Highly diastereoselective aldol reactions of 3-Fluorooxindoles promoted by MgBr2?OEt2/iPr2NEt

Article abstract of DOI:10.1016/j.jfluchem.2020.109594

A highly diastereoselective aldol reaction between 3-fluorooxindoles and aromatic aldehydes has been developed. Commercially available, cheap Lewis acid MgBr₂^[rad]OEt₂ was used to promote the reaction. The reaction has a broad substrate scope with respect to both 3-fluorooxindoles and aromatic aldehydes, giving a series of α-fluoro-β-hydroxyoxindoles in good yields with high diastereoselectivities (63–94 percent yield, up to 99:1 anti/syn).

Full text of DOI:10.1016/j.jfluchem.2020.109594

Journal Pre-proof
Highly Diastereoselective Aldol Reactions of 3-Fluorooxindoles Promoted
by MgBr •OEt /iPr NEt
2
2
2
Zi-Bin Qiu, Ling-Yan Chen, Jian Ji, Xinfeng Ren, Ya Li
PII:
S0022-1139(20)30292-X
DOI:
https://doi.org/10.1016/j.jfluchem.2020.109594
FLUOR 109594
Reference:
To appear in:
Journal of Fluorine Chemistry
Received Date:
Revised Date:
Accepted Date:
24 November 2019
3 May 2020
13 June 2020
Please cite this article as: Qiu Z-Bin, Chen L-Yan, Ji J, Ren X, Li Y, Highly Diastereoselective
Aldol Reactions of 3-Fluorooxindoles Promoted by MgBr •OEt /iPr NEt, Journal of Fluorine
2
2
2
Chemistry (2020), doi: https://doi.org/10.1016/j.jfluchem.2020.109594
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Highly
Diastereoselective
Aldol
•OEt
Reactions
/iPr NEt
of
3
-Fluorooxindoles Promoted by MgBr
2
2
2
Zi-Bin Qiu, Ling-Yan Chen,* Jian Ji, Xinfeng Ren, Ya Li*
School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333
Longteng Road, Shanghai 201620, China
E-mail: lingyan.chen@hotmail.com, ya.li@sues.edu.cn
Graphical abstract
Highlights
·
·
·
MgBr
2
•OEt
2
/iPr NEt-promoted direct Aldol reactions of 3-fluorooxindoles
2
A variety of aromatic aldehydes has been successfully reacted
Mild reaction conditions
Abstract
A highly diastereoselective aldol reaction between 3-fluorooxindoles and
aromatic aldehydes has been developed. Commercially available, cheap Lewis acid
MgBr •OEt was used to promote the reaction. The reaction has a broad substrate
2
2
scope with respect to both 3-fluorooxindoles and aromatic aldehydes, giving a series
of α-fluoro-β-hydroxyoxindoles in good yields with high diastereoselectivities (63–94%

yield, up to 99:1 anti/syn).
Keywords: fluorine, fluoroalkylation, aldol reaction, Lewis acid, addition
1
. Introduction
Fluorinated organic molecules are important in the pharmaceutical and
agrochemical industries because of their unique physical and chemical benefits [1–5].
The 3-fluorooxindole framework is common in many biologically relevant
compounds and drug candidates [6–9]. For example, compound A, bearing a 3-aryl
3
-fluorooxindole structural unit, has been reported to be an effective maxi-K channel
opener [6], and compound B, which contains a 3-alkyl 3-fluorooxindole fragment, has
been reported to be bioactive against neurological disorders (Figure 1) [7].
Consequently, extensive efforts have been made towards the synthesis of such
structural motifs by fluorination [10–17] or using 3-fluorooxindole (or its equivalent)
as the building block [18–23]. Recently, the direct functionalization of commonly
available 3-fluorooxindoles has attracted great interest and several kinds of
transformations, such as the Mannich reaction [24–26], the arylation reaction [27], the
allylic alkylation reaction [28], and the conjugate addition with α,β-unsaturated
compounds [29–32], have been reported. Although significant progress has been
achieved, it is still highly desirable to explore other chemical transformations in order
to access structurally diverse 3-substituted 3-fluorooxindoles.

Figure 1 Bioactive compounds bearing a 3-fluorooxindole unit.
The Aldol reaction is one of the most important transformations in synthetic
chemistry, and the aldol reaction of 3-fluorooxindole has received considerable
attention in recent years [19,33]. For example, Wolf and co-workers have reported a
highly diastereoselective organocatalytic reaction of 3-fluorooxindoles with Isatins
(
Scheme 1a) [33]. This reaction occurs in nonhazardous isopropyl alcohol in the
presence of triethylamine as catalyst. Han, Soloshonok and co-workers have described
Cu(I)/bisoxazoline ligand-catalyzed asymmetric aldol reaction between
a
detrifluoroacetylatively in situ generated 3-fluorooxindole-derived enolates and
aldehydes (Scheme 1b) [19]. However, the use of such enolate precursors is not green
from the perspective of atom economy. Recently, we have been interested in the use
of 3-fluorooxindoles to access 3-substituted 3-fluorooxindoles [34–37]. Herein, we
report our studies on highly diastereoselective aldol reactions between
3
-fluorooxindoles and aromatic aldehydes, which was promoted by commonly
available MgBr ·OEt in the presence iPr NEt [38–40]. This reaction enabled the
2
2
2
synthesis of a series of α-fluoro-β-hydroxyoxindoles in good yields with high
diastereoselectivities (Scheme 1c).

Scheme 1 The aldol reactions of 3-fluorooxindoles

2
. Results and Discussion
Inspired by reports that the use of a relatively weakly basic amine in combination
with a Lewis-acid enables α-deprotonation of relatively less acidic carbonyl
compounds (such as carboxylic esters and thioesters) [39–41], we started the aldol
reaction between 3-fluorooxindole 2a and benzaldehyde 1a in the presence of CuCl
o
and iPr
2
NEt in DCM at 20 C (Table 1). The reaction proceeded sluggishly and the
desired product 3a was obtained in only 5% yield, with slight diastereoselectivity
after a 24 h reaction time (58:42 anti/syn , entry 1). In order to improve the results of
the reaction, other Lewis acids were then examined (entries 2–8). The use of
Cu(OAc)
diastereoselectivity (20–26% yield with diastereoselectivity ranging from 50:50 to
2:38 anti/syn, entries 2-4), whereas the use of Sc(OTf) or TiCl failed to give the
desired aldol product 3a (entries 5 and 6). To our delight, when Lewis acid
MgBr ·OEt was used, 3-fluorooxindole 2a reacted with 1a smoothly and gave
product 3a in an improved yield of 65% with a diastereoselectivity of 67:33 anti/syn
2
, Cu(OTf)
2
or La(OTf)
3
gave 3a in a low yield with no or a very low
6
3
4
2
2
(
entry 7). In comparison, the use of MgBr
2
gave a lower yield and diastereoselectivity
·OEt as the Lewis acid, the
or DCE
(60% yield, 55:45 anti/syn, entry 8). Using MgBr
2
2
reaction solvent was then screened (entries 9-11). While the use of CHCl
3
gave a comparable yield and diastereoselectivity (entry 9 vs entry 7, and entry 10 vs
entry 7), the use of THF achieved the best result (81% yield, 67:33 anti/syn, entry 11).
o
When the reaction temperature was lowered to 5 C, the reaction gave the expected
aldol product 3a in 94% yield with a diastereoselectivity of 95:5 anti/syn (entry 12).

The role of additives including MgBr
examined. With only MgBr ·OEt included, the aldol reaction failed to give product
a (entry 13). Using iPr NEt alone, the desired product 3a could be obtained in 13%
yield with low diastereoselectivity (58:42 anti/syn, entry 14). These experiments
2
·OEt
2
and iPr
2
NEt in the reaction was further
2
2
3
2
demonstrate that both MgBr
2
·OEt
2
and iPr NEt are essential for promoting the
2
reaction.
Table 1 Optimization of the aldol reaction between 3-fluorooxindole 2a and
benzaldehyde 1aa
entry reaction conditions
yield (%)b anti/syn c
o
1
2
3
4
5
6
7
8
9
1
CuCl, iPr
Cu(OAc)
Cu(OTf)
La(OTf)
Sc(OTf)
TiCl , iPr
2
NEt, DCM, 20 C
5
58:42
50:50
62:38
61:39
n.d
o
2
, iPr
, iPr
, iPr
, iPr
2
NEt, DCM, 20 C
20
20
26
0
o
2
2
NEt, DCM, 20 C
o
3
2
NEt, DCM, 20 C
o
3
2
NEt, DCM, 20 C
o
n.d
4
2
NEt, DCM, 20 C
0
o
MgBr
MgBr
MgBr
MgBr
MgBr
2
2
2
2
2
·OEt
, iPr
2
, iPr
2
NEt, DCM, 20 C
65
60
67:33
55:45
62:38
64:36
67:33
o
2
NEt, DCM, 20 C
o
·OEt
·OEt
·OEt
2
2
2
, iPr
, iPr
, iPr
2
2
2
NEt, CHCl
3
, 20 C 65
o
0
NEt, DCE, 20 C
80
81
o
11
NEt, THF, 20 C
o
12
13
14
MgBr
2
2
·OEt
·OEt
2
2
, iPr
2
NEt, THF, 5 C
94
0
95:5
n.d
o
MgBr
, THF, 5 C
o
iPr
2
NEt, THF, 5 C
13
58:42
a
Reaction conditions: 3-fluoro-1-methylindolin-2-one (2a, 0.5 mmol) in solvent (1.0 mL) was
added to a mixture of Lewis acid (0.5 mmol), benzaldehyde (1a, 0.6 mmol), iPr NEt and solvent
2

(1.0 mL) at the specified temperature. The reaction mixture was stirred for 24h and monitored by
TLC, followed by routine workup.
b
Isolated yield of the combined syn- and anti-3a.
c
19
The anti/syn ratio was determined by F NMR on the crude product 3a. The chemical shift
of the fluorine in anti- and syn-3a was about δ−163.3 and δ−167.7 ppm, respectively.
d
Not determined.
Under the optimized reaction conditions (Table 1, entry 12), the scope of current
aldol reaction with respect to aromatic aldehydes was examined (Table 2). Various
groups, such as alkyl (3b, 3d, and 3h–3j), alkoxy (3e and 3g), halogen (3c, 3f and 3k),
and cyano (3l) were well tolerated. Either the electronic nature or the position of the
substituents on the phenyl ring of aromatic aldehydes has no significant effect on the
outcome of the reaction: they all successfully reacted and gave the corresponding
product in very good to excellent yields with very high diastereoselectivity (3a–3l,
8
2–94% yield with diastereoselectivity ranging from 90:10 to 98:2 anti/syn). We then
investigated the substrate scope with regard to 3-fluorooxindoles. 4-Chloro- and
-bromo substituted substrates afforded the corresponding products 3m and 3n in 65%
yield with 99:1 anti/syn and 67% yield with 94:6 anti/syn, respectively. For 5- and
-substituted 3-fluorooxindoles (except 5-fluoro oxindole), substrate bearing either an
4
6
electron-withdrawing halogen substituent (3p, 3q, 3s, and 3t) or an electron-donating
methoxy group (3r) proved competent and gave the desired product in a good yield
(75–82%) with very high stereoselectivity (>90:10 anti/syn). In comparison, the
5
-fluorooxindole delivered product 3o with a relatively lower diastereoselectivity
(84:16 anti/syn). Finally, exploration of the reaction scope focused on varying the
2
N-substituents on 3-fluorooxindoles. When R was 4-methoxyphenyl, the desired

product 3u was obtained in 63% yield with a remarkable diastereoselectivity of >99:1
anti/syn. Other 3-fluorooxindoles with N-substituents such as propargyl (3v), ally
(3w), benzyl (3x) and ethyl (3y) reacted and gave the desired products in a very good
yield (76–81%) with a very good diastereoselectivity (ranging from 90:10 to 97:3
anti/syn). Aliphatic aldehyde such as butyraldehyde was also tried, but failed to give
the desired product 3z, which was probably caused by enolization (see the supporting
information).
Table 2 The aldol reaction of 3-Fluorooxindoles with aldehydesa,b,c

a
Reaction conditions: 3-fluoroindolin-2-one (2, 0.5 mmol) in THF (1.0 mL) was added to a
mixture of MgBr
2
•OEt
2
(1.0 mmol), aldehyde (1, 0.6 mmol), N, N-diisopropylethylamine (1.0
o
mmol) and THF (1.0 mL) at 5 C. The reaction mixture was kept stirring for 12 h, followed by
routine workup.
b
The yield referred to the isolated yield of the syn- and anti-3.
c
19
The anti/syn was determined by F NMR spectroscopy on the crude product 3.
The relative anti configuration of the major diastereomer of the compounds in
series 3 was confirmed by comparison with the NMR data reported in the literature
19]. To illustrate the observed stereochemical outcome of the reaction, one can
consider the transition states shown in Scheme 2. In Scheme 2a, the enolate of
-fluorooxindole would adopt an antiperiplanar orientation and attack the aldehyde
[
3
through an open transition state to afford the observed stereoselectivity. Alternatively,
addition of the enolate of 3-fluorooxindole to the aldehyde through a chair-like
transition state gives the anti-aldol product (Scheme 2b). However, the R group is
placed in the axial position and is likely to be involved in repulsive steric interactions.
Based on these factors, we tentatively conclude that the open transition state mode is
preferred (Scheme 2a).
Scheme 2 Transition state models proposed for the aldol reaction of 3-fluorooxindoles
with aldehydes.
Furthermore, we tried to apply the present approach to N-methyl 3-chlorooxindole

4
. However, compound 4 failed to give the corresponding aldol product under the
identical reaction conditions used in Table 2, with the starting materials recovered
almost quantitatively. This result indicates that the reactivity of oxindole in the current
reaction was greatly affected by the electronic effect of the fluorine.
3
. Conclusions
We have developed a highly diastereoselective MgBr
2
·OEt
2
/iPr NEt-promoted
2
aldol reaction between 3-fluorooxindoles and aromatic aldehydes. A wide range of
substituted 3-fluorooxindoles and aromatic aldehydes were successfully used and a
series of α-fluoro-β-hydroxyoxindole were obtained in good yields with high
diastereoselectivities. This approach has the advantage of using easily available
reagents and mild reaction conditions.
4
. Experimental
4
.1. General
Flash chromatography was performed on silica gel with petroleum ether/ethyl
acetate as the eluent. Melting points were measured on an electrothermal digital
1
13
19
melting point apparatus. H, C and F NMR spectra were recorded on a 400 or 500
MHz NMR spectrometer. HRMS data were obtained on an ESI-FTMS mass
spectrometer.
4
.2. Synthesis of 3 (general procedure)
-fluorooxindole (2, 0.5 mmol) in THF (1.0 mL) was added to a mixture of
3

MgBr
2
•OEt
2
(1.0 mmol), aldehyde (1, 0.6 mmol), N, N-diisopropylethylamine (1.0
o
mmol) and THF (1.0 mL) at 5 C. After 12h, the reaction mixture was concentrated
under reduced pressure. The residue was purified by flash column chromatography on
silica gel to give the corresponding product 3.
4
.2.1 anti-3-fluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one (anti-3a)[19]
1
Colorless solid. m. p. 115–116 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.26–7.21 (m,
3
3
3
6
5
−
H), 6.85 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H),
1
9
.40–5.33 (m, 1H), 3.33–3.26 (m, 1H), 3.02 (s, 3H). F NMR (376 MHz, CDCl
3
) δ =
) δ = 171.7 (d, 2JCF = 21.2 Hz), 144.0 (d, JCF
.0 Hz), 135.9 (s), 130.4 (d, JCF = 3.0 Hz), 127.4 (s), 126.8 (s), 126.3 (d, JCF = 2.0 Hz),
1
3
163.3 (s). C NMR (101 MHz, CDCl
3
=
5
1
1
25.2 (s), 121.8 (d, 2JCF = 19.2 Hz), 121.7 (d, JCF = 2.0 Hz), 107.6 (s), 92.1 (d, 1JCF
93.9 Hz), 73.2 (d, 2JCF = 31.3 Hz), 25.1 (s).
=
4
.2.2 syn-3-fluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one (syn-3a)
1
Colorless solid. m. p. 109–110 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.49–7.40 (m,
3
1
1
H), 7.38–7.31 (m, 1H), 7.24–7.05 (m, 6H), 6.63 (d, J = 7.8 Hz, 1H), 5.39–5.26 (m,
1
9
13
H), 3.51–3.39 (m, 1H), 2.97 (s, 3H). F NMR (376 MHz, CDCl
) δ = 171.8 (d, 2JCF = 21.2 Hz), 144.1 (d, JCF = 5.0 Hz), 135.1
d, JCF = 6.1 Hz), 131.3 (d, JCF = 3.0 Hz), 128.5 (s), 127.7 (s), 127.6 (d, JCF = 1.0 Hz),
3
) δ = −167.7 (s). C
NMR (101 MHz, CDCl
3
(
1
1
1
27.0 (s), 123.0 (d, 2JCF = 2.0 Hz), 122.6 (d, JCF = 19.2 Hz), 108.3 (s), 94.6 (d, 1JCF
=
95.9 Hz), 76.1 (d, 2JCF = 25.2 Hz), 25.9 (s). IR (cm ): 3362, 1637, 1612, 1457, 1426,
−1
+
358, 1076, 965, 747. MS (ESI) m/z: 272.1 [M + H] . HRMS (ESI) m/z: calcd for

15FNO +
[M + H] 272.1082, found 272.1078.
+
C
16
H
2
4
.2.3 anti-3-fluoro-3-(hydroxy(o-tolyl)methyl)-1-methylindolin-2-one (anti-3b) [19]
1
Colorless solid. m. p. 146–147 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.36–7.29 (m,
3
1
H), 7.21–7.05 (m, 4H), 6.97–6.91 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.68–6.62 (m,
3
19
1
H), 5.44–5.37 (m, 1H), 3.12 (s, 3H), 3.05 (d, J = 8.0 Hz, 1H), 2.30 (s, 3H). F
1
3
NMR (376 MHz, CDCl
3
) δ = −162.8 (s). C NMR (101 MHz, CDCl ) δ = 172.7 (d,
3
2JCF = 20.2 Hz), 145.0 (d, JCF = 5.0 Hz), 137.4 (s), 136.8 (s), 131.4 (d, JCF = 3.0 Hz),
29.1 (s), 128.0 (d, JCF = 1.0 Hz), 127.7 (s), 126.2 (s), 124.4 (d, JCF = 1.0 Hz), 122.9
1
(
d, 2JCF = 18.2 Hz), 122.6 (d, JCF = 3.0 Hz), 108.5 (s), 93.1 (d, 1JCF = 193.9 Hz), 74.4
d, 2JCF = 31.3 Hz), 26.1 (s), 21.4 (s).
(
4
.2.4
anti-3c) [19]
Colorless solid. m. p. 171–172 ˚C. H NMR (400 MHz, CDCl
H), 7.42–7.38 (m, 1H), 7.37–7.27 (m, 2H), 7.22–7.11 (m, 2H), 7.04–6.98 (m, 1H),
anti-3-((2-bromophenyl)(hydroxy)methyl)-3-fluoro-1-methylindolin-2-one
(
1
3
) δ = 7.50–7.45 (m,
1
3
19
6
.77–6.71 (m, 1H), 5.95 (d, J = 8.0 Hz, 1H), 3.50–3.42 (br, 1H), 3.16 (s, 3H). F
1
3
NMR (376 MHz, CDCl
3
) δ = −164.7 (s). C NMR (101 MHz, CDCl ) δ = 172.3 (d,
3
2JCF = 21.2 Hz), 144.5 (d, JCF = 5.0 Hz), 136.4 (s), 133.0 (s), 131.5 (d, JCF = 3.0 Hz),
30.1 (s), 129.3 (s), 126.9 (s), 126.7 (s), 124.1 (s), 122.7 (d, 2JCF = 18.2 Hz), 122.6 (d,
CF = 2.0 Hz), 108.4 (s), 93.6 (d, 1JCF = 195.9 Hz), 73.6 (d, 2JCF = 31.3 Hz), 26.2 (s).
1
J
4
.2.5 anti-3-fluoro-3-(hydroxy(m-tolyl)methyl)-1-methylindolin-2-one (anti-3d) [19]
1
Colorless solid. m. p. 249–250 ˚C. H NMR (500 MHz, CDCl
3
) δ = 7.35–7.29 (m,

3
1
1
2
H), 7.21–7.15 (m, 1H), 7.14–7.05 (m, 3H), 6.98–6.91 (m, 1H), 6.74 (d, J = 8.0 Hz,
3
H), 6.68–6.63 (m, 1H), 5.41 (d, J = 8.0 Hz, 1H), 3.12 (s, 3H), 3.14–3.02 (br, 1H),
19
13
.30 (s, 3H). F NMR (376 MHz, CDCl
) δ = 172.7 (d, 2JCF = 21.2 Hz), 145.0 (d, JCF = 5.0 Hz), 137.4 (s), 136.8 (s),
31.3 (d, JCF = 3.0 Hz), 129.1 (s), 128.0 (d, JCF = 2.0 Hz), 127.7 (s), 126.2 (s), 124.3
3
) δ = −162.8 (s). C NMR (101 MHz,
CDCl
3
1
(
d, JCF = 2.0 Hz), 122.9 (d, 2JCF = 19.2 Hz), 122.6 (d, JCF = 3.0 Hz), 108.5 (s), 93.1
d,1JCF = 193.9 Hz), 74.5 (d, 2JCF = 30.3 Hz), 26.1 (s), 21.3 (s).
(
4
.2.6
anti-3-fluoro-3-(hydroxy(3-methoxyphenyl)methyl)-1-methylindolin-2-one
(anti-3e)
1
Colorless solid. m. p. 123–124 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.36–7.30 (m,
3
1
H), 7.25–7.18 (m, 1H), 6.99–6.82 (m, 4H), 6.75 (d, J = 8.0 Hz, 1H), 6.70–6.64 (m,
3
19
1
H), 5.42 (d, J = 8.0 Hz, 1H), 3.73 (s, 3H), 3.26–3.12 (br, 1H), 3.12 (s, 3H). F
1
3
NMR (376 MHz, CDCl
3
) δ = −162.6 (s). C NMR (101 MHz, CDCl ) δ = 172.7 (d,
3
2JCF = 21.2 Hz), 159.2 (s), 145.1 (d, JCF = 6.1 Hz), 138.5 (s), 131.4 (d, JCF = 3.0 Hz),
1
1
28.8 (s), 126.2 (s), 122.9 (d, 2JCF = 18.2 Hz), 122.7 (d, JCF = 3.0 Hz), 119.7 (d, JCF
=
.0 Hz), 114.6 (s), 112.4 (d, JCF = 2.0 Hz), 108.6 (s), 93.0 (d, 1JCF = 193.9 Hz), 74.3 (d,
2JCF = 31.3 Hz), 55.2 (s), 26.1 (s). IR (cm ): 3373, 1687, 1605, 1463, 1428, 1373,
−1
+
1
098, 1060, 1005, 747. MS (ESI) m/z: 302.1 [M + H] . HRMS (ESI) m/z: calcd for
17FNO +
[M + H] 302.1187, found 302.1178.
+
C
17
H
3
4
.2.7
anti-3-((3-chlorophenyl)(hydroxy)methyl)-3-fluoro-1-methylindolin-2-one
(anti-3f)

1
Colorless solid. m. p. 162–163 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.38–7.27 (m,
3
H), 7.26–7.20 (m, 2H), 6.99–6.93 (m, 1H), 6.81–6.74 (m, 1H), 6.61–6.55 (m, 1H),
3
19
5
.42 (d, J = 8.0 Hz, 1H), 3.50–3.38 (br, 1H), 3.13 (s, 3H). F NMR (376 MHz,
) δ = −162.5 (s). C NMR (101 MHz, CDCl
) δ = 172.5 (d, 2JCF = 21.2 Hz),
1
3
CDCl
3
3
1
45.0 (d, JCF = 5.0 Hz), 139.2 (s), 134.0 (s), 131.6 (d, JCF = 2.0 Hz), 129.1 (s), 128.5
(s), 127.5 (d, JCF = 2.0 Hz), 126.1 (s), 125.6 (d, JCF = 3.0 Hz), 122.9 (d, JCF = 3.0 Hz),
1
2
22.5 (d, 2JCF = 18.2 Hz), 108.7 (s), 92.9 (d, 1JCF = 194.9 Hz), 73.5 (d, 2JCF = 32.3 Hz),
−
1
6.2 (s). IR (cm ): 3307, 1678, 1606, 1462, 1374, 1091, 1046, 1005, 742, 720. MS
+
14ClFNO + [M + H]+
(
ESI) m/z: 306.1 [M + H] . HRMS (ESI) m/z: calcd for C16
H
2
3
06.0692, found 306.0686.
4
.2.8
anti-3-((3,4-dimethoxyphenyl)(hydroxy)methyl)-3-fluoro-1-methylindolin-2-one
(anti-3g)
1
Colorless solid. m. p. 140–141 ˚C. H NMR (400 MHz, CDCl ) δ = 7.37–7.30 (m,
3
3
1
3
−
H), 6.96 (t, J = 8.0 Hz, 1H), 6.90–6.70 (m, 5H), 5.42–5.36 (m, 1H), 3.87 (s, 3H),
.76 (s, 3H), 3.28–3.22 (m, 1H), 3.12 (s, 3H). 19F NMR (376 MHz, CDCl
) δ =
) δ = 172.7 (d, 2JCF = 20.2 Hz), 149.0 (s),
48.3 (s), 145.0 (d, 2JCF = 10.1 Hz), 131.4 (d, JCF = 3.0 Hz), 129.3 (s), 126.2 (s), 123.0
d, 2JCF = 18.4 Hz), 122.6 (d, JCF = 3.0 Hz), 119.76 (s), 119.75 (s), 110.5 (s), 108.6 (s),
3.2 (d, 1JCF = 192.9 Hz), 74.3 (d, 2JCF = 31.3 Hz), 55.8 (d, JCF = 6.1 Hz), 26.1 (s). IR
3
1
3
162.8 (s). C NMR (101 MHz, CDCl
3
1
(
9
−
1
(
cm ): 3385, 1702, 1606, 1503, 1455, 1370, 1101, 1149, 1015, 754. MS (ESI) m/z:

+
18FNaNO +
[M + Na] 354.1112,
+
3
32.1 [M + H] . HRMS (ESI) m/z: calcd for C18
H
4
found 354.1095.
4
.2.9
anti-3-((3,4-dimethylphenyl)(hydroxy)methyl)-3-fluoro-1-methylindolin-2-one
(anti-3h)
1
Colorless solid. m. p. 168–169 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.36–7.29 (m,
3
1
H), 7.09–6.90 (m, 4H), 6.75 (d, J = 8.0 Hz, 1H), 6.71–6.65 (m, 1H), 5.42–5.32 (m,
3
2
19
1
H), 3.13 (s, 3H), 2.95 (d, J = 6.0 Hz, 1H), 2.23 (d, J = 13.2 Hz, 6H). F NMR (376
) δ = −162.5 (s). C NMR (101 MHz, CDCl
) δ = 172.8 (d, 2JCF = 20.2
1
3
MHz, CDCl
3
3
Hz), 145.1 (d, JCF = 6.1 Hz), 136.7 (s), 136.0 (s), 134.3 (s), 131.3 (d, JCF = 3.0 Hz),
1
1
3
1
29.1 (s), 128.5 (d, JCF = 2.0 Hz), 126.3 (s), 124.7 (d, JCF = 1.0 Hz), 123.0 (d, 2JCF
8.2 Hz), 122.5 (d, JCF = 3.0 Hz), 108.5 (s), 93.0 (d, 1JCF = 192.9 Hz), 74.3 (d, 2JCF
=
=
−
1
1.3 Hz), 26.1 (s), 19.7 (s), 19.5 (s). IR (cm ): 3314, 2898, 1693, 1604, 1462, 1371,
+
098, 1053, 1006, 695. MS (ESI) m/z: 300.1 [M + H] . HRMS (ESI) m/z: calcd for
19FNO +
[M + H] 300.1394, found 300.1386.
+
C
18
H
2
4
.2.10
anti-3-((4-(tert-butyl)phenyl)(hydroxy)methyl)-3-fluoro-1-methylindolin-2-one
(anti-3i)
1
Colorless solid. m. p. 145–146 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.37–7.30 (m,
3
3
3
H), 7.25–7.21 (m, 2H), 6.94 (t, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.66–6.61
1
9
(
m, 1H), 5.45–5.39 (m, 1H), 3.13 (s, 3H), 2.90–2.80 (m, 1H), 1.32 (s, 9H). F NMR
) δ = −162.7 (s). C NMR (101 MHz, CDCl =
) δ = 172.7 (d, 2JCF
1
3
(
376 MHz, CDCl
3
3

2
0.2 Hz), 151.6 (s), 145.1 (d, JCF = 5.0 Hz), 133.9 (s), 131.3 (d, JCF = 3.0 Hz), 127.0
d, JCF = 2.0 Hz), 126.3 (s), 124.7 (s), 122.9 (d, 2JCF = 18.2 Hz), 122.6 (d, JCF = 2.0
Hz), 108.5 (s), 93.0 (d, 1JCF = 192.9 Hz), 74.2 (d, 2JCF = 31.3 Hz), 34.6 (s), 31.3 (s),
(
2
6.1 (s). IR (cm−1): 3314, 2942, 1681, 1607, 1463, 1373, 1096, 1051, 1004, 739. MS
+
23FNO + [M + H]+
(
ESI) m/z: 328.2 [M + H] . HRMS (ESI) m/z: calcd for C20
H
2
3
28.1707, found 328.1700.
4
.2.11
anti-3-((4-ethylphenyl)(hydroxy)methyl)-3-fluoro-1-methylindolin-2-one
(anti-3j)
1
Colorless solid. m. p. 136–137 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.36–7.30 (m,
3
3
1
H), 7.24–7.10 (m, 4H), 6.94 (t, J = 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.68–6.63
2
(
m, 1H), 5.45–5.38 (m, 1H), 3.12 (s, 3H), 3.04–2.97 (m, 1H), 2.64 (dd, J = 15.2 Hz,
3
3
19
J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). F NMR (376 MHz, CDCl
3
) δ = −162.6
1
3
) δ = 172.7 (d, 2JCF = 21.2 Hz), 145.1 (d, JCF = 6.1
(
s). C NMR (101 MHz, CDCl
3
Hz), 144.6 (s), 134.1 (s), 131.3 (d, JCF = 3.0 Hz), 127.31 (s), 127.28 (d, JCF = 1.0 Hz),
1
1
1
26.3 (s), 122.9 (d, 2JCF = 19.2 Hz), 122.6 (d, JCF = 3.0 Hz), 108.5 (s), 93.1 (d, 1JCF
=
92.9 Hz), 74.3 (d, 2JCF = 31.3 Hz), 28.6 (s), 26.1 (s), 15.5 (s). IR (cm ): 3343, 2945,
−1
679, 1605, 1462, 1371, 1095, 1054, 1005, 741. MS (ESI) m/z: 300.1 [M + H]+.
19FNO +
[M + H] 300.1394, found 300.1386.
+
HRMS (ESI) m/z: calcd for C18
.2.12
anti-3k) [19]
H
2
4
anti-3-((4-bromophenyl)(hydroxy)methyl)-3-fluoro-1-methylindolin-2-one
(
1
Colorless solid. m. p. 145–146 ˚C. H NMR (400 MHz, CDCl ) δ = 7.46–7.42 (m,
3
3
2
H), 7.38–7.32 (m, 1H), 7.21–7.16 (m, 2H), 6.97 (t, J = 8.0 Hz, 1H), 6.79–6.74 (m,

1
H), 6.66–6.62 (m, 1H), 5.43–5.37 (m, 1H), 3.29–3.24 (m, 1H), 3.13 (s, 3H). 19F
1
3
NMR (376 MHz, CDCl
3
) δ = −162.5 (s). C NMR (101 MHz, CDCl ) δ = 172.4 (d,
3
2JCF = 20.2 Hz), 145.0 (d, JCF = 5.0 Hz), 136.0 (s), 131.6 (d, JCF = 3.0 Hz), 131.0 (s),
1
1
29.1 (d, JCF = 2.0 Hz), 126.1 (s), 122.9 (d, JCF = 2.0 Hz), 122.6 (d, 2JCF = 11.1 Hz),
22.5 (s), 108.8 (s), 92.9 (d, 1JCF = 193.9 Hz), 73.8 (d, 2JCF = 31.3 Hz), 26.2 (s).
4
.2.13
anti-4-(3-fluoro-1-methyl-2-oxoindolin-3-yl)(hydroxy)methyl)benzonitrile
(anti-3l)
1
Colorless solid. m. p. 171–172 ˚C. H NMR (500 MHz, CDCl
3
) δ = 7.66–7.59 (m,
2
H), 7.50–7.43 (m, 2H), 7.40–7.34 (m, 1H), 7.00–6.93 (m, 1H), 6.81–6.76 (m, 1H),
3
19
6
.56–6.51 (m, 1H), 5.50 (d, J = 8.0 Hz, 1H), 3.47–3.38 (br, 1H), 3.13 (s, 3H). F
1
3
NMR (376 MHz, CDCl
3
) δ = −162.95 (s). C NMR (101 MHz, CDCl ) δ = 172.1 (d,
3
2JCF = 21.2 Hz), 145.0 (d, JCF = 5.5 Hz), 142.4 (s), 131.9 (d, JCF = 3.0 Hz), 131.6 (s),
28.1 (d, JCF = 2.0 Hz), 125.8 (s), 123.0 (d, JCF = 3.0 Hz), 122.2 (d, 2JCF = 18.2 Hz),
18.5 (s), 112.4 (s), 108.9 (s), 92.8 (d, 1JCF = 194.9 Hz), 73.6 (d, 2JCF = 31.3 Hz), 26.2
1
1
−
1
(
s). IR (cm ): 3343, 2218, 1695, 1605, 1460, 1374, 1094, 1054, 1006, 748. MS
+
+
[M + H]+
(
ESI) m/z: 297.1 [M + H] . HRMS (ESI) m/z: calcd for C17
H
14FN
2
O
2
2
97.1034, found 297.1029.
4
.2.14
anti-4-chloro-3-fluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one
(
anti-3m) [19]
Colorless solid. m. p. 136–137 ˚C. H NMR (400 MHz, CDCl
H), 6.56–6.26 (m, 1H), 6.08–5.74 (m, 1H), 4.40–4.09 (m, 1H), 2.93 (s, 3H). F
1
3
) δ = 7.26–6.98 (m,
1
9
7

1
3
NMR (376 MHz, CDCl
3
) δ = −172.5 (s). C NMR (101 MHz, CDCl ) δ = 170.9 (d,
3
2JCF = 22.0 Hz), 145.4 (d, JCF = 4.3 Hz), 136.0 (d, JCF = 6.3 Hz), 132.6 (d, 2JCF = 12.3
Hz), 132.1 (s), 128.5 (d, JCF = 9.3 Hz), 127.8 (d, JCF = 9.7 Hz), 126.3 (d, 2JCF = 19.5
Hz), 124.4 (d, 2JCF = 17.0 Hz), 121.0 (d, 2JCF = 17.2 Hz), 107.1 (d, 2JCF = 16.8 Hz),
9
3.7 (d, 1JCF = 201.6 Hz), 74.2 (d, 2JCF = 25.1 Hz), 25.9 (s).
4
.2.15
anti-4-bromo-3-fluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one
(anti-3n)
1
Colorless solid. m. p. 151–152 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.24–7.19 (m,
3
1
1
H), 7.16–7.06 (m, 6H), 6.48–6.39 (m, 1H), 6.01 (t, J = 8.0 Hz, 1H), 4.25–4.19 (m,
1
9
13
H), 2.88 (s, 3H). F NMR (376 MHz, CDCl
) δ = 170.9 (d, 2JCF = 22.2 Hz), 145.7 (d, JCF = 5.0 Hz), 136.0 (d, JCF = 6.1 Hz),
32.6 (d, JCF = 2.0 Hz), 128.4 (s), 127.8 (s), 127.5 (d, JCF = 2.0 Hz), 126.4 (s), 123.0
d, 2JCF = 17.2 Hz), 120.0 (s), 107.5 (s), 94.2 (d, 1JCF = 203.5 Hz), 73.9 (d, 2JCF = 25.2
3
) δ = −173.9 (s). C NMR (101 MHz,
CDCl
3
1
(
−
1
Hz), 25.8 (s). IR (cm ): 3419, 1714, 1599, 1482, 1386, 1089, 1048, 1004, 701, 632.
+
14BrFNO + [M + H]+
MS (ESI) m/z: 350.0 [M + H] . HRMS (ESI) m/z: calcd for C16
H
2
3
50.0186, found 350.0180.
4
.2.16 anti-3,5-difluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one (anti-3o)
1
Colorless solid. m. p. 129–130 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.39–7.30 (m,
3
5
1
−
H), 7.07–6.99 (m, 1H), 6.72–6.64 (m, 1H), 6.33–6.24 (m, 1H), 5.44 (d, J = 8.0 Hz,
1
9
H), 3.23–3.10 (br, 1H), 3.13 (s, 3H). F NMR (376 MHz, CDCl
3
) δ = −119.47 (s),
1
3
) δ = 172.5 (d, 2JCF = 20.2 Hz), 160.0 (d, JCF
162.76 (s). C NMR (101 MHz, CDCl
3

=
3.0 Hz), 157.6 (d, JCF = 3.0 Hz), 141.0 (dd, JCF = 6.1 Hz, JCF = 2.0 Hz), 136.6 (s),
28.7 (s), 128.0 (s), 127.2 (d, JCF = 2.0 Hz), 117.6 (dd, 2JCF = 23.2 Hz, JCF = 3.0 Hz),
14.5 (d, 2JCF = 26.3 Hz), 109.1 (d, JCF = 8.1 Hz), 92.8 (d, 1JCF = 194.9 Hz), 74.1 (d,
1
1
2JCF = 31.3 Hz), 26.3 (s). IR (cm ): 3354, 1681, 1616, 1464, 1406, 1161, 1092, 1046,
−1
+
+
1
009, 694. MS (ESI) m/z: 290.1 [M + H] . HRMS (ESI) m/z: calcd for C16
H
14 2
F
NO
2
+
[
M + H] 290.0987, found 290.0981.
4
.2.17
anti-5-chloro-3-fluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one
(anti-3p) [19]
1
Colorless solid. m. p. 155–156 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.47–7.29 (m,
6
2
H), 6.78–6.64 (m, 1H), 6.60–6.48 (m, 1H), 5.52–5.39 (m, 1H), 3.17 (s, 3H), 2.85–
1
9
13
.77 (m, 1H). F NMR (376 MHz, CDCl
) δ = 172.1 (d, 2JCF = 20.6 Hz), 143.6 (d, JCF = 4.9 Hz), 136.3 (s), 131.2 (d, 2JCF
12.2 Hz), 128.9 (s), 128.0 (d, JCF = 3.2 Hz), 127.2 (d, JCF = 2.3 Hz), 126.9 (s), 126.6
s), 124.3 (d, 2JCF = 18.6 Hz), 109.4 (s), 92.7 (d, 1JCF = 194.0 Hz), 74.3 (d, 2JCF = 11.1
Hz), 26.3 (s).
3
) δ = −163.2 (s). C NMR (101 MHz,
CDCl
3
=
(
4
.2.18
anti-5-bromo-3-fluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one
(anti-3q)
1
Colorless solid. m. p. 135–136 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.49–7.43 (m,
1
H), 7.40–7.26 (m, 5H), 6.69–6.58 (m, 2H), 5.48–5.38 (m, 1H), 3.13 (s, 3H), 3.00 (d,
3
19
13
J = 4.0 Hz, 1H). F NMR (376 MHz, CDCl
3
) δ = −163.1 (s). C NMR (101 MHz,
CDCl
3
) δ = 172.1 (d, 2JCF = 21.2 Hz), 144.1 (d, JCF = 5.0 Hz), 136.4 (s), 134.1 (d, JCF

=
3.0 Hz), 129.5 (s), 128.8 (s), 128.0 (s), 127.3 (d, JCF = 2.0 Hz), 124.7 (d, 2JCF = 18.2
Hz), 115.2 (s), 110.0 (s), 92.7 (d, 1JCF = 194.9 Hz), 74.2 (d, 2JCF = 31.3 Hz), 26.3 (s).
−
1
IR (cm ): 3380, 1695, 1598, 1478, 1364, 1094, 1050, 1006, 705, 629. MS (ESI) m/z:
+
14BrFNO +
[M + H] 350.0186, found
+
3
3
50.0 [M + H] . HRMS (ESI) m/z: calcd for C16
H
2
50.0179.
4
.2.19
anti-3-fluoro-3-(hydroxy(phenyl)methyl)-5-methoxy-1-methylindolin-2-one
(
anti-3r)
Colorless solid. m. p. 139–140 ˚C. H NMR (400 MHz, CDCl
m, 5H), 6.92–6.81 (m, 1H), 6.74–6.61 (m, 1H), 6.18–6.07 (m, 1H), 5.52–5.40 (m,
1
3
) δ = 7.52–7.29
(
1
9
1
H), 3.78–3.59 (m, 3H), 3.59–3.47 (m, 1H), 3.23–3.04 (m, 3H). F NMR (376 MHz,
) δ = −162.1 (s). C NMR (101 MHz, CDCl
) δ = 172.5 (d, 2JCF = 20.2 Hz),
1
3
CDCl
3
3
1
55.7 (d, JCF = 2.8 Hz), 138.3 (d, JCF = 5.0 Hz), 137.0 (s), 128.4 (s), 127.8 (s), 127.4
(
d, JCF = 2.0 Hz), 123.8 (d, 2JCF = 18.2 Hz), 116.4 (d, JCF = 3.0 Hz), 113.0 (s), 109.1
s), 93.3 (d, 1JCF = 193.9 Hz), 74.0 (d, 2JCF = 31.3 Hz), 55.7 (s), 26.2 (s). IR (cm−1):
(
3
298, 1679, 1616, 1464, 1431, 1373, 1097, 1049, 1001, 693. MS (ESI) m/z: 302.1 [M
+
17FNO +
[M + H] 302.1187, found 302.1181.
+
+
H] . HRMS (ESI) m/z: calcd for C17
H
3
4
.2.20
anti-6-chloro-3-fluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one
(anti-3s) [19]
1
Colorless solid. m. p. 112–113 ˚C. H NMR (500 MHz, CDCl
3
) δ = 7.44–7.29 (m,
5
3
H), 6.98–6.88 (m, 1H), 6.84–6.74 (m, 1H), 6.55–6.41 (m, 1H), 5.55–5.39 (m, 1H),
1
9
13
.18 (s, 3H), 2.78–2.65 (br, 1H). F NMR (471 MHz, CDCl ) δ = −162.17 (s). C
3

NMR (126 MHz, CDCl
3
) δ = 172.5 (d, 2JCF = 20.3 Hz), 146.4 (d, JCF = 6.5 Hz), 137.5
(s), 136.5 (s), 128.7 (s), 128.0 (s), 127.2 (s), 127.2 (s), 122.5 (s), 121.1 (s), 109.4 (s),
9
2.5 (d, 1JCF = 192.8 Hz), 74.1 (d, 2JCF = 31.9 Hz), 26.3 (s).
4
.2.21
anti-6-bromo-3-fluoro-3-(hydroxy(phenyl)methyl)-1-methylindolin-2-one
(anti-3t)
1
Colorless solid. m. p. 138–139 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.39–7.30 (m,
5
3
H), 7.09–7.01 (m, 1H), 6.96–6.89 (m, 1H), 6.38–6.25 (m, 1H), 5.50–5.36 (m, 1H),
1
9
13
.13 (s, 3H), 3.12–3.10 (m, 1H). F NMR (376 MHz, CDCl
) δ = 172.6 (d, 2JCF = 20.2 Hz), 146.4 (d, JCF = 5.0 Hz), 136.7
s), 128.6 (s), 128.0 (s), 127.5 (s), 127.3 (d, JCF = 2.0 Hz), 125.5 (d, JCF = 2.0 Hz),
3
) δ = −162.3 (s). C
NMR (101 MHz, CDCl
3
(
1
25.45 (d, JCF = 3.0 Hz), 121.6 (d, 2JCF = 19.2 Hz), 112.2 (s), 92.6 (d, 1JCF = 194.9
Hz), 73.8 (d, 2JCF = 32.3 Hz), 26.3 (s). IR (cm ): 3480, 1723, 1600, 1485, 1367, 1084,
−1
+
1
053, 1002, 712, 636. MS (ESI) m/z: 350.0 [M + H] . HRMS (ESI) m/z: calcd for
14BrFNO +
[M + H] 350.0186, found 350.0181.
+
C
16
H
2
4
.2.22
anti-3-fluoro-3-(hydroxy(phenyl)methyl)-1-(4-methoxyphenyl)indolin-2-one
(anti-3u)
1
Colorless solid. m. p. 170–171 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.36–7.26 (m,
5
6
H), 7.25–7.20 (m, 1H), 7.13–7.07 (m, 2H), 7.03–6.94 (m, 3H), 6.90–6.84 (m, 1H),
1
9
.60–6.54 (m, 1H), 5.52–5.44 (m, 1H), 3.83 (s, 3H), 3.40–3.28 (m, 1H). F NMR
1
3
) δ = 171.9 (d, 2JCF
=
(
376 MHz, CDCl
3
) δ = −163.9 (s). C NMR (101 MHz, CDCl
3
2
1.2 Hz), 159.6 (s), 145.4 (d, JCF = 5.0 Hz), 136.6 (s), 131.3 (d, JCF = 2.0 Hz), 128.4

(s), 127.8 (d, JCF = 2.0 Hz), 127.4 (d, JCF = 1.0 Hz), 126.0 (s), 125.9 (s), 123.0 (d, JCF
=
2.0 Hz), 122.8 (s), 122.7 (s), 115.0 (s), 109.7 (s), 93.4 (d, 1JCF = 195.9 Hz), 75.2 (d,
2JCF = 30.3 Hz), 55.5 (s). IR (cm ): 3364, 1700, 1601, 1502, 1454, 1376, 1105, 1049,
−1
+
19FNO +
1
019, 696. MS (ESI) m/z: 364.1 [M + H] . HRMS (ESI) m/z: calcd for C22
H
3
+
[
M + H] 364.1343, found 364.1337.
4
.2.23
anti-3-fluoro-3-(hydroxy(phenyl)methyl)-1-(prop-2-yn-1-yl)indolin-2-one
(anti-3v)
1
Colorless solid. m. p. 129–129 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.51–7.30 (m,
6
3
H), 7.09–6.95 (m, 2H), 6.79–6.62 (m, 1H), 5.63–5.38 (m, 1H), 4.63–4.32 (m, 2H),
1
9
.23–2.94 (m, 1H), 2.37–2.13 (m, 1H). F NMR (376 MHz, CDCl
) δ = 171.7 (d, 2JCF = 21.2 Hz), 143.1 (d, JCF = 6.1 Hz),
36.6 (s), 131.4 (d, JCF = 2.0 Hz), 128.5 (s), 127.9 (s), 127.3 (d, JCF = 2.0 Hz), 126.3
3
) δ = −162.5 (s).
13C NMR (101 MHz, CDCl
3
1
(
s), 123.0 (d, JCF = 2.0 Hz), 122.7 (d, 2JCF = 19.2 Hz), 109.6 (s), 93.1 (d, 1JCF = 194.9
Hz), 76.0 (s), 74.5 (d, 2JCF = 31.3 Hz), 72.7 (s), 29.3 (s). IR (cm ): 3452, 3291, 1701,
−1
+
1
603, 1456, 1362, 1115, 1049, 999, 701. MS (ESI) m/z: 296.1 [M + H] . HRMS (ESI)
15FNO +
[M + H] 296.1081, found 296.1077.
+
m/z: calcd for C18
H
2
4
.2.24 anti-1-allyl-3-fluoro-3-(hydroxy(phenyl)methyl)indolin-2-one (anti-3w)
1
Colorless solid. m. p. 110–111 ˚C. H NMR (400 MHz, CDCl ) δ = 7.36–7.27 (m,
3
4
5
H), 7.27–7.16 (m, 2H), 7.09–6.94 (m, 1H), 6.79–6.63 (m, 2H), 5.75–5.38 (m, 2H),
3
.19–4.84 (m, 2H), 4.50–4.33 (m, 1H), 4.20–3.89 (m, 1H), 3.26 (d, J = 4.0 Hz, 1H).
19F NMR (376 MHz, CDCl
) δ = −162.5 (s). C NMR (101 MHz, CDCl
13
3
3
) δ = 172.2
(
d, 2JCF = 21.2 Hz), 144.2 (d, JCF = 5.0 Hz), 136.7 (s), 131.3 (d, JCF = 3.0 Hz), 130.3

(
s), 128.4 (s), 127.9 (s), 127.4 (s), 126.1 (s), 123.0 (d, 2JCF = 19.2 Hz), 122.6 (d, JCF
=
3
.0 Hz), 117.7 (s), 109.5 (s), 93.0 (d, 1JCF = 193.9 Hz), 74.6 (d, 2JCF = 30.3 Hz), 42.3
−
1
(
s). IR (cm ): 3401, 1692, 1643, 1599, 1478, 1361, 1100, 1049, 1010, 696. MS (ESI)
+
17FNO +
[M + H] 298.1238,
+
m/z: 298.1 [M + H] . HRMS (ESI) m/z: calcd for C18
H
2
found 298.1233.
4
.2.25 anti-1-benzyl-3-fluoro-3-(hydroxy(phenyl)methyl)indolin-2-one (anti-3x)
1
Colorless solid. m. p. 144–145 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.39–7.29 (m,
6
6
3
H), 7.28–7.19 (m, 3H), 7.13–7.05 (m, 2H), 7.00–6.92 (m, 1H), 6.84–6.74 (m, 1H),
.61–6.54 (m, 1H), 5.62–5.49 (m, 1H), 5.16–5.02 (m, 1H), 4.71–4.56 (m, 1H), 3.32–
1
9
13
.14 (m, 1H). F NMR (376 MHz, CDCl
) δ = 172.6 (d, 2JCF = 21.2 Hz), 144.2 (d, JCF = 5.5 Hz), 136.7 (d, JCF = 1.0 Hz),
34.7 (s), 131.4 (d, JCF = 3.0 Hz), 128.8 (s), 128.4 (s), 128.0 (s), 127.6 (s), 127.4 (d,
3
) δ = −161.4 (s). C NMR (101 MHz,
CDCl
3
1
J
CF = 1.0 Hz), 126.9 (s), 126.1 (s), 123.0 (d, 2JCF = 18.2 Hz), 122.7 (d, JCF = 3.0 Hz),
09.8 (s), 93.1 (d, 1JCF = 193.9 Hz), 74.7 (d, 2JCF = 31.3 Hz), 43.8 (s). IR (cm ): 3392,
−1
1
1
706, 1606, 1480, 1365, 1088, 1051, 1022, 693. MS (ESI) m/z: 348.1 [M + H]+.
19FNO +
[M + H] 348.1394, found 348.1389.
+
HRMS (ESI) m/z: calcd for C22
H
2
4
.2.26
anti-5-chloro-1-ethyl-3-fluoro-3-(hydroxy(phenyl)methyl)indolin-2-one
(anti-3y)
1
Colorless solid. m. p. 113–114 ˚C. H NMR (400 MHz, CDCl
3
) δ = 7.35–7.27 (m,
3
6
2
H), 6.69–6.65 (m, 1H), 6.64–6.59 (m, 1H), 5.42 (d, J = 8.0 Hz, 1H), 3.79–3.49 (m,
3
19
H), 3.29–3.15 (br, 1H), 1.12 (t, J = 8.0 Hz, 3H). F NMR (376 MHz, CDCl ) δ =
3

1
3
) δ = 171.7 (d, 2JCF = 20.2 Hz), 142.6 (d, JCF
=
−
164.0 (s). C NMR (101 MHz, CDCl
3
5
.0 Hz), 136.3 (d, JCF = 0.7 Hz), 131.1 (d, JCF = 3.0 Hz), 128.7 (s), 128.0 (s), 127.3 (d,
J
CF = 1.0 Hz), 126.7 (s), 124.9 (s), 124.7 (s), 109.6 (s), 92.7 (d, 1JCF = 194.9 Hz), 74.5
d, 2JCF = 31.3 Hz), 34.9 (s), 12.1 (s). IR (cm ): 3385, 1702, 1602, 1477, 1361, 1109,
−1
(
+
1
048, 1020, 710, 634. MS (ESI) m/z: 320.1 [M + H] . HRMS (ESI) m/z: calcd for
16ClFNO +
[M + H] 320.0848, found 320.0843.
+
C
17
H
2
Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
The authors acknowledge financial support from the National Natural Science
Foundation of China (21102089), the Natural Science Foundation of Shanghai
(16ZR1413800), and Shanghai University of Engineering Science (2012td09,
nhrc-2015-09).

References
[
[
1] S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Fluorine in medicinal
chemistry, Chem. Soc. Rev. 37 (2008) 320–330.
2] P.A. Champagne, J. Desroches, J.-D. Hamel, M. Vandamme, J.-F. Paquin,
Monofluorination of organic compounds: 10 years of innovation. Chem. Rev. 115
(2015) 9073–9174.
[
3] X. Yang, T. Wu, R.J. Phipps, F.D. Toste, Advances in catalytic enantioselective
fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation
reactions, Chem. Rev. 115 (2015) 826–870.
[
[
4] J.-P. Bégué, D. Bonnet-Delpon, Bioorganic and medicinal chemistry of fluorine,
John Wiley & Sons, 2008.
5] Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J.L. Aceꢀa, V.A. Soloshonok, K.
Izawa, H. Liu, Next generation of fluorine-containing pharmaceuticals,
compounds currently in phase II–III clinical trials of major pharmaceutical
companies: new structural trends and therapeutic areas, Chem. Rev. 116 (2016)
4
22–518.
[
6] V.K. Gribkoff, J.E. Starrett Jr, S.I. Dworetzky, P. Hewawasam, C.G. Boissard,
D.A. Cook, S.W. Frantz, K. Heman, J.R. Huston Hibbard, G. Johnson, B.S.
Krishnan, G.G. Kinney, L.A. Lombardo, N.A. Meanwell, P.B. Molinoff, R.A.
Myers, S.L. Moon, A. Ortiz, L. Pajor, R.L. Pieschl, D.J. Post-Munson, L.J.
Signor, N. Srinivas, M.T. Taber, G. Thalody, J.T. Trojnacki, H. Wiener, K.
Yeleswaram, S.W. Yeola, Targeting acute ischemic stroke with a
calcium-sensitive opener of maxi-K potassium channels, Nat. Med. 7 (2001) 471–
4
77.
[
[
7] K.L. Spear, U. Campbell, Heterocyclic compounds and methods of use thereof.
Patent WO2014106238 A1, Jul 3, 2014.
8] B. Atkinson, D. Culshaw, A.J. Culshaw, J. Dale, N.J. Devereux, J. Mckenna,
Cyclohexyl amide derivatives as CRF receptor antagonists. Patent
WO2011092293 A2, Aug 4, 2011.

[
[
9] M. Kaur, M. Singh, N. Chadha, O. Silakaria, Oxindole: a chemical prism carrying
plethora of therapeutic benefits, Eur. J. Med. Chem. 123 (2016) 858–894.
10]X. Gu, Y. Zhang, Z.-J. Xu, C.-M. Che, Iron(III)-Salan Complexes catalysed
highly enantioselective fluorination and hydroxylation of β-keto esters and N-Boc
oxindoles. Chem. Commun. 50 (2014) 7870–7873.
[
[
[
[
[
11]F. Wang, J. Li, Q. Hu, X. Yang, X.-Y. Wu, H. He, Enantioselective fluorination
of 2-oxindoles by structure-micro-tuned N-fluorobenzenesulfonamides. Eur. J.
Org. Chem. 2014 (2014) 3607–3613.
12]J. Li, Y. Cai, W. Chen, X. Liu, L. Lin, X. Feng, Highly enantioselective
fluorination of unprotected 3-substituted oxindoles: one-step synthesis of BMS
2
04352 (MaxiPost). J. Org. Chem. 77 (2012) 9148–9155.
13]T. Ishimaru, N. Shibata, T. Horikawa, N. Yasuda, S. Nakamura, T. Toru, M.
Shiro, Cinchona alkaloid catalyzed enantioselective fluorination of allyl silanes,
silyl enol ethers, and oxindoles. Angew. Chem. Int. Ed. 47 (2008) 4157–4161.
14]Y. Hamashima, T. Suzuki, H. Takano, Y. Shimura, M. Sodeoka, Catalytic
enantioselective fluorination of oxindoles. J. Am. Chem. Soc. 127 (2005) 10164–
1
0165.
15]N. Shibata, T. Ishimaru, E. Suzuki, K.L. Kirk, Enantioselective fluorination
mediated by N-fluoroammonium salts of cinchona alkaloids: first
enantioselective synthesis of BMS-204352 (MaxiPost). J. Org. Chem. 68 (2003)
2
494–2497.
[
[
16]L. Zoute, C. Audouard, J.-C. Plaquevent, D. Cahard, Enantioselective synthesis
of BMS-204352 (MaxiPostTM) using N-fluoroammonium salts of cinchona
alkaloids (F-CA-BF4). Org. Bio. Chem. 1 (2003) 1833–1834.
17]N. Shibata, E. Suzuki, T. Asahi, M. Shiro, Enantioselective fluorination mediated
by cinchona alkaloid derivatives/Selectfluor combinations: reaction scope and
structural information for N-fluorocinchona alkaloids. J. Am. Chem. Soc. 123
(2001) 7001–7009.
[
18]Y. Zhu, Y. Mao, H. Mei, Y. Pan, J. Han, V.A. Soloshonok, T. Hayashi,
Palladium-catalyzed asymmetric allylic alkylations of Colby pro-enolates with

MBH carbonates: enantioselective access to quaternary C-F oxindoles.
Chem.-Eur. J. 24 (2018) 8994–8998.
[
[
19]L. Zhang, W. Zhang, H. Mei, J. Han, V.A. Soloshonok, Y. Pan, Catalytic
asymmetric Aldol addition reactions of 3-fluoro-indolinone derived enolates.
Org. Biomol. Chem. 15 (2017) 311–315.
20]C. Xie, L. Zhang, W. Sha, V.A. Soloshonok, J. Han, Y. Pan,
detrifluoroacetylative in situ generation of free 3-fluoroindolin-2-one-derived
tertiary enolates: design, synthesis, and assessment of reactivity toward
asymmetric Mannich reactions. Org. Lett. 18 (2016) 3270–3273.
21]W. Zhang, W. Sha, Y. Zhu, J. Han, V.A. Soloshonok, Y. Pan, Asymmetric
synthesis of quaternary β-perfluorophenyl-β-amino-indolin-2-ones. Eur. J. Org.
Chem. 2017 (2017) 1540–1546.
[
[
22]C. Xie, W. Sha, Y. Zhu, J. Han, V.A. Soloshonok, Y. Pan, Asymmetric synthesis
of C-F quaternary α-fluoro-β-amino-indolin-2-ones via Mannich addition
reactions; facets of reactivity, structural generality and stereochemical outcome.
RSC Adv. 7 (2017) 5679–5683.
[
23]Y. Zhu, H. Mei, J. Han, V.A. Soloshonok, J. Zhou, Y. Pan, Chemoselective S
allylations of detrifluoroacetylatively in situ generated
-fluoroindolin-2-one-derived tertiary enolates with Morita-Baylis-Hillman
carbonates. J. Org. Chem. 82 (2017) 13663–13670.
N
2′
3
[
[
[
24]S. Paladhi, S.Y. Park, J.W. Yang, C.E. Song, Asymmetric synthesis of
α-fluoro-β-amino-oxindoles with tetrasubstituted C-F stereogenic centers via
cooperative cation-binding catalysis. Org. Lett. 19 (2017) 5336–5339.
25]B.-Y. Li, D.-M. Du, Chiral squaramide-catalyzed asymmetric mannich reactions
for synthesis of fluorinated 3,3′-bisoxindoles. Adv. Synth. Catal. 360 (2018)
3
164–3170.
26]B.-Y. Li, Y. Lin, D.-M. Du, Organocatalytic asymmetric mannich addition of
-fluorooxindoles to dibenzo[b,f][1,4]oxazepines: highly enantioselective
construction of tetrasubstituted C–F stereocenters. J. Org. Chem. 84 (2019)
1752–11762.
3
1

[
[
27]Y. Jin, M. Chen, S. Ge, J.F. Hartwig, Palladium-catalyzed, enantioselective
α-arylation of α-fluorooxindoles. Org. Lett. 19 (2017) 1390–1393.
28]K. Balaraman, C. Wolf, Catalytic enantioselective and diastereoselective allylic
alkylation with fluoroenolates: efficient access to C3-fluorinated and all-Carbon
quaternary oxindoles. Angew. Chem. Int. Ed. 56 (2017) 1390–1395.
[
[
29]R. Ding, C. Wolf, Organocatalytic asymmetric synthesis of α-oxetanyl and
α-azetidinyl tertiary alkyl fluorides and chlorides. Org. Lett. 20 (2018) 892–895.
30]K. Balaraman, R. Ding, C. Wolf, Stereoselective synthesis of 3,3’-bisindolines by
organocatalytic michael additions of fluorooxindole enolates to isatylidene
malononitriles in aqueous solution. Adv. Synth. Catal. 359 (2017) 4165–4169.
31]T. Wang, D.L. Hoon, Y. Lu, Enantioselective synthesis of
[
[
3
3
1
-fluoro-3-allyl-oxindoles via phosphine-catalyzed asymmetric γ-addition of
-fluoro-oxindoles to 2,3-butadienoates. Chem. Commun. 51 (2015) 10186–
0189.
32]X. Dou, Y. Lu, Enantioselective conjugate addition of 3-fluoro-oxindoles to vinyl
sulfone: an organocatalytic access to chiral 3-fluoro-3-substituted oxindoles. Org.
Biomol. Chem. 11 (2013) 5217–5221.
[
[
33]M. Moskowitz, K. Balaraman, C. Wolf, Organocatalytic stereoselective synthesis
of fluorinated 3,3′-linked bisoxindoles. J. Org. Chem. 83 (2018) 1661–1666.
34]X. Chen, Y. Li, J. Zhao, B. Zheng, Q. Lu, X. Ren, Stereoselective mannich
reaction of N-(tert-butylsulfinyl)imines with 3-fluorooxindoles and
fluoroacetamides. Adv. Synth. Catal. 359 (2017) 3057–3062.
[
[
35]B. Zheng, L. Chen, J. Zhao, J. Ji, Z. Qiu, X. Ren, Y. Li, Organocatalytic
asymmetric syntheses of 3-fluorooxindoles containing vicinal fluoroamine
motifs. Org. Biomol. Chem. 16 (2018) 8989−8993.
36]J. Zhao, Y. Li, L. Chen, X. Ren, Enantioselective mannich reactions of 3‑
fluorooxindoles with cyclic N-sulfamidate aldimines. J. Org. Chem. 84 (2019)
5
099–5108.

[
[
37]J. Ji, L.-Y. Chen, Z.-B. Qiu, X. Ren, Y. Li, Visible light photoredox-catalyzed
cross-dehydrogenative coupling of tetrahydroisoquinolines with
-fluorooxindoles. Asian. J. Org. Chem. 8 (2019) 1436–1440.
38]Z.-B Qiu, X.-F Ren, X.-Y. Chen, L.-Y. Chen, J. Ji, Y. Li, MgBr
direct aldol reactions of S-aryl 2-fluoroethanethioate, J. Fluorine. Chem. 227
2019), 109368.
3
2
•OEt -promoted
2
(
[
[
[
39]G. Zhou, J.M. Yost, D.M. Coltart, A direct aldol addition of simple thioesters
employing soft enolization, Synthesis (2007) 478–482.
40]J.M. Yost, G. Zhou, D.M. Coltart, A facile and efficient direct aldol addition of
simple thioesters, Org. Lett. 8 (2006) 1503–1506.
41]R. Nagase, N. Matsumoto, K. Hosomi, T. Higashi, S. Funakoshi, T. Misaki, Y.
Tanabe, Ti-Direct, powerful, stereoselective aldol-type additions of esters and
thioesters to carbonyl compounds: application to the synthesis and evaluation of
lactone analogs of jasmone perfumes, Org. Biomol. chem. 5 (2007) 151–159.