Cinchona-alkaloid-catalyzed enantioselective hydroxymethylation of 3-fluorooxindoles with paraformaldehyde

Article abstract of DOI:10.1016/j.jfluchem.2018.09.004

Cinchona-alkaloid-catalyzed hydroxymethylation of 3-fluorooxindoles using paraformaldehyde as the C1 unit was achieved. A wide range of 3-fluorooxindoles was successfully reacted to give the corresponding 3-fluoro-3-hydroxymethyloxindoles with high efficiency and moderate to good enantioselectivity.

Full text of DOI:10.1016/j.jfluchem.2018.09.004

Accepted Manuscript
Title: Cinchona-Alkaloid-Catalyzed Enantioselective
Hydroxymethylation of 3-Fluorooxindoles with
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Authors: Jian-bo Zhao, Xinfeng Ren, Bu-quan Zheng, Jian Ji,
Zi-bin Qiu, Ya Li
PII:
S0022-1139(18)30303-8
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https://doi.org/10.1016/j.jfluchem.2018.09.004
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Please cite this article as: Zhao J-bo, Ren X, Zheng B-quan, Ji J, Qiu Z-
bin, Ya L, Cinchona-Alkaloid-Catalyzed Enantioselective Hydroxymethylation of
3-Fluorooxindoles with Paraformaldehyde, Journal of Fluorine Chemistry (2018),
https://doi.org/10.1016/j.jfluchem.2018.09.004
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Cinchona-Alkaloid-Catalyzed Enantioselective Hydroxymethylation
of 3-Fluorooxindoles with Paraformaldehyde
Jian-bo Zhao, Xinfeng Ren,* Bu-quan Zheng, Jian Ji, Zi-bin Qiu, Ya Li*
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science,
333 Longteng Road, Shanghai 201620, China
Graphical Abstract
Highlights



The first organocatalytic asymmetric hydroxymethylation of 3-fluorooxindoles
Paraformaldehyde used as the C1 source
High efficiency

Abstract:
Cinchona-alkaloid-catalyzed hydroxymethylation of 3-fluorooxindoles using
paraformaldehyde as the C1 unit was achieved. A wide range of 3-fluorooxindoles
was successfully reacted to give the corresponding 3-fluoro-3-
hydroxymethyloxindoles with high efficiency and moderate to good
enantioselectivity.
Keywords: fluorine; fluoroalkylation; enantioselective; condensation;
hydroxymethylation
1. Introduction
Fluorine has attracted enormous attention from both synthetic and medicinal
chemists, largely because incorporation of fluorine(s) can improve the properties of a
bioactive compound, such as metabolic stability, binding affinity, and lipophilicity
[1–2]. In this context, chiral molecules that contain stereogenic carbon-fluorine units
are of particular importance in the pharmaceutical industry [3–4]. For example,

sofosbuvir (Figure 1a) has been used clinically for the treatment of patients with
hepatitis C virus infection [3].
The 3,3-disubstituted oxindole is a structural motif that occurs in many bioactive
compounds and drug candidates [5–11]. Among these, 3-substituted 3-fluorooxindole
frameworks have attracted great interest in medicinal chemistry since the 3-
fluorooxindole BMS-204352 (Figure 1b) was reported to be a potent and effective
maxi-K channel opener [11]. Intense efforts have been devoted to the synthesis of
such structural motifs [12–41]. Two main strategies have been developed: fluorination
[12–25] and the use of 3-fluorooxindoles as the building blocks [26-40]. The latter
approach is particularly useful because it allows facile synthesis of libraries of
fluorinated compounds. However, compared with their non-fluorinated analogs [42–
44], the use of 3-fluorooxindoles in the asymmetric synthesis of 3-substituted 3-
fluorooxindoles remains scarce, probably because of the decreased reactivity of 3-
fluorooxindole imparted by a fluorine substitution. In this regard, only three kinds of
asymmetric reactions, addition of 3-fluorooxindoles to carbon-carbon double bonds
(Scheme 1a) [32–35], allylic alkylation and arylation (Scheme 1b) [36,37], and the
Mannich reaction of 3-fluorooxindoles (Scheme 1c and 1d) [38–40], have been
reported. Thus, it is still highly valuable to develop asymmetric reactions of 3-
fluorooxindoles to access structurally diverse 3-substituted 3-fluorooxindoles.
On the other hand, asymmetric hydroxymethylation of oxindoles is of high
importance because the resulting 3-hydroxymethyloxindoles serve as valuable
building blocks for the syntheses of useful oxindole derivatives. Not surprisingly,

several reports on the asymmetric hydroxymethylation of oxindoles have been
reported [45–50]. Thus, development of a comparable hydroxymethylation reaction of
3-fluorooxindoles to afford 3-fluoro-3-hydromethyloxindoles would be valuable from
a synthetic point of view. However, we are not aware of any report regarding the
hydroxymethylation of 3-fluorooxindoles. Recently, we have been interested in the
use of 3-fluorooxindoles to access 3-substituted 3-fluorooxindoles and have
developed a highly diastereoselective Mannich reaction of 3-fluorooxindoles with
Ellman’s imines (Scheme 1d) [40]. Here, we report a cinchona-alkaloid-catalyzed
hydroxymethylation of 3-fluorooxindoles with paraformaldehyde as the C1 unit,
enabling an enantioselective synthesis of 3-fluoro-3-hydroxymethyloxindoles
(Scheme 2).

2. Results and discussion
Using paraformaldehyde 1 as the hydroxymethylating reagent and 3-
fluorooxindole 2a as a model substrate, we initiated our study by the examination of a
series of commercially available organocatalysts 3a–3n (Figure 2). When prolinol 3a
[51], phosphoric acid 3b [52], and tertiary amine-thiourea catalyst 3c [46, 53] were
used, the corresponding 3-hydroxymethylated product 4a was not observed (Table 1,
entries 1-3). Bifunctional cinchona alkaloids and their derivatives (3d–3j) were found
to be active (entries 4–10). The use of quinine 3d (entry 4), hydroquinine 3e (entry 5),
and cinchonidine 3f (entry 6) led to the formation of 4a in excellent yields, with
cinchonidine 3f (entry 6) giving the best enantioselectivity (22:78). Interestingly, a
reverse in stereoselectivity was observed when quinidine 3g (entry 7) and C-6′-OH
cinchona-alkaloids 3h−3j (entries 8–10) were used. Among the C-6′-OH cinchona-
alkaloids examined, catalyst 3h gave the best yield and enantioselectivity (entry 8).
Catalyst 3k, derived from quinine with C-9-OH-protected by a benzyl group, was also
evaluated. However, the reaction was slow and product 4a was obtained with less
than 10% yield after a 3-day reaction (entry 11). These above results indicate that the
existence of a free hydroxyl group at either the aromatic ring (3h–3j) or the aliphatic
chain (3d–3g) of the cinchona-alkaloid catalyst is essential for the successful
transformation of the reaction. Further catalyst screening revealed that catalyst 3l−3n
proved to be unsuitable for the reaction (entries 12–14). Using catalyst 3h, several
solvents were examined. While no reaction occurred in MeCN (entry 15), Et2O,
toluene, and DCM gave a slightly lower enantioselectivity (entries 16–18) than that in

DCE (entry 8). Using DCE as the solvent, the reaction temperature was also
evaluated; raising the temperature to 25 °C gave a comparable yield and
enantioselectivity (entry 19 vs entry 8). Finally, formalin proved to be competent,
giving product 4a in a comparable enantioselectivity, albeit in a lower yield (entry
20).

Using entry 19 as the optimal reaction conditions, we then checked the generality
of the reaction in terms of 3-fluorooxindole substrates (Scheme 2). A variety of N-
methyl 3-fluorooxindoles 2 with substituents at positions 4 to 7 were reacted with
high efficiency, giving the corresponding 3-hydroxymethylated products 4 in very
good to excellent yields (4a–4k). The electronic donating/withdrawing nature of the
substituents had little effect on stereoselectivity, with product 4 being formed in
moderate to good enantioselectivity. For instance, very close enantioselectivity ratio
(around 77:23) was obtained when a substituent, including methyl, methoxy, chloro,
fluoro, and bromo groups, was located at the 5-position (4d–4h). The effect of the N-
substituents on the reaction was also examined. The N-benzyl substituent resulted in a
slight lower enantioselectivity, as exemplified by the enantioselectivity value of 4a vs
4a′, 4b vs 4b′, 4g vs 4g′, and 4h vs 4h′. The N-Ph substrate was also reacted with
high efficiency (4l, 98% yield, er = 59:41), although a dramatic decrease in the
enantioselectivity was observed. These results indicate that the bulkiness of the N-
substituents plays a role in controlling the stereoselectivity of the reaction. In addition,
the N-Boc 3-fluorooxindoles was successfully reacted to give 4m with an
enantioselectivity of 87:13, albeit in a lower yield due to incomplete conversion of
2m. Finally, the N-H 3-fluorooxindole 2n proved to be competent, giving 4n in 92%
yield with an enantiomaric ratio of 64:36.

The absolute configurations of 4 were determined by the single-crystal X-ray
analysis of compound (R)-4a (Figure 3) [54]. By analogy, (S)-configuration was
assigned to all the major enantiomer of compounds 4.
Aromatic aldehydes were also tried using the same catalytic system as shown in
Table 2. The reaction of 3-fluorooxindole 2a with benzaldehyde 5a gave only traces
of the corresponding Aldol product (< 5%) after a three-day reaction. When more
reactive 4-nitrobenzaldehyde 5b was used, the desired product 6 was obtained in 48%
yield with a diastereoselectivity of 2:1 (Scheme 3).
Furthermore, we tried to apply the present catalytic approach to other 3-
halogenated oxindoles. However, 3-chloro- and 3-bromooxindole failed to give the
corresponding 3-hydroxymethlated products under the identical reaction conditions
used in Table 2. This result indicates that the reactivity of oxindole in the current
reaction was greatly affected by a fluorine substitution.
3. Conclusions
We have developed a new catalytic asymmetric method for the
hydroxymethylation of 3-fluorooxindoles for the first time. Using a commercially
available quinine-derived catalyst, various substituted 3-fluorooxindoles were
successfully reacted with paraformaldehyde to give 3-fluoro-3-
hydroxymethyloxindoles with high efficiency and moderate to good
enantioselectivity. Further investigations on this catalytic system by using cinchona-

alkaloid-derived catalysts to produce important 3-substituted 3-fluorooxindoles are
currently underway in our laboratory.
4. Experimental
4.1 General
Compounds 3-fluorooxindoles were prepared according to literature methods.12
DCE was dried with 4Å molecular sieves. Flash chromatography was performed on
silica gel with petroleum ether/ethyl acetate as the eluent. Optical rotations were
measured with a polarimer with the solvent indicated. Melting points were measured
on an electrothermal digital melting point apparatus. 1H, 13C and 19F NMR spectra
were recorded on a 400 MHz NMR spectrometer. HRMS data were obtained on an
ESI-FTMS mass spectrometer.
4.2 Synthesis of 4 (general procedure)
In an ordinary vial equipped with a magnetic stirring bar, paraformaldehyde (0.6
mmol) was added into a mixture of 3-fluorooxindole 2 (0.2 mmol), cat. 3h (0.02
mmol), and freshly distilled DCE (2.0 mL). The reaction mixture was stirred at 25 ˚C
for 1-2 days until the complete conversion of the starting material 2, which was then
directly loaded onto silica gel and purified by flash chromatography to give the
desired product 4 as a white solid. Enantiomerically pure (S)-4 can be obtained
through recrystallization.
4.2.1 (S)-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (4a).

White solid. Yield = 97 %. er = 78:22. [α]16 = −15.5 (c = 0.55, CHCl3). m. p.
D
100.2–100.7 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H
column (94/6 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400
MHz, CDCl3) δ = 7.53 (d, 3J = 7.4 Hz, 1H), 7.44 (t, 3J = 7.8 Hz, 1H), 7.15 (t, 3J = 7.6
Hz, 1H), 6.90 (d, 3J = 7.8 Hz, 1H), 4.06–4.16 (m), 3.22 (s, 3H), 2.71 (s, 1H). 19F
NMR (376 MHz, CDCl3) δ = −169.6 (t, 3JHF = 17.1 Hz). 13C NMR (101 MHz, CDCl3)
δ = 171.8 (d, JCF = 20.8 Hz), 144.3 (d, JCF = 5.2 Hz), 131.5 (d, JCF = 2.9 Hz), 125.3
(s), 124.0 (d, JCF = 18.5 Hz), 123.4 (d, JCF = 2.5 Hz), 108.8 (s), 91.5 (d, 1JCF = 189.6
Hz), 64.3 (d, JCF = 30.3 Hz), 26.2 (s). IR (cm−1): 3401, 1710, 1685, 1682, 1615, 1568,
1475, 1389, 1248, 1053, 1007, 756. MS (ESI) m/z: 196.1 [M + H]+. HRMS (ESI) m/z:
calcd for C10H11O2NF+ [M + H]+ 196.0768, found 196.0768.
4.2.2 (S)-1-benzyl-3-fluoro-3-(hydroxymethyl)indolin-2-one (4a′).
White solid. Yield = 92 %. er = 76:24. [α]16 = −10.4 (c = 0.52, CHCl3). m. p.
D
131.0–131.6 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-
1
H column (85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). H NMR
(400 MHz, CDCl3) δ = 7.54 (d, 3J = 7.4 Hz, 1H), 7.29–7.39 (m, 6H), 7.12 (t, 3J =
7.6 Hz, 1H), 6.77 (d, 3J = 7.9 Hz, 1H), 4.99 (d, 2J = 15.7 Hz, 1H), 4.87 (d, 2J = 15.7
Hz, 1H), 4.30–4.06 (m, 2H), 2.38–2.41 (m, 1H). 19F NMR (376 MHz, CDCl3) δ =
13
−169.1 (t, 3JHF = 16.0 Hz). C NMR (101 MHz, CDCl3) δ = 172.0 (d, JCF = 20.7
Hz), 143.5 (d, JCF = 5.1 Hz), 134.8 (s), 131.5 (d, JCF = 2.8 Hz), 128.9 (s), 127.9 (s),
127.1 (s), 125.3 (s), 124.0 (d, JCF = 18.6 Hz), 123.4 (d, JCF = 2.6 Hz), 109.9 (s), 91.6
(d, 1JCF = 190.0 Hz), 64.4 (d, JCF = 31.3 Hz), 43.8 (s). IR (cm−1): 3409, 1714, 1651,

1611, 1568, 1491, 1466, 1393, 1183, 1060, 998, 752. MS (ESI) m/z: 272.1 [M + H]+.
HRMS (ESI) m/z: calcd for C16H15O2NF+ [M + H]+ 272.1081, found 272.1080.
4.2.4 (S)-4-chloro-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (4b).
White solid. Yield = 91 %. er = 83:17. [α]16 = −26.4 (c = 0.52, CHCl3). m. p. 120.7–
D
121.7 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H column
(97/3 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400 MHz, CDCl3)
δ = 7.37 (td, 3J = 8.1 Hz, 4J = 1.7 Hz, 1H), 7.10 (d, 3J = 8.3 Hz, 1H), 6.80 (d, 3J = 7.8
19
Hz, 1H), 4.47–4.52 (m, 1H), 4.41–4.28 (m, 1H), 3.24 (s, 3H), 2.30 (s, 1H). F NMR
13
(376 MHz, CDCl3) δ = −174.1 (d, 3JHF = 13.0 Hz). C NMR (101 MHz, CDCl3) δ =
171.6 (d, JCF = 20.6 Hz), 146.5 (d, JCF = 4.4 Hz), 134.1–131.4 (m), 124.5 (d, JCF = 2.1
Hz), 120.8 (d, JCF = 16.9 Hz), 107.3 (s), 91.7 (d, JCF = 193.6 Hz), 61.7 (d, JCF = 33.8
Hz), 26.5 (s). IR (cm−1): 3408, 1697, 1651, 1612, 1597, 1296, 1123, 1058, 1020, 821,
782, 764. MS (ESI) m/z: 230.0 [M + H]+. HRMS (ESI) m/z: calcd for C10H10O2NClF+
[M + H]+ 230.0379, found 230.0378.
4.2.5 (S)-1-benzyl-4-chloro-3-fluoro-3-(hydroxymethyl)indolin-2-one (4b′).
White solid. Yield = 92 %. er = 73:27. [α]24 = +149.9 (c = 0.52, CHCl3). m. p. 154.8–
D
155.4 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H column
(97/3 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400 MHz, CDCl3)
δ = 7.29–7.39 (m, 5H), 7.23 (td, 3J = 8.1 Hz, 4J = 1.6 Hz, 1H), 7.05 (d, 3J = 8.3 Hz, 1H),
6.63 (d, 3J = 7.9 Hz, 1H), 5.04 (d, 3J = 15.9 Hz, 1H), 4.82 (d, 3J = 15.9 Hz, 1H), 4.34–
4.59 (m, 2H), 2.17–2.31 (m, 1H). 19F NMR (376 MHz, CDCl3) δ = −173.6 (s). 13C NMR

(101 MHz, CDCl3) δ = 171.8 (d, JCF = 20.3 Hz), 145.8 (d, JCF = 4.6 Hz), 134.4 (s),
132.68 (d, JCF = 2.0 Hz), 132.6 (s), 129.0 (s), 127.9 (s), 127.0 (s), 124.5 (d, JCF = 2.1
Hz), 120.9 (s), 120.8 (d, JCF = 17.2 Hz), 108.4 (s), 91.8 (d, JCF = 193.7 Hz), 61.7 (d, JCF
= 34.3 Hz), 44.0 (s). IR (cm−1): 3409, 1718, 1683, 1651, 1593, 1500, 1353, 1249, 1114,
1060, 1011, 819. MS (ESI) m/z: 306.0 [M + H]+. HRMS (ESI) m/z: calcd for
C16H13ClO2NF+ [M + H]+ 306.0694, found 306.0692.
4.2.6 (S)-4-bromo-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (4c).
White solid. Yield = 98 %. er = 78:22. [α]27 = +35.2 (c = 0.52, CHCl3). m. p.
D
122.2–123.1 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H
column (97/3 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400
MHz, CDCl3) δ = 7.28–7.32 (m, 1H), 7.24–7.28 (m, 1H), 6.83 (dd, 3J = 7.1 Hz, 4J =
1.3 Hz, 1H), 4.29–4.57 (m, 2H), 3.22 (s, 3H), 2.40 (br, 1H). 19F NMR (376 MHz,
CDCl3) δ = −175.5 (dd, 3JHF = 12.4, 3JHF = 7.1 Hz). 13C NMR (101 MHz, CDCl3) δ =
171.7 (d, JCF = 20.6 Hz), 146.7 (d, JCF = 4.4 Hz), 132.8 (d, JCF = 2.4 Hz), 127.5 (d, JCF
= 2.1 Hz), 122.6 (d, JCF = 16.9 Hz), 120.2 (s), 107.8 (s), 92.1 (d, 1JCF = 194.5 Hz),
61.6 (d, JCF = 33.6 Hz), 26.4 (s). IR (cm−1): 3386, 1708, 1651, 1609, 1588, 1455,
1295, 1225, 1115, 1057, 1012, 779. MS (ESI) m/z: 273.9 [M + H]+. HRMS (ESI) m/z:
calcd for C10H9O2NBrF+ [M + H]+ 273.9873, found 273.9869.
4.2.7 (S)-3-fluoro-3-(hydroxymethyl)-1,5-dimethylindolin-2-one (4d).
White solid. Yield = 92 %. er = 76:24. [α]16 = −13.1 (c = 0.57, CHCl3). m. p. 119.3–
D
119.7 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H column

(96/4 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400 MHz, CDCl3)
δ = 7.35 (s, 1H), 7.24 (d, 3J = 7.4 Hz, 1H), 6.79 (d, 3J = 7.9 Hz, 1H), 3.98–4.18 (m, 2H),
3.22 (s, 3H), 2.51 (s, 1H), 2.38 (s, 3H). 19F NMR (376 MHz, CDCl3) δ = −169.5 (t, 3JHF
= 17.1 Hz). 13C NMR (101 MHz, CDCl3) δ = 171.8 (d, JCF = 20.8 Hz), 141.8 (d, JCF
=
5.2 Hz), 133.2 (d, JCF = 2.6 Hz), 131.7 (d, JCF = 2.9 Hz), 126.0 (s), 123.9 (d, JCF = 18.4
Hz), 108.6 (s), 91.6 (d, 1JCF = 189.5 Hz), 64.4 (d, JCF = 30.5 Hz), 26.2 (s), 20.9 (s). IR
(cm−1): 3439, 1710, 1684, 1652, 1634, 1623, 1500, 1353, 1114, 1060, 1011, 819. MS
(ESI) m/z: 227.1 [M + H]+. HRMS (ESI) m/z: calcd for C11H13O2NF+ [M + H]+
210.0925, found 210.0924.
4.2.8 (S)-3-fluoro-3-(hydroxymethyl)-5-methoxy-1-methylindolin-2-one (4e).
White solid. Yield = 94 %. er = 80:20. [α]16= −10.7 (c = 0.57, CHCl3). m. p. 123.2–
D
123.5 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H column
(96/4 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400 MHz, CDCl3)
3
4
δ = 7.13–7.16 (m, 1H), 6.92–6.98 (m, 1H), 6.81 (dd, J = 8.5 Hz, J = 0.9 Hz, 1H),
4.00–4.17 (m, 2H), 3.83 (s, 3H), 3.21 (s, 3H), 2.52 (s, 1H). 19F NMR (376 MHz, CDCl3)
δ = −169.7 (t, 3JHF = 17.4 Hz). 13C NMR (101 MHz, CDCl3) δ = 171.5 (d, JCF = 20.9
Hz), 156.5 (d, JCF = 2.7 Hz), 137.4 (d, JCF = 5.2 Hz), 125.1 (d, JCF = 18.3 Hz), 116.0 (d,
1
JCF = 2.7 Hz), 112.4 (s), 109.4 (s), 91.8 (d, JCF = 190.2 Hz), 64.4 (d, JCF = 30.2 Hz),
55.9 (s), 26.3 (s). IR (cm−1): 3416, 1706, 1651, 1604, 1542, 1499, 1295, 1115, 1059,
1030, 875, 819. MS (ESI) m/z: 226.1 [M + H]+. HRMS (ESI) m/z: calcd for
C11H13O3NF+ [M + H]+ 226.0874, found 226.0873.

4.2.9 (S)-5-chloro-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (4f).
White solid. Yield = 91 %. er = 76:24; [α]16 = −65.8 (c = 0.55, CHCl3). m. p. 99.1–
D
100.7 ˚C. The er was determined by HPLC analysis using a Chiralpak AS-H column
1
(90/10 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm); H NMR (400 MHz,
CDCl3) δ = 7.54 (t, 4J = 1.8 Hz, 1H), 7.42 (dd, 3J = 8.3 Hz, 4J = 1.8 Hz, 1H), 6.83 (dd,
3J = 8.3 Hz, 4J = 0.8 Hz, 1H), 4.11–4.23 (m, 1H), 3.97–4.05 (m, 1H), 3.23 (s, 3H), 2.39–
19
3
2.42 (m, 1H). F NMR (376 MHz, CDCl3) δ = −169.7 (t, JHF = 18.8 Hz). 13C NMR
(101 MHz, CDCl3) δ = 171.2 (d, JCF = 20.6 Hz), 142.7 (d, JCF = 5.1 Hz), 131.3 (d, JCF
= 2.7 Hz), 128.9 (d, JCF = 2.9 Hz), 126.1 (s), 125.6 (d, JCF = 18.7 Hz), 109.8 (s), 91.4
(d, JCF = 191.0 Hz), 64.1 (d, JCF = 30.3 Hz), 26.4 (s). IR (cm−1): 3405, 1707, 1651,
1613, 1568, 1491, 1465, 1360, 1245, 1057, 1011, 822. MS (ESI) m/z: 230.0 [M + H]+.
HRMS (ESI) m/z: calcd for C10H10O2NClF+ [M + H]+ 230.0379, found 230.0378.
4.2.10 (S)-3,5-difluoro-3-(hydroxymethyl)-1-methylindolin-2-one (4g).
White solid. Yield = 92 %. er = 78:22. [α]16 = +17.5 (c = 0.53, CHCl3). m. p. 118.9–
D
119.1 ˚C. The er was determined by HPLC analysis using a Chiralpak OD-H column
1
(90/10 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). H NMR (400 MHz,
CDCl3) δ = 7.30–7.34 (m, 1H), 7.11–7.19 (m, 1H), 6.82–6.85 (m, 1H), 4.13–4.20 (m,
1H), 3.96–4.07 (m, 1H), 3.23 (s, 3H), 2.42–2.45 (m, 1H). 19F NMR (376 MHz, CDCl3)
δ = −118.8 (s), −169.9 (t, 3JHF = 17.3 Hz). 13C NMR (101 MHz, CDCl3) δ = 171.4 (d,
JCF = 20.5 Hz), 159.4 (d, 1JCF = 242.0 Hz), 140.1 (s), 125.4 (dd, JCF = 18.5 Hz, JCF
=
8.2 Hz), 117.7 (d, JCF = 23.6 Hz), 113.8 (d, JCF = 25.3 Hz), 109.5 (d, JCF = 7.8 Hz), 91.5
(d, JCF = 190.7 Hz), 64.2 (d, JCF = 30.0 Hz), 26.4 (s). IR (cm−1): 3405, 1708, 1651,

1624, 1556, 1480, 1357, 1180, 1115, 1061, 1014, 893. MS (ESI) m/z: 214.1 [M + H]+.
+
HRMS (ESI) m/z: calcd for C10H10O2NF2 [M + H]+ 214.0674, found 214.0674.
4.2.11 (S)-1-benzyl-3,5-difluoro-3-(hydroxymethyl)indolin-2-one (4g′).
White solid. Yield = 96 %. er = 75:25. [α]23 = +115.2 (c = 0.53, CHCl3). m. p.
D
160.2–161.7 ˚C. The er was determined by HPLC analysis using a Chiralpak OD-H
column (90/10 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm); 1H NMR (400
MHz, CDCl3) δ = 7.24–7.45 (m, 6H), 7.01 (t, 3J = 8.8 Hz, 1H), 6.67 (dd, 3J = 8.0, 3.3
Hz, 1H), 4.86 (d, 2J = 15.8 Hz, 1H), 4.78 (d, 2J =15.8 Hz, 1H), 4.05–4.55 (m, 2H),
2.50 (s, 1H). 19F NMR (376 MHz, CDCl3) δ = −118.7 (s), −169.4 (d, 3JHF = 1.5 Hz).
13C NMR (101 MHz, CDCl3) δ = 171.6 (d, JCF = 20.0 Hz), 159.2 (d, 1JCF = 247.5 Hz),
139.3 (s), 134.5 (s), 129.0 (s), 128.0 (s), 127.1 (s), 117.7 (d, JCF = 25.9 Hz), 113.8 (d,
JCF = 25.4 Hz), 110.7 (d, JCF = 7.6 Hz), 91.6 (d, 1JCF = 191.6 Hz), 64.2 (d, JCF = 31.3
Hz), 44.0 (s). IR (cm−1): 3410, 1713, 1651, 1626, 1560, 1489, 1359, 1283, 1180,
1061, 995, 821. MS (ESI) m/z: 290.0 [M + H]+. HRMS (ESI) m/z: calcd for
+
C16H13O2NF2 [M + H]+ 290.0987, found 290.0982.
4.2.12 (S)-5-bromo-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (4h).
White solid. Yield = 90 %. er = 77:23. [α]16 = +12.4 (c = 0.54, CHCl3). m. p. 130.4–
D
130.6 ˚C. The er was determined by HPLC analysis using a Chiralpak AS-H column
1
(85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). H NMR (400 MHz,
CDCl3) δ = 7.68 (t, 4J = 1.8 Hz, 1H), 7.58 (dd, 3J = 8.3 Hz, 4J = 1.8 Hz, 1H), 6.79 (dd,
3J = 8.3 Hz, 4J = 0.9 Hz, 1H), 3.97–4.20 (m, 2H), 3.22 (s, 3H), 2.35–2.38 (m, 1H). 19F

NMR (376 MHz, CDCl3) δ = −169.6 (d, 3JHF = 18.6 Hz). 13C NMR (101 MHz, CDCl3)
δ = 171.1 (d, JCF = 20.7 Hz), 143.3 (d, JCF = 5.0 Hz), 134.3 (d, JCF = 2.7 Hz), 128.8 (s),
125.9 (d, JCF = 18.7 Hz), 116.1 (d, JCF = 3.1 Hz), 110.3 (s), 91.3 (d, 1JCF = 191.1 Hz),
64.2 (d, JCF = 30.3 Hz), 26.4 (s). IR (cm−1): 3420, 1723, 1652, 1611, 1541, 1487, 1463,
1361, 1350, 1102, 1067, 803. MS (ESI) m/z: 274.0 [M + H]+. HRMS (ESI) m/z: calcd
for C10H10O2NBrF+ [M + H]+ 273.9873, found 273.9872.
4.2.13 (S)-1-benzyl-5-bromo-3-fluoro-3-(hydroxymethyl)indolin-2-one (4h′).
White solid. Yield = 90 %. er = 73:27. [α]24 = +139.8 (c = 0.54, CHCl3). m. p.
D
161.1–162.1 ˚C. The er was determined by HPLC analysis using a Chiralpak AS-H
column (85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400
MHz, CDCl3) δ = 7.67 (s, 1H), 7.43 (d, 3J = 8.4 Hz, 1H), 7.27–7.39 (m, 5H), 6.62 (d,
3J = 8.3 Hz, 1H), 4.97 (d, 2J = 16.0 Hz, 1H), 4.85 (d, 2J = 16.0 Hz, 1H), , 4.04–4.28
(m, 2H), 2.42 (br, 1H). 19F NMR (376 MHz, CDCl3) δ = −169.1 (d, 3JHF = 3.3 Hz).
13C NMR (101 MHz, CDCl3) δ = 171.3 (d, JCF = 20.6 Hz), 142.5 (s), 134.3 (s), 134.2
(d, JCF = 2.6 Hz), 129.0 (s), 128.8 (s), 128.0 (s), 127.1 (s), 126.1 (s), 125.9 (s), 116.1
(s), 111.4 (s), 91.4 (d, 1JCF = 191.5 Hz), 64.2 (d, JCF = 32.2 Hz), 43.9 (s). IR (cm−1):
3412, 1719, 1684, 1651, 1611, 1589, 1484, 1273, 1180, 1063, 997, 875. MS (ESI)
m/z: 372.0 [M + Na]+. HRMS (ESI) m/z: calcd for C16H13O2NBrNaF+ [M + Na]+
372.0006, found 372.0003.
4.2.14 (S)-6-bromo-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (4i).

White solid. Yield = 93 %. er = 77:23. [α]16 = +16.7 (c = 0.54, CHCl3). m. p. 129.2–
D
130.3 ˚C. The er was determined by HPLC analysis using a Chiralpak OD-H column
1
(85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). H NMR (400 MHz,
3
CDCl3) δ = 7.41 (dd, J = 7.9 Hz, 4J = 1.8 Hz, 1H), 7.29–7.33 (m, 1H), 7.06 (s, 1H),
3.97–4.18 (m, 2H), 3.22 (s, 3H), 2.34–2.37 (m, 1H). 19F NMR (376 MHz, CDCl3) δ =
−169.2 (t, 3JHF = 16.0 Hz). 13C NMR (101 MHz, CDCl3) δ = 171.5 (d, JCF = 20.7 Hz),
145.6 (d, JCF = 5.0 Hz), 126.7 (s), 126.3 (d, JCF = 2.5 Hz), 125.5 (d, JCF = 3.5 Hz), 122.9
1
(d, JCF = 19.0 Hz), 112.5 (s), 91.2 (d, JCF = 190.3 Hz), 64.1 (d, JCF = 30.7 Hz), 26.4
(s). IR (cm−1): 3464, 1715, 1684, 1651, 1635, 1600, 1378, 1289, 1086, 1059, 978, 850.
MS (ESI) m/z: 274.0 [M + H]+. HRMS (ESI) m/z: calcd for C10H10O2NBrF+ [M + H]+
273.9873, found 273.9872.
4.2.15 (S)-3-fluoro-3-(hydroxymethyl)-1,6-dimethylindolin-2-one (4j).
White solid. Yield = 91 %. er = 72:28. [α]27 = +42.5 (c = 0.52, CHCl3). m. p.
D
116.7–117.2 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H
column (85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400
MHz, CDCl3) δ = 7.39 (dd, 3J = 7.5 Hz, 4J = 1.8 Hz, 1H), 6.96 (d, 3J = 7.5 Hz, 1H),
6.72 (s, 1H), 4.00–4.15 (m, 2H), 3.21 (s, 3H), 2.54 (s, 1H), 2.43 (s, 3H). 19F NMR
(376 MHz, CDCl3) δ = −168.4 (s). 13C NMR (101 MHz, CDCl3) δ = 172.1 (d, JCF
=
20.9 Hz), 144.4 (d, JCF = 5.2 Hz), 142.3 (d, JCF = 3.1 Hz), 125.0 (s), 123.9 (d, JCF
3.1 Hz), 121.0 (d, JCF = 18.8 Hz), 109.8 (s), 91.5 (d, 1JCF = 189.2 Hz), 64.3 (d, JCF
31.0 Hz), 26.2 (s), 22.0 (s). IR (cm−1): 3460, 1708, 1684, 1651, 1624, 1576, 1468,
=
=

1388, 1118, 1054, 1012, 823. MS (ESI) m/z: 248.0 [M + K]+. HRMS (ESI) m/z: calcd
for C11H12O2NKF+ [M + K]+ 248.0484, found 248.0475.
4.2.16 (S)-7-chloro-3-fluoro-3-(hydroxymethyl)-1-methylindolin-2-one (4k).
White solid. Yield = 96 %. er = 72:28. [α]28 = +67.0 (c = 0.59, CHCl3). m. p. 119.9–
D
120.3 ˚C. The er was determined by HPLC analysis using a Chiralpak OD-H column
1
(85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). H NMR (400 MHz,
CDCl3) δ = 7.37 (td, 3J = 8.1 Hz, 4J = 1.8 Hz, 1H), 7.09 (d, 3J = 8.3 Hz, 1H), 6.79 (d,
3J = 7.9 Hz, 1H), 4.42–4.49 (m, 1H), 4.31–4.38 (m, 1H), 3.22 (s, 3H), 2.45–2.56 (m,
19
13
1H). F NMR (376 MHz, DMSO) δ = −174.6 (s). C NMR (101 MHz, CDCl3) δ =
171.7 (d, JCF = 20.7 Hz), 146.5 (d, JCF = 4.4 Hz), 132.8 (d, JCF = 2.5 Hz), 132.5 (s),
124.5 (d, JCF = 2.1 Hz), 120.7 (d, JCF = 16.8 Hz), 107.4 (s), 91.7 (d, 1JCF = 193.5 Hz),
61.7 (d, JCF = 33.9 Hz), 26.5 (s). IR (cm−1): 3407, 1710, 1651, 1610, 1589, 1340, 1259,
1139, 1011, 989, 856, 745. MS (ESI) m/z: 252.0 [M + Na]+. HRMS (ESI) m/z: calcd
+
for C10H9ClNaFNO2 [M + Na]+ 252.0198, found 252.0200.
4.2.16 (S)-3-fluoro-3-(hydroxymethyl)-1-phenylindolin-2-one (4l).
White solid. Yield = 98 %. er = 59:41. [α]26 = −17.2 (c = 0.56, CHCl3). m. p.
D
119.2–119.7 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H
column (85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400
MHz, CDCl3) δ 7.63–7.54 (m, 3H), 7.50–7.43 (m, 3H), 7.41–7.33 (m, 1H), 7.20 (t, 3J
= 7.6 Hz, 1H), 6.89 (d, 3J = 7.9 Hz, 1H), 4.30–4.09 (m, 2H), 2.47 (s, 1H). 19F NMR
(376 MHz, CDCl3) δ −168.0 (t, 3JHF = 16.2 Hz). 13C NMR (101 MHz, CDCl3) δ 171.2

(d, JCF = 20.7 Hz), 144.5 (s), 133.4 (s), 131.4 (d, JCF = 2.9 Hz), 129.7 (s), 128.5 (s),
126.3 (s), 125.6 (s), 123.8 (d, JCF = 10.5 Hz), 110.1 (s), 91.70 (d, 1JCF = 190.2 Hz),
64.5 (d, JCF = 31.2 Hz), 29.6 (s). IR (cm−1): 3432, 1790, 1628, 1605, 1574, 1488,
1354, 1239, 1190, 1061, 924, 802. MS (ESI) m/z: 258.1 [M + H]+. HRMS (ESI) m/z:
+
calcd for C15H12FNO2 [M + Na]+ 258.0925, found 258.0924.
4.2.17 tert-butyl (S)-3-fluoro-3-(hydroxymethyl)-2-oxoindoline-1-carboxylate (4m).
White solid. Yield = 52 %. er = 87:13. [α]16 = −22.2 (c = 0.57, CHCl3). m. p.
D
103.6–103.8 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H
column (85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400
MHz, CDCl3) δ = 7.95 (d, 3J = 8.2 Hz, 1H), 7.58 (d, 3J = 7.5 Hz, 1H), 7.50 (t, 3J = 7.9
Hz, 1H), 7.29 (t, 4J = 3.8 Hz, 1H), 4.23–3.97 (m, 2H), 2.17–2.29 (m, 1H), 1.66 (s,
8H). 19F NMR (376 MHz, CDCl3) δ = −162.5 (s). 13C NMR (101 MHz, CDCl3) δ =
170.2 (d, JCF = 20.6 Hz), 148.5 (s), 140.7 (d, JCF = 5.1 Hz), 131.8 (d, JCF = 3.0 Hz),
125.2 (s), 125.1 (d, JCF = 2.7 Hz), 123.0 (d, JCF = 18.7 Hz), 115.6 (s), 91.1 (d, 1JCF
189.9 Hz), 85.2 (s), 64.4 (d, JCF = 32.5 Hz), 28.0 (s). IR (cm−1): 3463, 1787, 1710,
=
1685, 1648, 1612, 1466, 1345, 1152, 1070, 951, 839. MS (ESI) m/z: 299.1 [M + H]+.
HRMS (ESI) m/z: calcd for C14H20O4N2F+ [M + H]+ 299.1402, found 299.1400.
4.2.18 (S)-3-fluoro-3-(hydroxymethyl)indolin-2-one (4n).
White solid. Yield = 96 %. er = 64:36. [α]26 = −60.8 (c = 0.50, CHCl3). m. p. 92.6
D
–92.8 ˚C. The er was determined by HPLC analysis using a Chiralpak AD-H column
(85/15 hexane/i-PrOH; flow rate: 1.0 mL/min; λ = 214 nm). 1H NMR (400 MHz,

CDCl3) δ 7.49 (d, 3J = 7.4 Hz, 1H), 7.45–7.40 (m, 1H), 7.16 (t, 3J = 7.6 Hz, 1H), 7.10
(d, 3J = 7.9 Hz, 1H), 5.28 (d, 3J = 11.8 Hz, 1H), 5.07 (d, 3J = 11.8 Hz, 1H), 4.45 (br,
1H), 3.35 (s, 1H). 19F NMR (376 MHz, CDCl3) δ −168.8 (d, J = 8.9 Hz). 13C NMR
(101 MHz, CDCl3) δ 172.38 (d, JCF = 20.8 Hz), 142.6 (d, JCF = 5.1 Hz), 131.7 (d, JCF
= 3.0 Hz), 125.3 (s), 123.9 (s), 123.6 (d, JCF = 18.5 Hz), 110.1 (s), 92.0 (d, 1JCF
=
190.5 Hz), 63.9 (t, JCF = 16.4 Hz). IR (cm−1): 3402, 1790, 1624, 1615, 1582, 1490,
1345, 1211, 1192, 1060, 892, 756. MS (ESI) m/z: 182.1 [M + H]+. HRMS (ESI) m/z:
+
calcd for C9H8FNO2 [M + H]+ 182.0612, found 182.0615.
4.2.19 3-fluoro-3-(hydroxy(4-nitrophenyl)methyl)-1-methylindolin-2-one (6).
White solid. Yield = 32 % (major diasteromer). d. r. = 67:33. [α]2D6 = +84.6 (c = 0.50,
CHCl3). m. p. 158.1–159.9 ˚C. 1H NMR (400 MHz, CDCl3) δ 8.03 (d, 3J = 8.8 Hz, 2H),
7.49 (d, 3J = 7.4 Hz, 1H), 7.36 (d, 3J = 8.8 Hz, 3H), 7.11 (t, 3J = 7.6 Hz, 1H), 6.66 (d,
3J = 7.9 Hz, 1H), 5.48 (d, 3J = 8.0 Hz, 1H), 3.77 (s, 1H), 3.02 (s, 3H). 19F NMR (376
MHz, DMSO) δ −166.8 (s). 13C NMR (101 MHz, CDCl3) δ 171.2 (d, JCF = 20.7 Hz),
147.9 (s), 143.9 (d, JCF = 5.5 Hz), 142.3 (d, JCF = 5.9 Hz), 131.7 (d, JCF = 2.7 Hz), 128.5
(s), 126.8 (s), 123.3 (d, JCF = 2.4 Hz), 122.8 (s), 122.0 (s), 121.8 (s), 120.1 (d, JCF
=
1
15.9 Hz), 108.6 (s), 94.0 (d, JCF = 195.8 Hz), 75.2 (d, JCF = 26.9 Hz), 26.0 (s). IR
(cm−1): 3460, 1720, 1693, 1642, 1590, 1531, 1498, 1365, 1264, 1113, 1003, 923. MS
+
(ESI) m/z: 317.1 [M + H]+. HRMS (ESI) m/z: calcd for C16H13FN2O4 [M + H]+
317.0932, found 317.0930.
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).
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