60-3.72 (m, 2H), 1.63-1.71 (m, 2H), 1.33-1.36 (m, 4H),
MHz, DMSO-d
1H), 6.84 (d, J = 7.6 Hz, 1H), 5.89 (d, JH-F = 50.0 Hz, 1H).
NMR (100 MHz, DMSO-d ) δ 177.1 (d, J = 18.0 Hz), 147.9 (d, J =
6
) δ 10.79 (s, 1H), 7.67 (s, 1H), 7.53 (d, J = 7.6 Hz,
13
13
C
.90 (t, J = 6.8 Hz, 3H). C NMR (100 MHz, CDCl
3
) δ 171.0 (d, J
18.0 Hz), 144.2 (d, J = 5.0 Hz), 131.4 (d, J = 3.0 Hz), 126.2,
6
123.0 (d, J = 3.0Hz), 122.9 (d, J = 16.0 Hz), 85.5 (d, J = 187.0Hz),
5.0 Hz), 139.2 (d, J = 3.0 Hz), 134.2, 130.8 (d, J = 15.0 Hz), 118.9
1
9
19
40.1, 29.0, 26.9, 22.3, 13.9. F NMR (376 MHz, CDCl
3
+
) δ -193.1
(d, J = 3.0 Hz), 117.6, 90.9 (d, J = 183.0Hz). F NMR (376 MHz,
(d, JH-F = 51.2 Hz). HRMS (ESI-TOF) m/z: [M + H] Calcd for
6
DMSO-d ) δ -192.7 (d, JH-F = 50.0 Hz). HRMS (ESI-TOF) m/z: [M
+
C13H17FNO 222.1289, Found 222.1286.
+ H] Calcd for C8H6BrFNO 229.9611, Found 229.9609.
3-Fluoro-1-hexylindolin-2-one (2j) (General Procedure B) White
5-Methyl-3-fluoro-indolin-2-one (2p) (General Procedure A)
1
1
solid, 92.9 mg, 79% yield, mp 38-39 °C. H NMR (400 MHz,
CDCl ) δ 7.47 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.10 (t,
J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 5.65 (d, JH-F = 50.8 Hz,
White solid, 40.4 mg, 49% yield, mp 107-109 °C. H NMR (400
3
MHz, DMSO-d
= 8.0 Hz, 1H), 5.65 (d, JH-F = 50.8 Hz, 1H), 2.33 (s, 3H). C NMR
(100 MHz, DMSO-d ) δ 173.6 (d, J = 18.0 Hz), 139.4 (d, J = 6.0
6
) δ 8.27 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.78 (d, J
1
3
1
0
=
1
H), 3.60-3.72 (m, 2H), 1.64-1.70 (m, 2H), 1.29-1.34 (m, 6H),
6
13
.88 (t, J = 7.0 Hz, 3H). C NMR (100 MHz, CDCl
3
) δ 171.0 (d, J
Hz), 133.0 (d, J = 3.0 Hz), 131.8 (d, J = 3.0 Hz), 127.0, 123.3 (d, J
19
17.9 Hz), 144.2 (d, J = 5.0 Hz), 131.4 (d, J = 3.0 Hz), 126.2,
23.0 (d, J = 3.0Hz), 122.9 (d, J = 16.0 Hz), 109.1, 85.5 (d, J =
= 16.0 Hz), 110.5, 86.0 (d, J = 188.0Hz), 21.0. F NMR (376
6
MHz, DMSO-d ) δ -193.4 (d, JH-F = 50.8 Hz). HRMS (ESI-TOF)
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2
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
13
m/z: [M + H] Calcd for C9H9FNO 166.0663, Found 166.0660.
-Fluoro-3-fluoro-indolin-2-one (2q) (General Procedure A)
3
7.2 Hz, 3H). C NMR (100MHz, CDCl ) δ 164.9 (t, J = 30.0 Hz),
7
143.1 (t, J = 7.0 Hz), 133.6 (t, J = 1.5 Hz), 124.8, 123.7 (t, J = 1.5
Hz), 120.3 (t, J = 23.0 Hz), 110.9 (t, J = 247.5 Hz), 109.6, 35.0,
1
Light-yellow solid, 50.7 mg, 60% yield, mp 103-105 °C. H NMR
400 MHz, DMSO-d ) δ 11.17 (s, 1H), 7.27-7.34 (m, 2H),
1
9
(
6
3
12.3. F NMR (376 MHz, CDCl ) δ -112.5 (s, 2F).
1
3
7
.05-7.10 (m, 1H), 5.95 (d, JH-F = 50.0 Hz, 1H). C NMR (100
3,3-Difluoro-1-propylindolin-2-one (3d). (General Procedure C)
1
MHz, DMSO-d
6
) δ 172.6 (d, J = 17.0 Hz), 146.9 (d, J = 242.0 Hz),
White solid, 42.2 mg, 40% yield, mp 60-62 °C. H NMR (400
1
30.8 (q, J = 6.0 Hz), 126.5-126.7 (m), 123.7 (q, J = 3.0 Hz),
3
MHz, CDCl ) δ 7.55 (d, J = 7.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H),
19
1
22.7 (d, J = 3.0 Hz), 118.7-118.9 (m), 86.2 (d, J = 183.0Hz).
F
7.16 (t, J = 7.6 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 3.66 (t, J = 7.2 Hz,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
NMR (376 MHz, DMSO-d
6
) δ -132.3, -192.0 (d, JH-F = 50.0 Hz).
2H), 1.69-1.78 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). C NMR
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C8H6F2NO 170.0412,
Found 170.0409.
(100MHz, CDCl
3
) δ 165.4 (t, J = 30.0 Hz), 143.5 (t, J = 7.0 Hz),
133.6 (t, J = 1.5 Hz), 124.7, 123.7 (t, J = 2 Hz), 120.2 (t, J = 23.0
1
9
7
-Chloro-3-fluoro-indolin-2-one (2r) (General Procedure A)
Hz), 110.9 (t, J = 248.0 Hz), 109.8, 41.8, 20.5, 11.2. F NMR
(376 MHz, CDCl ) δ -112.3 (s, 2F). HRMS (ESI-TOF) m/z: [M +
H] Calcd for C11H12F2NO 212.0881, Found 212.0878.
1
White solid, 50.6 mg, 54% yield, mp 119-121 °C. H NMR (400
MHz, DMSO-d ) δ 11.10 (s, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.08 (t,
J = 7.8 Hz, 1H) 5.96 (d, JH-F = 50.0 Hz, 1H). C NMR (100 MHz,
DMSO-d ) δ 172.7 (d, J = 17.0 Hz), 141.5 (d, J = 6.0 Hz), 131.6 (q,
J = 3.0 Hz), 121.6 (q, J = 16.0 Hz), 125.3, 124.0 (d, J = 3.0 Hz),
3
+
6
1
3
10
3,3-Difluoro-1-isopropylindolin-2-one
Procedure C) White solid, 63.3 mg, 60% yield. H NMR (400
MHz, CDCl ) δ 7.55 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H),
7.15 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 4.46-4.56 (m,
(3e)
(General
1
6
3
19
1
14.9, 86.7 (d, J = 183.0Hz). F NMR (376 MHz, DMSO-d
6
) δ
191.8 (d, JH-F = 50.0 Hz). HRMS (ESI-TOF) m/z: [M + H] Calcd
for C8H6ClFNO 186.0116, Found 186.0113.
,6-2-Fluoro-3-fluoro-indolin-2-one (2s) (General Procedure A)
+
13
-
3
1H), 1.50 (d, J = 7.2 Hz, 6H). C NMR (125MHz, CDCl ) δ 165.0
(t, J = 29.3 Hz), 142.9 (t, J = 7.5 Hz), 133.4, 124.9, 123.4, 120.5
5
(t, J = 22.5 Hz), 111.0, 110.5 (t, J = 2 Hz), 120.2 (t, J = 23.0 Hz),
1
19
White solid, 47.7 mg, 51% yield, mp 117-119 °C. H NMR (400
3
110.5 (t, J = 247.5 Hz), 44.8, 19.2. F NMR (376 MHz, CDCl ) δ
MHz, DMSO-d
6
) δ 10.78 (s, 1H), 7.69 (t, J = 8.0 Hz, 1H),
-112.4 (s, 2F).
13
6
.92-6.96 (m, 1H), 5.86 (d, JH-F = 50.4 Hz, 1H). C NMR (100
3,3-Difluoro-1-allylindolin-2-one (3f) (General Procedure C)
1
MHz, DMSO-d
6
) δ 172.8 (d, J = 17.0 Hz), 150.4-153.1 (m),
White solid, 62.7 mg, 60% yield, mp 41-42 °C. H NMR (500
1
44.7-147.2 (m), 140.8-141.0 (m), 119.6-119.8 (m), 116.7 (d, J
MHz, CDCl
3
) δ 7.56 (d, J = 7.5 Hz, 1H), 7.46 (t, J = 7.7 Hz, 1H),
19
=
21.0 Hz), 101.0 (q, J = 22.0 Hz), 85.9 (d, J = 184.0Hz). F NMR
7.17 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 7.5 Hz, 1H), 5.79-5.87 (m,
1
3
(
376 MHz, DMSO-d
6
) δ -133.6, -147.2, -192.0 (d, JH-F = 50.4 Hz).
1H), 5.29 (d, J = 12.0 Hz, 2H), 4.33 (d, J = 5.5 Hz, 2H). C NMR
(100MHz, CDCl ) δ 165.1 (t, J = 31.0 Hz), 143.2 (t, J = 6.9 Hz),
133.5, 130.1, 124.73, 123.9 (t, J = 1.5 Hz), 120.1 (t, J = 22.5 Hz),
+
HRMS (ESI-TOF) m/z: [M + H] Calcd for C8H5F3NO 188.0318,
Found 188.0314.
3
1
9
7-Trifluoromethyl-3-fluoro-indolin-2-one
(2t)
(General
118.6, 110.8 (t, J = 248.5 Hz), 110.4, 42.5. F NMR (376 MHz,
+
Procedure A) White solid, 61.3 mg, 56% yield, mp 101-103 °C.
3
CDCl ) δ -112.0 (s, 2F). HRMS (ESI-TOF) m/z: [M + H] Calcd for
1
H NMR (400 MHz, DMSO-d
6
) δ 11.14 (s, 1H), 7.77 (d, J = 7.2 Hz,
C11H10F2NO 210.0725, Found 210.0730.
1
=
1
=
H), 7.66 (d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 5.97 (d, JH-F
3,3-Difluoro-1-propargylindolin-2-one (3g) (General Procedure
13
1
50.4 Hz, 1H). C NMR (125 MHz, DMSO-d
6
) δ 173.2 (d, J =
C) White solid, 98.4 mg, 95% yield, mp 96-98 °C. H NMR (400
7.5 Hz), 141.2 (d, J = 2.5 Hz), 130.6, 127-128.0 (m), 125.7 (d, J
16.25 Hz), 122.9 (d, J = 1.2Hz), 123.7 (q, J = 270.6 Hz), 111.9
MHz, CDCl
3
) δ 7.58 (d, J = 7.2 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H),
7.22 (t, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6Hz, 1H), 4.50 (d, J = 2.4 Hz,
1
9
13
(
q, J = 31.9 Hz), 85.1 (d, J = 182.5Hz). F NMR (376 MHz,
DMSO-d ) δ -60.2, -193.2 (d, JH-F = 50.4 Hz). HRMS (ESI-TOF)
m/z: [M + H] Calcd for C9H6F4NO 220.0380, Found 220.0379.
3
2H), 2.31 (t, J = 2.6 Hz, 1H). C NMR (125MHz, CDCl ) δ 164.3
6
(t, J = 30.6 Hz), 142.1 (t, J = 6.8 Hz), 133.6, 124.7, 124.3, 120.0
+
(t, J = 23.1 Hz), 110.8 (t, J = 248.7 Hz), 110.6, 75.4, 73.5, 29.5.
12b
19
3
,3-Difluoroindolin-2-one (3a) (General Procedure C) White
3
F NMR (376 MHz, CDCl ) δ -111.4 (s, 2F). HRMS (ESI-TOF) m/z:
1
+
solid, 64.2 mg, 76% yield. H NMR (400 MHz, CDCl
3
) δ
[M + H] Calcd for C11H8F2NO 208.0568, Found 208.0564.
10
7
6
=
.55-7.60 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.17 (t, J = 7.4 Hz, 1H),
3,3-Difluoro-1-butylindolin-2-one (3h) (General Procedure C)
13
1
.92 (d, J = 8.0 Hz, 1H). C NMR (100 MHz, CDCl
3
) δ 166.2 (t, J
White solid, 61.9 mg, 55% yield. H NMR (400 MHz, CDCl
3
) δ
29.0 Hz), 143.0 (t, J = 8.0 Hz), 134.7, 125.3, 119.6 (t, J = 23.0
7.55 (d, J = 7.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.16 (t, J = 7.6 Hz,
1H), 6.90 (d, J = 8.0 Hz, 1H), 3.69 (t, J = 7.2 Hz, 2H), 1.63-1.71
1
9
3
Hz), 112.3, 111.7 (t, J = 247.0 Hz). F NMR (376 MHz, CDCl ) δ
13
-111.3 (s, 2F).
(m, 2H), 1.35-1.44 (m, 2H), 0.96 (t, J = 7.4Hz, 3H). C NMR
(125MHz, CDCl ) δ 165.3 (t, J = 30.0 Hz), 143.5 (t, J = 6.9 Hz),
133.5, 124.8, 123.7, 120.3 (t, J = 22.5 Hz), 110.9 (t, J = 247.5 Hz),
1
2c
3,3-Difluoro-1-methylindolin-2-one (3b) (General Procedure
3
1
C) White solid, 40.3 mg, 44% yield. H NMR (400 MHz, CDCl
3
) δ
1
9
7.55 (d, J = 7.2 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.18 (t, J = 7.6 Hz,
109.8, 40.0, 29.1, 20.0, 13.6 (d, J = 3.7 Hz). F NMR (376 MHz,
CDCl ) δ -112.4 (s, 2F).
13
1
H), 6.90 (d, J = 8.0 Hz, 1H), 3.22 (s, 3H). C NMR (125 MHz,
CDCl ) δ 165.3 (t, J = 30.0 Hz), 143.9 (t, J = 5.6 Hz), 133.6, 124.6,
23.9, 120.1 (t, J = 23.1 Hz), 110.9 (t, J = 248.1 Hz), 109.5, 26.3.
3
3
3,3-Difluoro-1-amylindolin-2-one (3i) (General Procedure C)
1
1
White solid, 77.8 mg, 65% yield, mp 37-40 °C. H NMR (500
1
9
F NMR (376 MHz, CDCl
3
) δ -112.3 (s, 2F).
3
MHz, CDCl ) δ 7.54 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H),
1
1a
3
,3-Difluoro-1-ethylindolin-2-one (3c) (General Procedure C)
7.16 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 3.67 (t, J = 7.5 Hz,
1
White solid, 50.2 mg, 51% yield. H NMR (400 MHz, CDCl
3
) δ
.56 (d, J = 7.2 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.17 (t, J = 7.6 Hz,
H), 6.91 (d, J = 8.0 Hz, 1H), 3.76 (q, J = 7.4 Hz, 2H), 1.30 (t, J =
2H), 1.66-1.71 (m, 2H), 1.34-1.36 (m, 4H), 0.89 (t, J = 6.7Hz, 3H).
13
7
1
3
C NMR (100MHz, CDCl ) δ 165.3 (t, J = 30.0 Hz), 143.5 (t, J =
7.0 Hz), 133.5, 124.8, 123.7 (t, J = 1.5 Hz), 120.3 (t, J = 23.0 Hz),
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10.9 (t, J = 247.5 Hz), 109.8, 40.3, 28.9, 26.8, 22.3, 13.9.
F
6
F NMR (376 MHz, DMSO-d ) δ -110.7 (s, 2F).
NMR (376 MHz, CDCl
3
) δ -112.4 (s, 2F). HRMS (ESI-TOF) m/z:
7-Fluoro-3,3-difluoroindolin-2-one (3q) (General Procedure C)
+
1
[M + H] Calcd for C13H16F2NO 240.1194, Found 240.1190.
White solid, 85.2 mg, 91% yield, mp 102-105 °C. H NMR (400
3
,3-Difluoro-1-hexylindolin-2-one (3j) (General Procedure C)
MHz, DMSO-d
6
) δ 11.82 (s, 1H), 7.47-7.55 (m, 2H), 7.18-7.23
1
13
White solid, 84.8 mg, 67% yield, mp 37-39 °C. H NMR (400
MHz, CDCl ) δ 7.55 (d, J = 7.2 Hz, 1H), 7.48 (t, J = 7.4 Hz, 1H),
.16 (t, J = 7.6Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 3.68 (t, J = 7.4 Hz,
H), 1.64-1.72 (m, 2H), 1.30-1.34 (m, 6H), 0.88 (t, J = 7Hz, 3H).
(m, 1H). C NMR (100MHz, DMSO-d ) δ 166.0 (t, J = 29.0 Hz),
6
3
147.35 (d, J = 243.0 Hz), 130.2-130.5 (m), 125.0 (d, J = 6.0 Hz),
7
2
121.8-122.3 (m), 121.7 (d, J = 7.0 Hz), 121.3 (d, J = 4.0 Hz),
19
6
108.5-113.5 (m). F NMR (376 MHz, DMSO-d ) δ -110.7,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
+
C NMR (100MHz, CDCl
3
) δ 165.2 (t, J = 30.0 Hz), 143.5 (t, J =
-131.1 (s, 2F). HRMS (ESI-TOF) m/z: [M + H] Calcd for
C8H5F3NO 188.0318, Found 188.0316.
7
.0 Hz), 133.6, 124.7, 123.7 (t, J = 2 Hz), 120.2 (t, J = 23.0 Hz),
10.9 (t, J = 248.0 Hz), 109.8, 40.3, 31.3, 27.0, 26.4, 22.5, 13.9.
1
7-Chloro-3,3-difluoroindolin-2-one (3r) (General Procedure C)
1
9
1
F NMR (376 MHz, CDCl
3
) δ -112.4 (s, 2F). HRMS (ESI-TOF) m/z:
White solid, 98.7 mg, 97% yield, mp 108-110 °C. H NMR (400
+
[M + H] Calcd for C14H18F2NO 254.1351,Found 254.1346.
6
MHz, DMSO-d ) δ 11.73 (s, 1H), 7.62-7.68 (m, 2H), 7.20 (t, J =
1
0
13
3,3-Difluoro-1-phenylindolin-2-one (3k) (General Procedure C)
7.8 Hz, 1H). C NMR (100MHz, DMSO-d
6
) δ 166.3 (t, J = 29.0
1
White solid, 104.2 mg, 85% yield. H NMR (500 MHz, CDCl
3
) δ
Hz), 140.8 (t, J = 7.5 Hz), 134.5, 125.2, 124.0, 121.4 (t, J = 23.0
1
9
7.63-7.64 (m, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.54 -7.57 (m, 2H),
6
Hz), 116.4, 111.3 (t, J = 248.0 Hz). F NMR (376 MHz, DMSO-d )
+
7
.41 -7.48 (m, 4H), 7.22 (t, J = 7.5 Hz, 1H), 6.88 (d, J = 8.0 Hz,
δ -110.2 (s, 2F). HRMS (ESI-TOF) m/z: [M + H] Calcd for
C8H5ClF2NO 204.0022, Found 204.0021.
1
3
1
3
H). C NMR (125MHz, CDCl ) δ 164.6 (t, J = 30.6 Hz), 144.2 (t,
J = 6.8 Hz), 133.5, 132.7, 130.0, 129.0, 126.2, 125.0, 124.4,
5,6-2-Fluoro-3,3-difluoroindolin-2-one (3s) (General Procedure
19
1
1
19.9 (t, J = 23.7 Hz), 110.8 (t, J = 248.1 Hz), 110.9. F NMR
376 MHz, CDCl ) δ -110.6 (s, 2F).
,3-Difluoro-1-benzylindolin-2-one (3l) (General Procedure C)
C) White solid, 67.7 mg, 66% yield, mp 107-109 °C. H NMR
(
3
6
(500 MHz, DMSO-d ) δ 11.39 (s, 1H), 8.03 (t, J = 8.5 Hz, 1H),
1
0
13
3
6
7.09-7.13 (m, 1H). C NMR (100MHz, DMSO-d ) δ 166.2 (t, J =
1
White solid, 115.3 mg, 89% yield. H NMR (400 MHz, CDCl
3
) δ
29.0 Hz), 152.2-154.9 (m), 145.3-147.8 (m), 140.3-140.6 (m),
7
1
.56 (d, J = 7.2 Hz, 1H), 7.28 -7.39 (m, 6H), 7.14 (t, J = 7.6 Hz,
115.8 (d, J = 21.0 Hz), 115.0-115.5 (m), 110.9 (t, J = 248.0 Hz),
13
19
H), 6.77 (d, J = 7.6 Hz, 1H), 4.90 (s, 2H). C NMR (100MHz,
) δ 165.5 (t, J = 30.0 Hz), 143.1 (t, J = 7.0 Hz), 134.3, 133.5,
29.1, 128.2, 127.3, 124.7, 124.0 (t, J = 2.0 Hz), 120.2 (t, J =
6
102.8 (d, J = 23.0 Hz). F NMR (376 MHz, DMSO-d ) δ -110.5 (s,
+
CDCl
3
2F), -128.7, -144.8. HRMS (ESI-TOF) m/z: [M + H] Calcd for
C8H4F4NO 206.0224, Found 206.0220.
1
2
1
9
3.0 Hz), 110.0 (t, J = 248.0 Hz), 110.6, 44.0. F NMR (376 MHz,
) δ -111.7 (s, 2F).
3,3-Difluoro-1-chloroethylindolin-2-one
Procedure C) White solid, 105.3 mg, 91% yield, mp 65-67 °C. H
NMR (400 MHz, CDCl ) δ 7.57 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.8
Hz, 1H), 7.20 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 4.05 (t, J
7-Trifluoromethyl-3,3-difluoroindolin-2-one
Procedure C) White solid, 112.6 mg, 95% yield, mp 96-99 °C. H
NMR (400 MHz, DMSO-d ) δ 11.74 (s, 1H), 8.00 (d, J = 7.6 Hz,
1H), 7.85 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H). C NMR
(100MHz, DMSO-d ) δ 166.6 (t, J = 29.0 Hz), 140.6 (t, J = 7.5 Hz),
130.9 (d, J = 4.0 Hz), 129.4, 123.2 (q, J = 270.0 Hz), 124.1, 121.3
(3t)
(General
1
CDCl
3
(3m)
(General
6
1
13
3
6
1
3
19
=
6.4 Hz, 2H), 3.77 (t, J = 6.4 Hz, 1H). C NMR (100MHz, CDCl
δ 165.5 (t, J = 26.0 Hz), 143.1 (t, J = 7.0 Hz), 133.7, 125.0, 124.2,
20.0 (t, J = 22.5 Hz), 110.6 (t, J = 247.5 Hz), 109.9, 42.1, 40.1.
3
)
(t, J = 23.0 Hz), 113.3 (q, J = 33.5 Hz), 109.9 (t, J = 246.5 Hz).
F
NMR (376 MHz, DMSO-d ) δ -60.3 (s, 3F), -110.2 (s, 2F). HRMS
6
+
1
(ESI-TOF) m/z: [M + H] Calcd for C9H5F5NO 238.0286, Found
238.0285.
1
9
F NMR (376 MHz, CDCl
3
) δ -111.8 (s, 2F). HRMS (ESI-TOF) m/z:
+
9c
[M + H] Calcd for C10H9ClF2NO 232.0335, Found 232.0331.
5-Nitryl-3,3-difluoroindolin-2-one (3u) (General Procedure D)
1
2b
1
5-Chloro-3,3-difluoroindolin-2-one (3n)
(General Procedure
White solid, 75.0 mg, 70% yield. H NMR (400 MHz, DMSO-d
6
)
1
C) Light-yellow solid, 97.7 mg, 96% yield. H NMR (500 MHz,
DMSO-d ) δ 11.35 (s, 1H), 7.83 (s, 1H), 7.57 (d, J = 8.5 Hz, 1H),
.01 (d, J = 8.5 Hz, 1H). C NMR (125MHz, DMSO-d
J = 23.5 Hz), 141.9 (t, J = 7.5 Hz), 134.5, 127.8, 125.6, 121.2 (t, J
δ 11.92 (s, 1H), 8.60 (s, 1H), 8.44 (d, J = 8.8 Hz, 1H), 7.18 (d, J =
13
6
13.6 Hz, 1H). C NMR (125MHz, DMSO-d
6
) δ 166.4 (t, J = 28.7
13
7
6
) δ 165.9 (t,
Hz), 149.1 (t, J = 7.5 Hz), 143.6, 131.1, 121.5, 120.2 (t, J = 23.1
19
Hz), 112.9, 110.4 (t, J = 248.7 Hz). F NMR (376 MHz, DMSO-d
δ -111.6 (s, 2F).
6
)
19
=
22.5 Hz), 114.0, 111.1 (t, J = 248.8 Hz). F NMR (376 MHz,
DMSO-d ) δ -111.1 (s, 2F).
-Bromo-3,3-difluoroindolin-2-one (3o) (General Procedure
1
2c
6
5-Fluoro-3,3-difluoroindolin-2-one (3v) (General Procedure C)
1
2b
1
5
White solid, 87.9 mg, 94% yield. H NMR (400 MHz, DMSO-d
6
)
1
C) White solid, 99.2 mg, 80% yield. H NMR (400 MHz,
DMSO-d ) δ 11.36 (s, 1H), 7.96 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H),
6.96 (d, J = 8.4 Hz, 1H). C NMR (100MHz, DMSO-d
J = 17.0 Hz), 139.9 (t, J = 7.0 Hz), 136.6, 128.4, 122.0 (t, J = 23.0
δ 11.25 (s, 1H), 7.70 (s, 1H), 7.39 (t, J = 9.0 Hz, 1H), 7.00-7.03
1
3
6
6
(m, 1H). C NMR (125MHz, DMSO-d ) δ 166.2 (t, J = 28.1 Hz),
1
3
6
) δ 166.2 (t,
158.8 (d, J = 238.8 Hz), 139.3 (t, J = 7.5 Hz), 121.3 (d, J = 22.5
Hz), 120.5-120.9 (m), 113.7 (d, J = 7.5 Hz), 113.4 (d, J = 26.3Hz),
1
9
19
Hz), 116.6, 113.1, 110.1 (t, J = 250.5 Hz). F NMR (376 MHz,
DMSO-d ) δ -111.0 (s, 2F).
-Methyl-3,3-difluoroindolin-2-one (3p) (General Procedure
6
111.3 (t, J = 248.1 Hz). F NMR (376 MHz, DMSO-d ) δ -111.6
6
(s, 2F), -119.0.
1
2b
12c
5
5-Bromo-3,3-difluoroindolin-2-one (3w) (General Procedure
1
1
C) White solid, 22.9 mg, 25% yield. H NMR (400 MHz,
DMSO-d ) δ 11.10 (s, 1H), 7.48 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H),
C) yellow oil, 102.9 mg, 83% yield. H NMR (400 MHz,
6
DMSO-d
7.2 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H). C NMR (100MHz,
DMSO-d ) δ 166.3 (t, J = 29.0 Hz), 142.5 (t, J = 7.5 Hz), 137.5,
125.5, 124.5, 121.4 (t, J = 23.0 Hz), 111.5 (t, J = 248.0 Hz), 104.5.
6
) δ 11.57 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.69 (d, J =
1
3
13
6
.89 (d, J = 8.0 Hz, 1H), 2.30 (s, 3H). C NMR (100MHz,
DMSO-d
6
) δ 166.3 (t, J = 29.0 Hz), 140.5 (t, J = 8.0 Hz), 134.8,
6
1
33.2, 125.6, 119.7 (t, J = 22.5 Hz), 112.0, 111.9 (t, J = 247.0 Hz).
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F NMR (376 MHz, DMSO-d
6
) δ -110.0 (s, 2F).
2015, 51, 10186-10190. (b) Dou, X.; Lu, Y. Enantioselective
Conjugate Addition of 3-Fluorooxindoles to Vinyl Sulfone: An
Organocatalytic access to Chiral 3-Fluoro-3-substituted
Oxindoles. Org. Biomol. Chem. 2013, 11, 5217-5221.
■ASSOCIATED CONTENT
Supporting Information
1
13
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(8) Dong, K.-L.; Yan, B.; Chang, S.-L.; Chi, Y-L.; Qiu, Y.-H.;
H, C, and F NMR spectra for all products (PDF)
Xu, X.-F.
Diazoacetamides:
-Fluorooxindoles. J. Org. Chem. 2016, 81, 6887-6892.
(9) (a) Umemoto, T.; Singh, R. P.; Xu, Y.; Saito, N.
Transition-Metal-Free Fluoroarylation of
A
Complementary Approach to
■
AUTHOR INFORMATION
3
Corresponding Authors
Discovery
Trifluoride as
of
4-tert-Butyl-2,6-dimethylphenylsulfur
Deoxofluorinating Agent with High
0
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*E-mail: zytang@csu.edu.cn (Z-Y.T.).
a
*
E-mail: luozhzhu@mail.sysu.edu.cn (Z.L.).
Thermal Stability as Well as Unusual Resistance to
Aqueous Hydrolysis, and Its Diverse Fluorination
Capabilities Including Deoxofluoro-Arylsulfinylation with
High Stereoselectivity. J. Am. Chem. Soc. 2010, 132,
Notes
The authors declare no competing financial interest.
1
8199-18205. (b) Singh, R. P.; Majumder, U.; Shreeve, J.
■ACKNOWLEDGMENTS
M. Nucleophilic Di- and Tetrafluorination of Dicarbonyl
Compounds. J. Org. Chem. 2001, 66, 6263-6267. (c)
Middleton, W. J.; Bingham, E. M. α, α-Difluoroarylacetic
Acids: Preparation from (Diethylamino)sulfur Trifluoride
Financial support was provided by the National Natural Science
Foundation of China 21302231, Hunan Provincial Natural
Science Foundation of China 14JJ3021, Ph.D. Programs
Foundation of Ministry of Education of China 20130162120032.
We thank advanced analysis laboratory of Hunan University for
HRMS-ESI assistance.
and
2
α
883-2887.
-Oxoarylacetates. J. Org. Chem. 1980
,
45,
(10) Lim, Y. H.; Ong, Q.; Duong, H. A.; Nguyen, T. M.;
Johannes, C. W. Direct Conversion of Indoles to
3,3-Difluoro-2-oxindoles via Electrophilic Fluorination. Org.
Lett. 2012, 14, 5676-5679.
■
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(b) Shi, S.-L.; Buchwald, S. L. Palladium-Catalyzed
Intramolecular C-H Difluoroalkylation: Synthesis of
Substituted 3,3-Difluoro-2-oxindoles. Angew. Chem., Int. Ed.
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015, 54, 1646-1650. (c) Wei, X.-J.; Wang, L.; Du, S.-F.; Wu,
L.-Z.; Liu, Q. Visible-light Photoredox Intramolecular
Difluoroacetamidation: Facile Synthesis of
,3-Difluoro-2-oxindoles from Bromodifluoroacetamides.
Org. Biomol. Chem.2016, 14, 2195-2199.
12) (a) Ohtsuka, Y.; Yamakawa, T. Direct Ethoxycarbonyl
(
3) Atkinson, B.; Beattie, D.; Culshaw, A. J.; Dale, J.; Devereux,
N. J.; Mckenna, J. Cyclohexyl Amide Derivatives as CRF
Receptor Antagonists. Patent US2011/02O1629 A1, Aug 18,
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(
(
4) Kath, J. C.; Luzzio, M. J. Pyrimidine Derivatives for the
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