Visible light induced hydrodifluoromethylation of alkenes derived from oxindoles with (difluoromethyl)triphenylphosphonium bromide

Article abstract of DOI:10.1016/j.jfluchem.2018.01.013

A visible light induced hydrodifluoromethylation of alkenes derived from oxindoles with (difluoromethyl)triphenylphosphonium bromide was developed. This reaction delivers a series of previously unknown difluoromethylated oxindoles containing C–CF₂H quaternary centers in moderate to excellent yields. The resulting CF₂H-containing oxindoles are potentially useful in drug discovery.

Full text of DOI:10.1016/j.jfluchem.2018.01.013

JournalofFluorineChemistry208(2018)73–79
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Visible light induced hydrodifluoromethylation of alkenes derived from
oxindoles with (difluoromethyl)triphenylphosphonium bromide
⁎
Wei-Qiang Hua, Xiu-Hua Xua, Feng-Ling Qinga,b,
a
Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of
Sciences, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China
b
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
A R T I C L E I N F O
A B S T R A C T
Keywords:
Oxindole
Alkene
Difluoromethylation
Phosphonium salt
Photoredox catalysis
A visible light induced hydrodifluoromethylation of alkenes derived from oxindoles with (difluoromethyl)tri-
phenylphosphonium bromide was developed. This reaction delivers a series of previously unknown di-
fluoromethylated oxindoles containing CeCF2H quaternary centers in moderate to excellent yields. The resulting
CF2H-containing oxindoles are potentially useful in drug discovery.
1. Introduction
sources (Scheme 1a). Although these methods are efficient, the sub-
strates are limited to the disubtituted terminal alkenes. Thus, the de-
The indolin-2-one (oxindole) frame is commonly found in natural
compounds as well as in biological active compounds [1]. Especially,
the 3-substituted oxindoles are widely recognized as valuable synthetic
intermediates [2]. On the other hand, the incorporation of fluorine
atom(s) and fluorine-containing groups into organic molecules has a
significant influence on the lipophilicity, metabolic stability, and
bioavailability of compounds [3]. Given the biological importance of
fluorinated functional groups and oxindole scaffolds, the fluorinated
oxindoles have many applications in drug development [4]. Over the
last decade, there has been continuous interest in the preparation of
oxindoles bearing fluorinated functional groups at the 3-position. Up to
now, numerous synthetic methods have been developed for the pre-
paration fluorinated oxindoles, such as 3-fluoro-2-oxindoles [5], 3,3-
difluoro-2-oxindoles [6], 3-trifluoromethyl-2-oxindoles [7], 3-di-
fluoroalkyl-2-oxindoles [8], and 3-monofluoroalkyl-2-oxindoles [9].
The difluoromethyl moiety (CF2H) is an intriguing structural motif
that has special biological properties [10]. Additionally, it is proposed
to act as a hydrogen bond donor and thus a surrogate for hydroxyl or
thiol groups [11]. Recently, a variety of methods have been developed
for the direct introduction of CF2H into organic compounds [12,13].
However, the synthesis of difluoromethylated oxindoles remains lim-
ited. In 2014, the groups of Dolbier [14a], Wang [14b,c], and Tan [14d]
independently reported the photoredox- or transition-metal-catalyzed
radical difluoromethylation/cyclization of N-arylacrylamides for the
construction of difluoromethylated oxindoles with different CF2H
velopment of new synthetic methods of difluoromethylated oxindoles is
highly desirable.
Very recently, our group disclosed that bromodifluoromethylpho-
sphonium bromide was used as a CF2H radical precursor for the di-
functionalization-type difluoromethylation reactions of alkenes under
visible light photoredox conditions [15]. To further extend the appli-
cation of difluoromethylphosphonium salts, we became interested in
the incorporation of CF2H into oxindoles (Scheme 1b). This protocol
affords a series of difluoromethylated oxindoles containing CeCF2H
quaternary centers, which are difficult to access by existing methods.
2. Results and discussion
We initiated our exploration by investigating the difluoromethyla-
tion of 3-(propan-2-ylidene)indolin-2-one (1a) with several di-
fluoromethylphosphonium salts (2a–d) in the presence of Ir(ppy)3
(3 mol%) under visible-light irradiation (Table 1). To our disappoint-
ment, no desired product was obtained using difluoromethylpho-
sphonium salts 2a–c (entries 1–3). In contrast, difluoromethylpho-
sphonium bromide (2d) could promote this reaction, giving the
difluoromethylated product 3a in 33% yield (entry 4). We envisioned
that the bromide anion probably acted as a reductive quencher in the
catalytic cycle of this reaction. Thus, we investigated different ad-
ditives, including tetra-n-butylammonium iodide (TBAI), diisopropy-
lethylamine (DIPEA), NaI, and KI (entries 5–8). Among them, KI was
⁎
Corresponding author at: Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
https://doi.org/10.1016/j.jfluchem.2018.01.013
Received 7 December 2017; Received in revised form 27 January 2018; Accepted 27 January 2018
0022-1139/©2018ElsevierB.V.Allrightsreserved.

W.-Q. Hu et al.
JournalofFluorineChemistry208(2018)73–79
Scheme 1. Synthesis of difluoromethylated oxindoles.
Table 1
Optimization of reaction conditions.a
Entry
2 (X)
Solvent
Additive
Yield (%)b
1
2
3
4
5
6
7
8
2a (PF6)
2b (BF4)
2c (OTf)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
2d (Br)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DCE
EA
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
–
–
–
–
0
0
0
33
72
50
75
77
84
0
89
96
71
85
0
TBAI
DIPEA
NaI
KI
KI
KI
KI
KI
KI
KI
9
10
11
12
13c
14d
15e
16f
17g
18h
KI
KI
KI
KI
94
0
0
a
Reaction conditions: 1a (0.2 mmol), difluoromethyltriphenylphosphonium salt (0.6 mmol), Ir(ppy)3 (0.006 mmol), additive (0.4 mmol), solvent (2.0 mL), visible light, rt, under N2.
b
c
d
e
f
Yields were determined by 19F NMR spectroscopy using fluorobenzene as an internal standard.
Difluoromethyltriphenylphosphonium bromide (0.4 mmol).
Ir(ppy)3 (0.002 mmol) was added.
Without degassing.
H2O (0.6 mmol) was added.
Without Ir(ppy)3.
g
h
No light.
superior to other additives, affording 3a in 77% yield (entry 8). Sub-
hydrodifluoromethylation to afford the corresponding products (3b–o)
in moderate to excellent yields. The substrates with either electron-
donating (1b and 1c) or electron-withdrawing substituents (1d and 1e)
were suitable substrates. Moreover, different halide substitutions on the
oxindole ring (1f–j) were well tolerated, and the corresponding adducts
were obtained in high yields. When compound 1k with methyl as the N-
protecting group was subjected to the reaction, slightly lower yield was
obtained. Finally, this photocatalytic protocol presented herein was
easily extended to other polysubstituted oxindole-derived alkenes
(1l–1o). The structure of these hydrodifluoromethylated products were
confirmed by the X-ray crystallographic analysis of 3g (see the Sup-
porting information).
sequent variation of the solvent led to the discovery that CH3CN was an
excellent solvent for this reaction (entries 9–12). Decreasing the
amount of 2d or Ir(ppy)3 resulted in lower yields (entries 13 and 14).
Notably, 1a was not converted at all without the degassing of the re-
action system, which signified that rigorous exclusion of oxygen is
necessary for this reaction (entry 15). Furthermore, the presence of
water did not affect the reaction (entry 16). Finally, the control ex-
periments showed that both the photocatalyst and visible light were
indispensable for this transformation (entries 17 and 18).
With the optimized reaction conditions in hand (Table 1, entry 12),
the substrate scope of this transformation was investigated. As shown in
Table 2, a series of oxindole-derived alkenes (1b–o) with different
To gain insight into the reaction mechanism, the isotopic labeling
experiments were conducted under standard reaction conditions. When
substituents
and
substitution
patterns
underwent
the
74

W.-Q. Hu et al.
JournalofFluorineChemistry208(2018)73–79
Table 2
Scope of substrates.a
aReaction conditions: 1a (0.5 mmol), difluoromethyltriphenylphosphonium salt (1.5 mmol), Ir(ppy)3 (0.015 mmol), KI (1.0 mmol), CH3CN (5.0 mL), visible light, rt, under N2, 10 h,
isolated yields.
bdr ratio was determined by 19F NMR spectroscopy.
Scheme 2. Isotopic mechanistic experiments.
the reaction of 1a was performed in CD3CN, we did not observe any
incorporation of the deuterium into product 3a (Scheme 2a). In con-
trast, the reaction in the presence of D2O (3.0 equiv) provided deuter-
ated product [D]-3a in 78% yield with a deuterium content of 33%
(Scheme 2b). These results indicated that the hydrogen atom probably
originates from trace amount of water in the reaction system.
On the basis of the above results and previous reports, a plausible
mechanism for this hydrodifluoromethylation is depicted in Scheme 3.
First, irradiation with visible light excites IrIII(ppy)3 into *IrIII(ppy)3.
Then, oxidation of *IrIII(ppy)3 by difluoromethylphosphonium 2d af-
fords IrIV(ppy)3 and CF2H radical [15]. Subsequently, the addition of
CF2H radical to alkenes 1 generates radical intermediate A, which is
reduced by iodide anion to give enolate anion B [16]. Finally, proto-
nation of enol anion B with H2O affords the desired product 3. On the
other hand, reduction of IrIV(ppy)3 by iodide anion regenerates the
ground-state photocatalyst IrIII(ppy)3 [17].
3. Conclusion
In conclusion, we have developed a hydrodifluoromethylation of
alkenes derived from oxindoles with (difluoromethyl)triphenylpho-
sphonium bromide under photoredox catalysis. This photocatalytic
protocol enables access to a variety of difluoromethylated oxindoles
containing CeCF2H quaternary centers in moderate to excellent yields.
Efforts are in progress towards the application of this protocol to syn-
thesize biologically active compounds.
75

W.-Q. Hu et al.
JournalofFluorineChemistry208(2018)73–79
Scheme 3. Proposed reaction mechanism.
4. Experimental section
678, 668, 653 cm−1; MS (ESI): m/z 204 (M+H)+; HRMS (ESI) m/z: [M
+H]+ Calculated for C12H14NO2+: 204.1019; Found: 204.1017.
4.1. General information
4.2.3. 5-Acetyl-3-(propan-2-ylidene)indolin-2-one (1d)
1H NMR (TMS as the internal standard), 19F NMR, and 13C NMR
spectra were recorded on a Agilent 400 MHz spectrometer, Bruker AM
400 MHz/500 MHz or VARIAN400 MHz spectrometer. Chemical shifts
(δ) are reported in ppm, and coupling constants (J) are in Hertz (Hz).
The following abbreviations were used to explain the multiplicities:
s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. HRMS
data using ESI were obtained on a Thermo Fisher Scientific LTQ FTICR-
MS. All reagents were used as received from commercial sources
without further purification or prepared as described in references.
Substrates 1a [18], 1g [19], 1h [20], 1l [20], 1m [21], 1n [22], and 1o
[23] are all known compounds.
White solid, mp 219–221 °C. 1H NMR (400 MHz, CDCl3) δ 9.31 (s,
1H), 8.17 (s, 1H), 7.85 (dd, J = 8.1, 1.2 Hz, 1H), 6.95 (d, J = 8.1 Hz,
1H), 2.64 (s, 3H), 2.60 (s, 3H), 2.47 (s, 3H). 13C NMR (101 MHz, CDCl3)
δ 197.2, 170.2, 158.4, 143.7, 131.5, 129.6, 124.6, 123.7, 122.3, 108.9,
26.5, 25.7, 23.5. IR (thin film) ν 2919, 2849, 1674, 1658, 1646, 1469,
668, 655 cm−1; MS (ESI): m/z 216 (M+H)+; HRMS (ESI) m/z: [M
+H]+ Calculated for C13H14NO2+: 216.1019; Found: 216.1017.
4.2.4. 3-(Propan-2-ylidene)-5-(trifluoromethyl)indolin-2-one (1e)
White solid, mp 172–174 °C. 1H NMR (400 MHz, CDCl3) δ 9.24 (s,
1H), 7.35 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H),
2.62 (s, 3H), 2.36 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 170.1, 158.2,
144.0 (d, J = 2.0 Hz), 138.2, 125.2, 122.8, 120.8 (q, J = 255.78 Hz),
120.6, 117.6, 109.8, 25.4, 23.5. IR (thin film) ν 1691, 1621, 1241,
1220, 1194, 1151, 688, 652 cm−1; MS (ESI): m/z 258 (M+H)+; HRMS
(ESI) m/z: [M+H]+ Calculated for C12H11FNO2+: 258.0736; Found:
258.0734.
4.2. General procedure for the synthesis of 3-(propan-2-ylidene)indolin-2-
one
A 50 mL round-bottom flask equipped with a reflux condenser and a
magnetic stir bar was charged with indolin-2-one (10.0 mmol), ethanol
(10 mL), acetone (7.3 mL, 0.1 mmol, 10.0 equiv), benzylamine
(0.33 mL, 3.0 mmol, 0.3 equiv), and acetic acid (0.17 mL, 3.0 mmol,
0.3 equiv). Then, the reaction mixture was heated under reflux for 2 h.
The precipitation was filtered off and washed with cold PE (10 mL). The
obtained product was dried for 30 min and used without further pur-
ification.
4.2.5. 5-Fluoro-3-(propan-2-ylidene)indolin-2-one (1f)
Yellow solid, mp 217–219 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.37
(s, 1H), 7.24 (dd, J = 9.9, 2.3 Hz, 1H), 6.93 (td, J = 9.2, 2.5 Hz, 1H),
6.72 (dd, J = 8.5, 4.8 Hz, 1H), 2.45 (s, 3H), 2.23 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 168.5, 157.5 (d, J = 234.3 Hz), 156.2, 136.6,
124.5 (d, J = 8.9 Hz), 122.6 (d, J = 2.7 Hz), 113.6 (d, J = 23.2 Hz),
110.9 (d, J = 26.3 Hz), 109.4 (d, J = 8.5 Hz), 24.7, 22.4. IR (thin film)
ν 2919, 2849, 1689, 1646, 1632, 668 cm−1; MS (ESI): m/z 192 (M
4.2.1. 5-Methyl-3-(propan-2-ylidene)indolin-2-one (1b)
Brown solid, mp 215–217 °C. 1H NMR (400 MHz, CDCl3) δ 8.87 (s,
1H), 7.32 (s, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H),
2.62 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
170.2, 155.2, 137.4, 130.8, 128.0, 124.6, 124.5, 123.4, 109.2, 25.4,
23.3, 21.6. IR (thin film) ν 2918, 2848, 1697, 1646, 1629, 1614,
655 cm−1; MS (ESI): m/z 188 (M+H)+; HRMS (ESI) m/z: [M+H]+
Calculated for C12H14NO+: 188.1070; Found: 188.1069.
; :
+H)+ HRMS (ESI) m/z: [M+H]+ Calculated for C11H11FNO+
192.0819; Found: 192.0818.
4.2.6. 6-Fluoro-3-(propan-2-ylidene)indolin-2-one (1i)
White solid, mp 193–195 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.49
(s, 1H), 7.41 (dd, J = 8.5, 5.6 Hz, 1H), 6.66 (ddd, J = 9.9, 8.7, 2.5 Hz,
1H), 6.54 (dd, J = 9.2, 2.5 Hz, 1H), 2.41 (s, 3H), 2.20 (s, 3H). 13C NMR
(101 MHz, DMSO-d6) δ 168.7, 161.7 (d, J = 244.4 Hz), 153.6 (d,
J = 2.5 Hz), 142.0 (d, J = 12.1 Hz), 124.8 (d, J = 9.6 Hz), 121.8, 120.0
(d, J = 2.7 Hz), 106.9 (d, J = 22.2 Hz), 96.9 (d, J = 26.3 Hz), 24.7,
22.2. IR (thin film) ν 2919, 2849, 1689, 1646, 1632, 668 cm−1; MS
(ESI): m/z 192 (M+H)+; HRMS (ESI) m/z: [M+H]+ Calculated for
4.2.2. 5-Methoxy-3-(propan-2-ylidene)indolin-2-one (1c)
Yellow solid, mp 202–204 °C. 1H NMR (400 MHz, CDCl3) δ 9.09 (s,
1H), 7.10 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.73 (dd,
J = 8.4, 2.3 Hz, 1H), 3.80 (s, 3H), 2.61 (s, 3H), 2.34 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 170.2, 155.8, 154.9, 133.6, 125.3, 123.5, 111.7,
111.6, 109.4, 56.0, 25.2, 23.2. IR (thin film) ν 2919, 1693, 1627, 1481,
C
11H11FNO+: 192.0819; Found: 192.0823.
76

W.-Q. Hu et al.
JournalofFluorineChemistry208(2018)73–79
4.2.7. 7-Fluoro-3-(propan-2-ylidene)indolin-2-one (1j)
4.3.3. 3-(1,1-Difluoro-2-methylpropan-2-yl)-5-methoxyindolin-2-one (3c)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–10/1) as the eluent, compound 3c
was obtained as a brown solid (56.1 mg, 44%), mp 152–154 °C. 1H NMR
(400 MHz, CDCl3) δ 9.29 (s, 1H), 6.90 (s, 1H), 6.79 (m, 2H), 6.38 (t,
J = 57.1 Hz, 1H), 3.77 (s, 3H), 3.49 (s, 1H), 1.22 (s, 3H), 1.00 (s, 3H).
19F NMR (376 MHz, CDCl3) δ −131.14 (dd, J = 278.2, 56.4 Hz, 1F),
−132.82 (dd, J = 278.2, 56.4 Hz, 1F). 13C NMR (101 MHz, CDCl3) δ
178.6, 155.5, 136.0, 127.3, 118.2 (t, J = 246.4 Hz), 114.2, 112.8,
110.3, 55.9, 51.4, 41.4 (t, J = 19.2 Hz), 17.6, 17.2. IR (thin film) ν
2922, 1698, 1490, 1471, 1216, 1080, 1051, 1036, 804 cm−1; MS (ESI):
White solid, mp 212–214 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.84
(s, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.04–6.98 (m, 1H), 6.87 (td, J = 8.1,
5.2 Hz, 1H), 2.45 (s, 3H), 2.23 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ
168.2, 156.4, 146.2 (d, J = 241.4 Hz), 127.3 (d, J = 12.8 Hz), 126.6 (d,
J = 4.8 Hz), 122.3 (d, J = 3.5 Hz), 121.5 (d, J = 6.0 Hz), 119.6 (d,
J = 2.9 Hz), 114.3 (d, J = 17.0 Hz), 24.9, 22.4. IR (thin film) ν 2919,
2849, 1686, 1658, 1621, 716 cm−1; MS (ESI): m/z 192 (M+H)+
;
HRMS (ESI) m/z: [M+H]+ Calculated for C11H11FNO+: 192.0819;
Found: 192.0818.
m/z 256 (M+H)+
;
HRMS (ESI) m/z: [M+H]+ Calculated for
4.2.8. 1-Methyl-3-(propan-2-ylidene)indolin-2-one (1k)
C
13H16F2NO2+: 256.1144; Found: 256.1142.
Yellow solid, mp 89–91 °C. 1H NMR (400 MHz, CDCl3) δ 7.51 (d,
J = 7.7 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 6.79
(d, J = 7.8 Hz, 1H), 3.22 (s, 3H), 2.61 (s, 3H), 2.35 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 168.0, 154.8, 142.2, 127.6, 123.7, 123.4, 122.8,
121.7, 107.6, 25.7, 25.3, 23.3. IR (thin film) ν 2919, 2849, 1696, 1632,
1469, 1338, 746, 668 cm−1; MS (ESI): m/z 188 (M+H)+; HRMS (ESI)
m/z: [M+H]+ Calculated for C12H14NO+: 188.1070; Found: 188.1069.
4.3.4. 5-Acetyl-3-(1,1-difluoro-2-methylpropan-2-yl)indolin-2-one (3d)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–10/1) as the eluent, compound 3d
was obtained as a white solid (89.9 mg, 67%), mp 156–158 °C. 1H NMR
(400 MHz, CDCl3) δ 9.82 (s, 1H), 7.94 (s, 1H), 7.91 (d, J = 7.4 Hz, 1H),
7.00 (d, J = 7.4 Hz, 1H), 6.31 (t, J = 56.8 Hz, 1H), 3.56 (s, 1H), 2.56 (s,
3H), 1.25 (s, 3H), 1.01 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −130.75
4.3. General procedure for the synthesis of 3-(1,1-difluoro-2-methylpropan-
(dd, J = 278.2, 56.4 Hz, 1F), −132.52 (dd, J = 278.2, 56.4 Hz, 1F). 13
C
2-yl)indolin-2-one
NMR (101 MHz, CDCl3) δ 197.0, 178.9, 147.0, 131.9, 130.6, 126.4,
117.9 (t, J = 245.3 Hz), 109.7, 50.7, 41.6 (t, J = 19.2 Hz), 26.5, 17.8,
17.4. IR (thin film) ν 2922, 1719, 1613, 1359, 1258, 1083, 1054, 825,
544 cm−1; MS (ESI): m/z 268 (M+H)+; HRMS (ESI) m/z: [M+H]+
Calculated for C14H16F2NO2+: 268.1144; Found: 268.1143.
A 25 mL Schlenk flask equipped with a rubber septum and a mag-
netic stir bar was charged with Ir(ppy)3 (9.8 mg, 0.015 mmol, 3 mol %),
substrates (1a–1o) (0.5 mmol, 1.0 equiv.), KI (165.0 mg, 1.0 mmol,
2.0 equiv.), [PPh3CF2H]+Br− (589.8 mg, 1.5 mmol, 3.0 equiv.), and
CH3CN (5.0 mL). The flask was sealed with 3 M vinyl electrical tape.
The mixture was degassed three times by the freeze-pump-thaw pro-
cedure. The flask was placed at a distance of 5 cm from the blue LEDs.
The mixture was stirred at room temperature under nitrogen atmo-
sphere and irradiated by blue LEDs for 10 h. After the reaction was
complete, the reaction mixture was concentrated under vacuum and the
crude product was purified by column chromatography on silica gel to
give the products (3a–3o).
4.3.5. 3-(1,1-Difluoro-2-methylpropan-2-yl)-5-(trifluoromethyl)indolin-2-
one (3e)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–15/1) as the eluent, compound 3e
was obtained as a pale brown solid (107 mg, 73%), mp 144–146 °C. 1H
NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 7.13 (s, 1H), 7.09 (d, J = 8.9 Hz,
1H), 6.87 (d, J = 8.5 Hz, 1H), 6.27 (t, J = 56.9 Hz, 1H), 3.50 (s, 1H),
1.18 (s, 3H), 0.96 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −58.54 (s, 3F),
−130.92 (dd, J = 278.2, 56.4 Hz, 1F), −132.69 (dd, J = 278.2,
56.4 Hz, 1F). 13C NMR (101 MHz, CDCl3)
δ 178.7, 144.4 (d,
4.3.1. 3-(1,1-Difluoro-2-methylpropan-2-yl)indolin-2-one (3a)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–17/1) as the eluent, compound 3a
was obtained as a light brown solid (92.6 mg, 82%), mp 154–156 °C. 1H
NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 7.27 (dd, J = 21.3, 7.1 Hz, 2H),
7.02 (t, J = 7.1 Hz, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.37 (t, J = 57.0 Hz,
1H), 3.54 (s, 1H), 1.23 (s, 3H), 1.02 (s, 3H). 19F NMR (376 MHz, CDCl3)
δ −131.30 (dd, J = 278.2, 56.4 Hz, 1F), −132.72 (dd, J = 274.5,
56.4 Hz, 1F). 13C NMR (101 MHz, CDCl3) δ 179.1, 142.6, 128.7, 126.4,
125.9, 122.3, 118.2 (t, J = 246.4 Hz), 110.3, 51.0, 41.4 (t,
J = 19.1 Hz), 17.7, 17.2. IR (thin film) ν 3181, 2919, 1700, 1618, 1473,
1237, 1077, 1046, 755, 671 cm−1; MS (ESI): m/z 226 (M+H)+; HRMS
(ESI) m/z: [M+H]+ Calculated for C12H14F2NO+: 226.1038; Found:
226.1037.
J = 1.9 Hz), 141.2, 127.3, 122.1, 120.7 (q, J = 257.6 Hz), 120.5, 118.0
(t, J = 245.4 Hz), 110.6, 51.3 (d, J = 3.8 Hz), 41.6 (t, J = 19.2 Hz),
17.7 (dd, J = 6.1, 4.0 Hz), 17.5 (dd, J = 5.1, 2.0 Hz). IR (thin film) ν
3180, 2984, 1711, 1489, 1198, 1153, 1081, 1050, 830, 673 cm−1; MS
(ESI): m/z 332 (M+K)+; HRMS (ESI) m/z: [M+K]+ Calculated for
C
13H12F5KNO2+: 332.0471; Found: 332.0468.
4.3.6. 3-(1,1-Difluoro-2-methylpropan-2-yl)-5-fluoroindolin-2-one (3f)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–15/1) as the eluent, compound 3f
was obtained as a light gray solid (81.1 mg, 67%), mp 143–145 °C. 1H
NMR (400 MHz, CCDl3) δ 9.55 (s, 1H), 7.10–6.83 (m, 3H), 6.37 (t,
J = 56.9 Hz, 1H), 3.55 (s, 1H), 1.25 (s, 3H), 1.03 (s, 3H). 19F NMR
(376 MHz, CDCl3) δ −120.47 to −120.52 (m, 1F), −131.09 (dd,
J = 278.2, 56.4 Hz, 1F), −132.70 (dd, J = 278.2, 56.4 Hz, 1F). 13C
NMR (101 MHz, CDCl3) δ 178.8, 158.8 (d, J = 240.4 Hz), 138.5 (d,
J = 2.0 Hz), 127.4 (d, J = 9.1 Hz), 118.0 (t, J = 43.4 Hz), 115.2 (d,
J = 23.2 Hz), 114.4 (d, J = 25.3 Hz), 110.7 (d, J = 8.3 Hz), 51.5, 41.5
(t, J = 19.2 Hz), 17.7, 17.3. IR (thin film) ν 2920, 2850, 1699, 1658,
1486, 1078, 1047, 777, 674 cm−1; MS (ESI): m/z 244 (M+H)+; HRMS
(ESI) m/z: [M+H]+ Calculated for C12H13F3NO+: 244.0944; Found:
244.0942.
4.3.2. 3-(1,1-Difluoro-2-methylpropan-2-yl)-5-methylindolin-2-one (3b)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–10/1) as the eluent, compound 3b
was obtained as a white solid (107.8 mg, 90%), mp 193–195 °C. 1H
NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.11 (s, 1H), 7.06 (d, J = 7.9 Hz,
1H), 6.80 (d, J = 7.9 Hz, 1H), 6.38 (t, J = 57.1 Hz, 1H), 3.50 (s, 1H),
2.34 (s, 3H), 1.23 (s, 3H), 1.03 (s, 3H). 19F NMR (376 MHz, CDCl3) δ
−131.48 (dd, J = 274.5, 56.4 Hz, 1F), −132.80 (dd, J = 274.5,
56.4 Hz, 1F). 13C NMR (126 MHz, CDCl3) δ 178.5, 140.0, 131.8, 129.0,
127.3, 126.0, 118.3 (t, J = 245.7 Hz), 109.7, 51.0, 41.4 (t,
J = 19.1 Hz), 21.4, 17.7, 17.2. IR (thin film) ν 3357, 2919, 2849, 1698,
1658, 1632, 1469 cm−1; MS (ESI): m/z 238 (M−H)−; HRMS (ESI) m/z:
[M−H]− Calculated for C13H14F2NO−: 238.1049; Found: 238.1045.
4.3.7. 5-Chloro-3-(1,1-difluoro-2-methylpropan-2-yl)indolin-2-one (3g)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–15/1) as the eluent, compound 3g
was obtained as a white solid (98.7 mg, 76%), mp 185–187 °C. 1H NMR
(400 MHz, CDCl3)
δ 9.43 (s, 1H), 7.33–7.22 (m, 2H), 6.87 (d,
77

W.-Q. Hu et al.
JournalofFluorineChemistry208(2018)73–79
J = 8.2 Hz, 1H), 6.35 (t, J = 56.9 Hz, 1H), 3.55 (s, 1H), 1.25 (s, 3H),
1.03 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −131.08 (dd, J = 278.2,
56.4 Hz, 1F), −132.71 (dd, J = 278.2, 56.4 Hz, 1F). 13C NMR
(101 MHz, CDCl3) δ 178.4, 141.0, 128.8, 127.8, 127.6, 126.8, 117.9 (t,
J = 245.4 Hz), 111.1, 51.1, 41.6 (t, J = 19.2 Hz), 17.8, 17.4. IR (thin
film) ν 2920, 2850, 1679, 1479, 1238, 1083, 1053, 817, 665 cm−1; MS
(ESI) m/z 260 (M+H)+ ; HRMS (ESI) m/z: [M+H]+ Calculated for
J = 3.0 Hz), 41.4 (t, J = 19.2 Hz), 26.1, 17.7 (dd, J = 5.3, 3.6 Hz), 17.2
(dd, J = 5.4, 2.3 Hz). IR (thin film) ν 2920, 1705, 1611, 1494, 1347,
1080, 1051, 752, 665 cm−1; MS (ESI): m/z 240 (M+H)+; HRMS (ESI)
+
m/z: [M+H]+ Calculated for C13H16F2NO
240.1192.
: 240.1194; Found:
4.3.12. 3-(1,1-Difluoro-2-methylbutan-2-yl)indolin-2-one (3l)
C
12H13ClF2NO+: 260.0648; Found: 260.0646.
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–15/1) as the eluent, compound 3l
was obtained as a pale yellow solid (110.2 mg, 91%). 1H NMR
4.3.8. 5-Bromo-3-(1,1-difluoro-2-methylpropan-2-yl)indolin-2-one (3h)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–15/1) as the eluent, compound 3h
was obtained as a pale yellow solid (105.3 mg, 69%), mp 205–207 °C.
1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 7.41 (t, J = 9.1 Hz, 2H), 6.82
(d, J = 8.2 Hz, 1H), 6.33 (t, J = 56.9 Hz, 1H), 3.55 (s, 1H), 1.24 (s, 3H),
1.03 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −131.06 (dd, J = 278.2,
56.4 Hz, 1F), −132.66 (dd, J = 278.2, 56.4 Hz, 1F). 13C NMR
(101 MHz, CDCl3) δ 178.2, 141.4, 131.7, 129.6, 128.0, 117.9 (t,
J = 246.4 Hz), 115.1, 111.5, 41.6 (t, J = 19.1 Hz), 17.8, 17.4. IR (thin
film) ν 2919, 1695, 1614, 1475, 1316, 1235, 1084, 1051, 884 cm−1; MS
(ESI): m/z 304 (M+H)+; HRMS (ESI) m/z: [M+H]+ Calculated for
C12H13BrF2NO+: 304.0143; Found: 304.0143.
(400 MHz, CDCl3)
δ 9.14 (s, 1H), 7.32–7.20 (m, 2H), 7.01 (t,
J = 7.6 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 6.23 (t, J = 60.0 Hz, 0.52H),
6.19 (t, J = 56.6 Hz, 0.48), 3.69 (s, 0.48H), 3.62 (s, 0.52H), 1.95–1.86
(m, 0.96H), 1.71–1.51 (m, 1.04H), 1.27 (s, 1.44H), 1.06 (s, 1.56H),
1.06 (t, J = 7.7 Hz, 0.96H), 0.88 (t, J = 7.8 Hz, 1.04H). 19F NMR
(376 MHz, CDCl3)
δ −125.87 (dd, J = 274.5, 56.4 Hz, 0.47F),
−128.22 (dd, J = 274.5, 56.4 Hz, 0.53F), −129.08 (dd, J = 274.5,
56.4 Hz, 0.53F), −130.47 (dd, J = 274.5, 56.4 Hz, 0.47F). 13C NMR
(101 MHz, CDCl3) δ 178.7 (dd, J = 18.8, 9.6 Hz), 142.4 (dd, J = 6.9,
3.7 Hz), 128.6 (d, J = 2.7 Hz), 126.3 (d, J = 12.5 Hz), 126.0, 122.3 (d,
J
= 4.2 Hz), 121.9, 121.4, 119.4, 119.0, 117.0, 116.5, 110.1 (t,
J = 3.6 Hz), 49.6, 48.9, 44.4 (dt, J = 35.5, 17.9 Hz), 25.0 (dd, J = 7.4,
4.2 Hz), 17.0 (dd, J = 6.3, 1.6 Hz), 15.6 (t, J = 4.5 Hz), 9.1 (d,
J = 3.2 Hz), 8.6. IR (thin film) ν 3216, 2971, 1704, 1619, 1472, 1333,
1084, 1061, 752, 672 cm−1; MS (ESI): m/z 240 (M+H)+; HRMS (ESI)
4.3.9. 3-(1,1-Difluoro-2-methylpropan-2-yl)-6-fluoroindolin-2-one (3i)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–10/1) as the eluent, compound 3i
was obtained as a white solid (99.7 mg, 82%), mp 148–150 °C. 1H NMR
(400 MHz, CDCl3) δ 9.57 (s, 1H), 7.17 (dd, J = 8.3, 5.2 Hz, 1H),
6.70–6.58 (m, 2H), 6.24 (t, J = 56 Hz, 1H), 3.44 (s, 1H), 1.14 (s, 3H),
0.96 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −111.68 to −111.74 (m,
1F), −131.12 (dd, J = 278.2, 56.4 Hz, 1F), −132.47 (dd, J = 278.2,
m/z: [M+H]+ Calculated for C13H16F2NO+
240.1193.
: 240.1194; Found:
4.3.13. 3-(1-(Difluoromethyl)cyclopentyl)indolin-2-one (3m)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–15/1) as the eluent, compound 3m
was obtained as a light red solid (72.4 mg, 58%), mp 138–140 °C. 1H
NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.25 (s,
1H), 7.05–6.98 (m, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.25 (t, J = 57.4 Hz,
1H), 3.60 (s, 1H), 2.15–2.02 (m, 2H), 1.97–1.87 (m, 1H), 1.77–1.63 (m,
2H), 1.62–1.45 (m, 3H). 19F NMR (376 MHz, CDCl3) δ −125.36 (dd,
J = 274.5, 56.4 Hz, 1F), −129.85 (dd, J = 274.5, 56.4 Hz, 1F). 13C
NMR (101 MHz, CDCl3) δ 178.5, 142.2, 128.7, 126.5, 125.8, 122.4,
118.5 (t, J = 245.4 Hz), 110.2, 52.2 (t, J = 18.7 Hz), 50.2, 31.2 (d,
J = 4.8 Hz), 29.4 (d, J = 4.5 Hz), 26.4, 26.3. IR (thin film) ν 2925,
1704, 1319, 1472, 1230, 1099, 1062, 750, 672 cm−1; MS (ESI): m/z
56.4 Hz, 1F). 13C NMR (101 MHz, CDCl3)
δ 179.3, 163.2 (d,
J = 247.5 Hz), 143.8 (d, J = 11.1 Hz), 127.5 (d, J = 9.1 Hz), 121.2 (d,
J = 3.0 Hz), 120.6 (t, J = 245.4 Hz), 108.8 (d, J = 22.2 Hz), 98.8 (d,
J = 27.3 Hz), 50.6 (q, J = 3.4 Hz), 41.5 (t, J = 19.2 Hz), 17.7 (dd,
J = 5.1, 4.0 Hz), 17.3 (dd, J = 5.1, 2.0 Hz). IR (thin film) ν 1709, 1627,
1503, 1465, 1337, 1082, 1056, 844, 787 cm−1; MS (ESI): m/z 244 (M
+
+H)+; HRMS (ESI) m/z: [M+H]+ Calculated for C12H13F3NO
244.0944; Found: 244.0942.
:
4.3.10. 3-(1,1-Difluoro-2-methylpropan-2-yl)-7-fluoroindolin-2-one (3j)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–15/1) as the eluent, compound 3j
was obtained as a brown solid (98.7 mg, 81%), mp 179–181 °C; 1H NMR
(400 MHz, CCDl3) δ 8.48 (s, 1H), 7.34 (s, 1H), 7.14–6.93 (m, 2H), 6.33
(t, J = 56.9 Hz, 1H), 3.60 (s, 1H), 1.23 (s, 3H), 1.05 (s, 3H). 19F NMR
(376 MHz, CDCl3) δ −131.29 (dd, J = 278.2, 56.4 Hz, 1F), −132.69
(dd, J = 278.2, 56.4 Hz, 1F), −113.79 to −111.83 (m, 1F). 13C NMR
252 (M+H)+
C
;
HRMS (ESI) m/z: [M+H]+ Calculated for
14H16F2NO+: 252.1194; Found: 252.1193.
4.3.14. 3-(1-(Difluoromethyl)cyclohexyl)indolin-2-one (3n)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (20/1–15/1) as the eluent, compound 3n
was obtained as a white solid (86.3 mg, 65%), mp 209–211 °C. 1H NMR
(101 MHz, CDCl3)
δ
177.0, 147.1 (d, J = 244.4 Hz), 129.7 (d,
(400 MHz, CDCl3) δ 8.78 (s, 1H), 7.30–7.18 (m, 2H), 6.97 (t,
J = 12.2 Hz), 128.5 (d, J = 3.0 Hz), 122.9 (d, J = 6.1 Hz), 122.2 (d,
J = 3.0 Hz), 118.0 (t, J = 236.3 Hz), 115.8 (d, J = 8.1 Hz), 51.2, 41.6
(t, J = 19.3 Hz), 17.7, 17.3. IR (thin film) ν 2919, 2849, 1707, 1644,
J = 7.6 Hz, 1H), 6.87 (d, J = 7.1 Hz, 1H), 5.51 (t, J = 56.3 Hz, 1H),
3.76 (s, 1H), 2.51 (d, J = 12.4 Hz, 1H), 2.09 (d, J = 10.0 Hz, 1H), 1.92
(s, 1H), 1.78–1.58 (m, 6H), 1.49–1.41 (m, 1H). 19F NMR (376 MHz,
1470, 1216, 1081, 1048, 771 cm−1; MS (ESI): m/z 244 (M+H)+
;
CDCl3) δ −125.68 (dd, J = 274.5, 56.4 Hz, 1F), −128.08 (dd,
HRMS (ESI) m/z: [M+H]+ Calculated for C12H13F3NO+: 244.0944;
Found: 244.0942.
J = 274.5, 56.4 Hz, 1F). 13C NMR (101 MHz, CDCl3) δ 178.3, 142.0,
128.4, 126.7, 126.2, 122.0, 119.0 (t, J = 247.5 Hz), 109.9, 45.6, 28.0
(d, J = 3.9 Hz), 26.2, 25.8, 21.3, 21.2. IR (thin film) ν 2921, 2861,
4.3.11. 3-(1,1-Difluoro-2-methylpropan-2-yl)-1-methylindolin-2-one (3k)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (30/1–20/1) as the eluent, compound 3k
was obtained as a yellow solid (76.8 mg, 64%), mp 54–56 °C. 1H NMR
(400 MHz, CDCl3) δ 7.32 (ddd, J = 5.5, 3.8, 0.7 Hz, 2H), 7.05 (td,
J = 7.6, 1.0 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.39 (t, J = 56.0 Hz, 1H),
3.50 (s, 1H), 3.18 (s, 3H), 1.20 (s, 3H), 0.95 (s, 3H). 19F NMR (376 MHz,
1706, 1619, 1474, 1060, 1043, 746, 635 cm−1; MS (ESI): m/z 266 (M
+H)+; HRMS (ESI) m/z: [M+H]+ Calculated for C15H18ONF2
266.1351; Found: 266.1350.
:
+
4.3.15. 3-(1,1-Difluoropropan-2-yl)indolin-2-one (3o)
After purification by silica gel column chromatography using pet-
roleum ether/ethyl acetate (30/1–15/1) as the eluent, compound 3o
was obtained as a yellow solid (84.5 mg, 80%). 1H NMR (500 MHz,
CDCl3) δ 8.71 (s, 0.37H), 8.61 (s, 0.63H), 7.30–7.23 (m, 2H), 7.08–7.05
(m, 1H), 6.93–6.92 (m, 1H), 6.23 (dt, J = 48.2, 7.8 Hz, 0.63H), 6.02
CDCl3)
δ −131.39 (dd, J = 274.5, 56.4 Hz, 1F), −132.92 (dd,
J = 274.5, 56.4 Hz, 1F). 13C NMR (101 MHz, CDCl3) δ 175.6, 145.2,
128.7, 126.2, 125.2, 122.3, 118.3 (t, J = 245.4 Hz), 108.3, 50.3 (t,
78

W.-Q. Hu et al.
JournalofFluorineChemistry208(2018)73–79
(dt, J = 44.8, 6.4 Hz, 0.37H), 3.78–3.75 (m, 1H), 2.88–2.77 (m, 0.37H),
2.70–2.60 (m, 0.63H), 0.96 (d, J = 4.8 Hz, 1.89H), 0.87 (d, J = 7.8 Hz,
1.11H). 19F NMR (376 MHz, CDCl3) δ −120.43 (dd, J = 274.5, 56.4 Hz,
0.74F), −120.50 (dd, J = 274.5, 56.4 Hz, 0.26F), −121.77 (dd,
J = 274.5, 56.4 Hz, 0.26F), −121.81 (dd, J = 274.5, 56.4 Hz, 0.74F).
13C NMR (101 MHz, CDCl3) δ 178.8, 178.3, 142.1, 142.0, 128.6, 127.0,
126.0, 125.7, 124.0, 122.9, 122.7, 118.1 (t, J = 244.4 Hz), 117.7 (t,
J = 242.4 Hz), 110.2, 110.1, 46.3, 46.1, 39.8 (t, J = 20.2 Hz), 38.9 (t,
J = 20.2 Hz), 38.7, 9.8, 9.0. IR (thin film) ν 3227, 1710, 1620, 1486,
1471, 1224, 1060, 751, 670 cm−1; MS (ESI): m/z 212 (M+H)+; HRMS
(ESI) m/z: [M+H]+ Calculated for C11H12F2NO+: 212.0881; Found:
212.0880.
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We thank National Natural Science Foundation of China (21332010,
21421002), Strategic Priority Research Program of the Chinese
Academy of Sciences (XDB20000000), and Youth Innovation
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