Axially chiral C2-symmetric N-heterocyclic carbene (NHC) palladium complex-catalyzed asymmetric fluorination and amination of oxindoles

Article abstract of DOI:10.1002/cjoc.201200289

Chiral C₂-symmetric N-heterocyclic carbene (NHC) palladium diaquo complex 5b prepared from (S)-BINAM was found to be a fairly effective catalyst for the enantioselective asymmetric fluorination of oxindoles to give the corresponding products in moderate enantioselectivities along with good to excellent yields.

Full text of DOI:10.1002/cjoc.201200289

FULL PAPER
DOI: 10.1002/cjoc.201200289
Axially Chiral C2-Symmetric N-Heterocyclic Carbene (NHC)
Palladium Complex-Catalyzed Asymmetric Fluorination
and Amination of Oxindoles†
Zhang, Ruia(张睿)
Wang, Dea(王德)
Xu, Qina(徐琴)
Jiang, Jiajuna(姜佳俊)
Shi, Min*,a,b (施敏)
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, School of Chemistry & Molecular Engi-
neering, East China University of Science and Technology, Shanghai 200237, China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
Chiral C2-symmetric N-heterocyclic carbene (NHC) palladium diaquo complex 5b prepared from (S)-BINAM
was found to be a fairly effective catalyst for the enantioselective asymmetric fluorination of oxindoles to give the
corresponding products in moderate enantioselectivities along with good to excellent yields.
Keywords chiral C2-symmetric N-heterocyclic carbene (NHC) palladium diaquo complex, (S)-BINAM, asym-
metric fluorination of oxindoles, N-fluorobenzenesulfonimide (NFSI), 1-chloromethyl-4-fluoro-1,4-diazoniabi-
cyclo[2.2.2]octane bis(tetrafluoroborate) (selectfluor)
Introduction
of medicinal chemistry.[62] In this context, we wish to
report that axially chiral C2-symmetric N-heterocyclic
carbene (NHC) palladium complex 5b is a fairly effec-
tive catalyst in the asymmetric fluorination of
3-substituted oxindoles to give the corresponding
fluorinated products in moderate enantioselectivities
along with good to excellent yields.
The stereoselective introduction of the C—F bond
into organic compounds has attracted much attention
because fluorine containing chiral organic molecules are
very fascinating in the field of medicinal chemistry.[1-12]
After the first work on catalytic enatioselective fluorina-
tion reported by Togni et al. in 2000,[13] catalytic asym-
metric fluorination has witnessed great progress in the
past eleven years.[14,15] Several chiral metal complexes
and phase transfer catalysts have been developed for the
fluorination of carbonyl compounds such as β-keto es-
ters, imides, and aldehydes.[16-46] However, stereoselec-
tive construction of fluorinated quaternary carbon cen-
ters via introduction of fluorine atoms is still a big chal-
lenge.[47,48]
Previously, we reported that axially chiral C2-sym-
metric N-heterocyclic carbene (NHC) palladium com-
plexes 5a — 5e were highly effective catalysts in
1,4-addition of α,β-unsaturated ketones, 1,2-addition of
aldehydes, and oxidative kinetic resolution of secondary
alcohols.[49-61] As a part of our ongoing research project
on the application of these chiral NHC-Pd complexes in
asymmetric catalysis, we attempted to utilize these
complexes in the fluorination reaction of 3-substituted
oxindoles, since these optically active fluorinated de-
rivatives could have significant applications in the field
Experimental
General methods
m.p. was obtained with a Yanagimoto micro melting
point apparatus and is uncorrected. Optical rotations
were determined in a solution of CHCl3, CH2Cl2, or
acetone at 20 ℃ by using a Perkin-Elmer-241 MC po-
larimeter; [α]D-Values are given in units of 10 －
1
－
(°)•cm2•g . Infra-red spectra were measured on a spec-
trometer. 1H NMR spectra were recorded for solution in
CDCl3 with tetramethylsilane (TMS) as internal stan-
dard; 31P NMR spectra were recorded at 121 MHz for a
solution in CDCl3 with 85% H3PO4 as the external ref-
erence. J values are in Hz. Mass spectra were recorded
with an HP-5989 instrument and HRMS was measured
by a Finnigan MA＋ mass spectrometer. Organic sol-
vents used were dried by standard methods when nec-
essary. Commercially obtained reagents were used
without further purification. All reactions were moni-
1
*
E-mail: mshi@mail.sioc.ac.cn; Tel.: 0086-021-54923137; Fax: 0086-021-64166128
Received March 24, 2012; accepted April 22, 2012; published online June 1, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200289 or from the author.
Dedicated to Professor Jun Zhou on the occasion of his 80th birthday.
†
Chin. J. Chem. 2012, 30, 1295—1304
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Zhang et al.
FULL PAPER
General procedure for the synthesis of NHC-Pd(II)
tored by TLC with Huanghai 60F254 silica gel coated
plates. Flash column chromatography was carried out
using 300—400 mesh silica gel at increased pressure.
All asymmetric addition reactions were performed un-
der argon using standard Schlenk techniques. The opti-
cal purities of adducts were determined by HPLC
analysis using a chiral stationary phase column (column,
Daicel Co. Chiralcel AD and OD) and the absolute con-
figuration of the major enantiomer was assigned ac-
cording to the sign of the specific rotation with those of
the reported literature compounds (see experimental
section).
complexes 5a—5e
Chiral C2-symmetric N-heterocyclic carbene (NHC)
palladium diaquo complexes 5a—5c as well as chiral
C2-symmetric NHC-palladium complexes 5d and 5e
were synthesized from (S)-BINAM or (R)-H8-BINAM,
respectively according to our previous literature
(Scheme 1).[57]
General procedure for the synthesis of imidazolium
salts 3a—3c
Compound 1 (485 mg, 0.4 mmol) and 2a—2c (0.5
Scheme 1 General procedure for the synthesis of NHC-Pd(II) complexes 5a—5e
R
R
N
N
N
N
—
N
N
RX (2a 2c) (X = Br or I)
N
N
Pd(OAc)2
THF, 70 oC, 12—24 h
2X-
dioxane, 100 oC, 5—24 h
2a = MeI, 2b = BnBr,
2c = 3,5-Me2C6H3CH2Br
1
—
3a 3c
2+
R
N
R
R
N
N
N
N
AgOTf
OH2
Pd
X
X
-
Pd
2OTf
OH2
CH2Cl2CH3CN (3:1), r.t., 10 min
N
N
N
R
—
4a 4c
R = Me, (S)-N-Me-NHC-Pd(II) 5a, 83%
R = Bn, (S)-N-Bn-NHC-Pd(II) 5b, 90%
R = 3,5-Me2C6H3CH2, (S)-N-3,5-Xyl-NHC-Pd(II) 5c, 88%
Me
N
N
Me
I
N
CF3COOAg
N
OCOCF3
Pd
Pd
N
CH2Cl2CH3CN (3:1), r.t., 10 min
OCOCF3
I
N
N
Me
N
Me
4a
(S)-N-Me-NHC-Pd(II) 5d, 83%
Me
Me
N
N
Pd
N
N
N
N
CF3COOAg
OCOCF3
I
Pd
CH2Cl2CH3CN (3:1), r.t., 10 min
OCOCF3
Me
I
N
N
Me
4e
(R)-H8-N-Me-NHC-Pd(II) 5e, 80%
1296
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Chin. J. Chem. 2012, 30, 1295—1304

(NHC) Palladium Complex-Catalyzed Asymmetric Fluorination and Amination of Oxindoles
mmol) (RX, X＝Br or I) in dioxane (10 mL) were
stirred under reflux for 5—24 h. After cooling down to
room temperature, volatiles were removed under re-
duced pressure and the obtained solid compounds 3a—
3c were used for the next reaction without any further
purification.
under reduced pressure to give 5a—5c as a white pow-
der.
(S)-Cationic NHC-Pd(II) diaquo complex 5a
This is a known compound,[57] a white solid; m.p. 289
1
℃ (Dec.); [a]2D0 －43.0 (c 0.315, CHCl3); H NMR
(300 MHz, CDCl3, TMS) δ: 8.14 (s, 4H), 7.76 (d, J＝
8.1 Hz, 2H), 7.30—7.27 (m, 2H), 7.05—6.91 (m, 8H),
6.84—6.77 (m, 4H), 3.93 (s, 6H), 2.16 (brs, 4H); 19F
NMR (282 MHz, CDCl3, CF3CO2H) δ: －83.8 (s).
(S)-Cationic NHC-Pd(II) diaquo complex 5b
This is a known compound,[57] a white solid; m.p. 259
(S)-2,2'-Di(1H-benzo[d]imidazol-1-yl)-1,1'-binaph-
thyl (1)
This is a known compound,[57] a white solid; m.p.
1
294.5—294.8 ℃; [α]D －516.7 (c 0.97, CHCl3); H
NMR (400 MHz, CDCl3, TMS) δ: 8.06 (d, J＝8.8 Hz,
4H), 7.67—7.63 (m, 2H), 7.55—7.48 (m, 6H), 7.43 (d,
J＝8.8 Hz, 2H), 6.99 (s, 2H), 6.95 (d, J＝8.0 Hz, 2H),
6.50 (t, J＝7.6 Hz, 2H), 6.11 (d, J＝8.0 Hz, 2H).
1
℃ (Dec.); [a]2D0 －66.0 (c 0.22, CHCl3); H NMR
(300 MHz, CDCl3, TMS) δ: 8.03 (d, J＝8.4 Hz, 2H),
7.93 (d, J＝8.4 Hz, 2H), 7.83 (d, J＝8.1 Hz, 2H),
7.35—7.32 (m, 8H), 7.03—6.89 (m, 6H), 6.84—6.72
(m, 10H), 5.84 (d, J＝16.2 Hz, 2H), 5.65 (d, J＝15.9 Hz,
2H), 4.13 (brs, ＞4H); 19F NMR (282 MHz, CDCl3,
CF3CO2H) δ: －83.6 (s).
General procedure for the synthesis of NHC-Pd(II)
complexes 4a—4c
Compounds 3a—3c (0.2 mmol) and Pd(OAc)2 (44.8
mg, 0.2 mmol) were refluxed in THF (10 mL) for 16—
30 h. The volatiles were then removed under reduced
pressure and the residue was purified by a silica gel
flash column chromatography (eluent: petroleum ether/
EtOAc, 2/1 to 0/1) to give 4a—4c as yellow solids.
(S)-NHC-Pd(II) complex 4a This is a known
compound,[57] a yellow solid; m.p. ＞300 ℃ (dec.);
(S)-Cationic NHC-Pd (II) diaquo complex 5c
This is a known compound,[57] a white solid; m.p.
1
＞250 ℃ (Dec.); [a]2D0 －95.0 (c 0.22, CHCl3); H
NMR (300 MHz, CDCl3, TMS) δ: 7.78 (d, J＝7.8 Hz,
2H), 7.44—7.34 (m, 4H), 6.97—6.73 (m, 18H), 6.66—
6.63 (m, 4H), 5.72 (d, J＝9.9 Hz, 2H), 5.37 (brs, 4H),
2.27 (s, 12H); 19F NMR (282 MHz, CDCl3, CF3CO2H)
δ: －83.6 (s).
1
[a]2D0 －270.0 (c 0.086, CHCl3); H NMR (300 MHz,
CDCl3, TMS) δ: 8.10—8.03 (m, 4H), 7.72 (d, J＝8.4 Hz,
2H), 7.25—7.19 (m, 2H), 6.94—6.87 (m, 4H), 6.85—
6.82 (m, 2H), 6.78—6.74 (m, 4H), 6.68 (d, J＝8.7 Hz,
2H), 3.82 (s, 6H).
General procedure for the synthesis of NHC-Pd(II)
complex 5d
NHC-Pd(II) complex 5d was prepared by the similar
procedure using (S)-2,2'-di(1H-benzo[d]imidazol-1-yl)-
1,1'-binaphthyl as the starting materials.
(S)-NHC-Pd(II) complex 4b This is a known
compound,[57] a pale-yellow solid; m.p. ＞ 300 ℃
1
(dec.); [a]2D0 －45.0 (c 0.245, CHCl3); H NMR (300
(S)-NHC-Pd(II) complex 5d This is a known
compound,[57] a white solid; m.p. ＞250 ℃ (Dec.);
MHz, CDCl3, TMS) δ: 7.84 (d, J＝8.4 Hz, 2H), 7.79 (d,
J＝8.4 Hz, 2H), 7.63 (d, J＝8.7 Hz, 2H), 7.33 (d, J＝
8.4 Hz, 2H), 7.30—7.27 (m, 6H), 6.94—6.85 (m, 10H),
6.77—6.71 (m, 8H), 5.39 (d, J＝15.9 Hz, 2H); 13C
NMR (75 MHz, CDCl3, TMS) δ: 170.9, 136.3, 135.3,
134.6, 133.0, 132.7, 132.1, 131.4, 130.5, 128.5, 128.1,
128.0, 127.8, 127.7, 127.4, 126.7, 124.5, 123.6, 123.1,
112.3, 111.5, 55.6.
1
[a]2D0 －33.0 (c 0.395, CHCl3); H NMR (300 MHz,
CDCl3, TMS) δ: 8.09 (s, 4H), 7.73 (d, J＝8.4 Hz, 2H),
7.27—7.23 (m, 3H), 6.97—6.75 (m, 11H), 3.88 (s, 6H).
General procedure for the synthesis of NHC-Pd(II)
complex 5e
NHC-Pd(II) complex 5e was prepared by the similar
procedure using (R)-1,1'-(4a,5,5',6,6',7,7',8,8a,8'-decahy-
dro-1,1'-binaphthyl-2,2'-diyl)bis(1H-benzo[d]imidazole)
as the starting materials.
(S)-NHC-Pd(II) complex 4c This is a known
compound,[57] a pale-yellow solid; m.p. ＞ 300 ℃
1
(dec.); [a]2D0 －132.0 (c 0.195, CHCl3); H NMR (300
(R)-NHC-Pd (II) complex 4e This is a known
MHz, CDCl3, TMS) δ: 7.62 (d, J＝8.1 Hz, 2H), 7.48 (d,
J＝8.4 Hz, 2H), 7.27—7.21 (m, 8H), 7.05—6.85 (m,
10H), 6.73 (d, J＝8.7 Hz, 2H), 6.60 (d, J＝8.1 Hz, 2H),
6.55 (d, J＝15.6 Hz, 2H), 5.29 (d, J＝14.4 Hz, 2H),
2.38 (s, 12H).
compound,[57] a pale-yellow solid; m.p. ＞ 300 ℃
1
(dec.); [a]2D0 ＋53 (c 0.24, CHCl3); H NMR (300
MHz, CDCl3, TMS) δ: 7.60 (d, J＝8.1 Hz, 2H), 7.24—
7.22 (m, 3H), 7.20—7.18 (m, 1H), 7.15—7.11 (m, 4H),
6.89 (d, J＝8.1 Hz, 2H), 3.92 (s, 6H), 2.66—2.56 (m,
2H), 2.31—2.20 (m, 2H), 1.91—1.81 (m, 2H), 1.64—
1.55 (m, 4H), 1.41—1.17 (m, 6H).
General procedure for the synthesis of cationic
NHC-Pd(II) diaquo complexes 5a—5c
(R)-NHC-Pd (II) complex 5e This is a known
Complexes 4a—4c (0.20 mmol) were suspended in a
mixture of CH2Cl2 (15 mL) and CH3CN (5 mL). AgOTf
(108 mg, 0.42 mmol) was added and the mixture was
stirred at room temperature for 10 min. The resulting
suspension was filtered from the precipitated AgX (X＝
Br or I) through the celite and the solvent was removed
1
compound,[57] a pale-yellow solid. H NMR (400 MHz,
CDCl3, TMS) δ: 7.68 (d, J＝8.0 Hz, 2H), 7.30—7.24
(m, 4H), 7.20—7.13 (m, 4H), 6.90 (d, J＝8.0 Hz, 2H),
3.96 (s, 6H), 2.65—2.60 (m, 2H), 2.32—2.26 (m, 2H),
2.01—1.93 (m, 2H), 1.77—1.72 (m, 2H), 1.44—1.40
Chin. J. Chem. 2012, 30, 1295—1304
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Zhang et al.
FULL PAPER
(m, 2H), 1.29—1.22 (m, 4H), 0.44—0.41 (m, 2H); 13C
NMR (100 MHz, CDCl3, TMS) δ: 166.7, 161.7 (q, J＝
35.3 Hz), 139.9, 137.6, 135.4, 134.5, 133.8, 133.7,
129.7, 124.9, 124.1, 123.8, 116.0 (q, J＝289.6 Hz),
112.6, 109.8, 34.9, 29.2, 27.2, 21.9, 21.5; 19F NMR (376
MHz, CDCl3, CF3CO2H) δ: －74.6 (s).
3.79 (s, 3H), 1.61 (s, 9H); 19F NMR (376 MHz, CDCl3,
CF3CO2H) δ: －146.2 (s).
( ＋ )-tert-Butyl 3,5-difluoro-2-oxo-3-phenylindo-
line-1-carboxylate (8d) A colorless oil, 84.6 mg, 98%
yield. [a]2D0 ＋47.8 (c 0.73, CHCl3), 59% ee [HPLC
conditions: Chiracel OD-H column, hexane/2-propanol
＝100∶2, flow rate＝0.5 mL/min, wavelength＝254
1
General procedure for the asymmetric fluorination
of oxindoles
nm, tminor＝12.17 min and tmajor＝16.31 min]; H NMR
(400 MHz, CDCl3, TMS) δ: 8.04—8.00 (m, 1H), 7.42
—7.33 (m, 5H), 7.21 (tt, J＝2.4, 9.2 Hz, 1H), 7.10—
7.07 (m, 1H), 1.60 (s, 9H); 19F NMR (376 MHz, CDCl3,
CF3CO2H) δ: －115.9 (d), －146.5 (s); 13C NMR (100
MHz, CDCl3, TMS) δ: 169.7 (d, J＝24.8 Hz), 160.1 (dd,
J＝3.9, 245.1 Hz), 148.8, 136.9 (dd, J＝2.9, 5.1 Hz),
135.0 (d, J＝26.7 Hz), 129.7 (d, J＝1.5 Hz), 128.7,
127.2 (dd, J＝7.9, 17.8 Hz), 126.0 (d, J＝5.7 Hz), 118.6
(dd, J＝3.0, 22.4 Hz), 117.3 (d, J＝7.2 Hz), 113.5 (d,
J＝24.9 Hz), 92.4 (d, J＝188.3 Hz), 85.3, 28.0; IR
(CH2Cl2) ν: 2925, 2847, 2357, 2345, 1784, 1732, 1340,
NHC-Pd(II) catalyst 5b (3 mol%, 7.5 μmol), oxin-
dole 6 (0.25 mmol) and 20 mg activated 4 Å molecule
sieves were dissolved in acetone (1.0 mL) in a flame-
dried Schlenk tube equipped with a septum and stirring
bar and the mixture was stirred under argon at －20 ℃
for 10 min. After that, the selectfluor 7c (0.375 mmol)
was added into the mixture and stirred for 24 h. And
then the mixture was concentrated under reduced pres-
sure, and purified by flash chromatography on silica gel
(eluent: EtOAc/petroleum ether＝1/8) to yield the cor-
responding pure product 8.
(S)-tert-Butyl 3-fluoro-2-oxo-3-phenylindoline-1-
carboxylate (8a) A known compound,[24,62] a color-
less solid, 81.3 mg, 99% yield. [a]2D0 ＋71.0 (c 0.785,
CHCl3), 56% ee [HPLC conditions: Chiracel OD-H
column, hexane/2-propanol＝100∶2, flow rate＝0.3
－
1
1294, 1268, 1251, 822, 719, 648 cm ; MS (ESI) m/z:
713.2 (2M ＋ ＋ Na, 100). HRMS (ESI) calcd for
C38H34N2O6F4Na 713.2251, found 713.2271.
(＋)-tert-Butyl 3-fluoro-3-(naphthalen-2-yl)-2-oxo-
indoline-1-carboxylate (8e) A colorless oil, 89.6 mg,
95% yield. [a]2D0 ＋17.1 (c 0.66, CHCl3), 42% ee
[HPLC conditions: Chiracel AD-H column, hexane/
2-propanol＝95∶5, flow rate＝0.5 mL/min, wave-
length＝254 nm, tminor＝10.78 min and tmajor＝12.08
mL/min, wavelength＝254 nm, tminor＝17.52 min and
1
t
major＝19.13 min]; H NMR (400 MHz, CDCl3, TMS)
δ: 8.01 (d, J＝8.4 Hz, 1H), 7.51 (t, J＝8.0 Hz, 1H),
7.49—7.34 (m, 6H), 7.29—7.25 (m, 1H), 1.62 (s, 9H);
19F NMR (376 MHz, CDCl3, CF3CO2H) δ: －145.4 (s).
(S)-tert-Butyl 3-fluoro-5-methyl-2-oxo-3-pheny-
lindoline-1-carboxylate (8b) A colorless oil, 82.0 mg,
96% yield. [a]2D0 ＋90.8 (c 0.91, CHCl3), 47% ee
[HPLC conditions: Chiracel OD-H column, hexane/
2-propanol＝100∶2, flow rate＝0.3 mL/min, wave-
length＝254 nm, tminor＝14.89 min and tmajor＝16.09
1
min]; H NMR (400 MHz, CDCl3, TMS) δ: 8.05 (d,
J＝8.4 Hz, 1H), 7.89—7.79 (m, 3H), 7.73 (s, 1H),
7.57—7.49 (m, 4H), 7.42 (d, J＝7.6 Hz, 1H), 7.30 (t,
J＝7.6 Hz, 1H), 1.61 (s, 9H); 19F NMR (376 MHz,
CDCl3, CF3CO2H) δ: －145.2 (s); 13C NMR (100 MHz,
CDCl3, TMS) δ: 170.1 (d, J＝25.1 Hz), 148.9, 141.0 (d,
J＝5.1 Hz), 133.6 (d, J＝1.6 Hz), 132.9 (d, J＝27.9 Hz),
132.6, 132.0 (d, J＝3.0 Hz), 128.7, 128.4, 127.7, 127.0,
126.6, 126.3, 126.0 (d, J＝5.3 Hz), 125.6, 125.4 (d, J＝
2.9 Hz), 123.3 (d, J＝5.0 Hz), 115.7, 92.9 (d, J＝187.2
Hz), 85.1, 28.0; IR (CH2Cl2) ν: 3133, 2917, 2851, 2361,
2324, 1782, 1736, 1342, 1278, 1250, 1149, 1099, 750
cm－ 1; MS (ESI) m/z (%): 777.3 (2M＋ ＋Na, 100).
HRMS (ESI) calcd for C46H40N2O6F2Na 777.2752,
found 777.2742.
1
min]; H NMR (400 MHz, CDCl3, TMS) δ: 7.88 (d,
J＝8.8 Hz, 1H), 7.40—7.34 (m, 5H), 7.30 (d, J＝8.4 Hz,
1H), 7.17 (s, 1H), 6.16 (s, 1H), 2.36 (s, 3H), 1.61 (s, 9H);
19F NMR (376 MHz, CDCl3, CF3CO2H) δ: －145.6 (s);
13C NMR (100 MHz, CDCl3, TMS) δ: 170.3 (d, J＝
24.9 Hz), 148.9, 138.5 (d, J＝5.5 Hz), 135.6 (d, J＝9.5
Hz), 135.2 (d, J＝2.7 Hz), 132.3 (d, J＝3.4 Hz), 129.4
(d, J＝1.4 Hz), 128.6, 126.6, 126.2 (d, J＝6.4 Hz),
125.5 (d, J＝17.6 Hz), 115.4, 92.8 (d, J＝186.7 Hz),
84.8, 28.0, 20.9; IR (CH2Cl2) ν: 3360, 3195, 2923, 2852,
( ＋ )-tert-Butyl 3-fluoro-3-(3-fluorophenyl)-2-
oxoindoline-1-carboxylate (8f) A colorless oil, 79.4
mg, 92% yield. [a]D20 ＋1.5 (c 0.75 CHCl3), 48% ee
[HPLC conditions: Chiracel OD-H column, hexane/
2-propanol＝99∶1, flow rate＝0.5 mL/min, wave-
length＝254 nm, tminor＝20.72 min and tmajor＝24.95
－
1
2358, 2324, 1786, 1736, 1153, 822, 719, 698 cm ; MS
(ESI) m/z: 705.3 (2M＋＋Na, 100). HRMS (ESI) calcd
for C40H40N2O6F2Na 705.2752, found 705.2752.
1
(S)-tert-Butyl 3-fluoro-5-methoxy-2-oxo-3-pheny-
lindoline-1-carboxylate (8c) A known compound,[24]
a colorless oil, 86.6 mg, 97% yield. [a]2D0 ＋13.9 (c
0.50, CHCl3), 44% ee [HPLC conditions: Chiracel
AD-H column, hexane/2-propanol ＝ 100 ∶ 2, flow
rate＝0.7 mL/min, wavelength＝254 nm, tminor＝12.24
min and tmajor＝12.81 min]; 1H NMR (400 MHz, CDCl3,
TMS) δ: 7.93 (dd, J＝0.8, 8.8 Hz, 1H), 7.40—7.34 (m,
5H), 7.03 (dt, J＝2.4, 8.8 Hz, 1H), 6.90—6.89 (m, 1H),
min]; H NMR (400 MHz, CDCl3, TMS) δ: 8.02 (d,
J＝8.4 Hz, 1H), 7.55—7.50 (m, 1H), 7.37—7.33 (m,
2H), 7.31—7.26 (m, 1H), 7.14—7.06 (m, 3H), 1.62 (s,
9H); 19F NMR (376 MHz, CDCl3, CF3CO2H) δ:
－111.5—－111.6 (m), －145.4 (s); 13C NMR (100
MHz, CDCl3, TMS) δ: 169.6 (d, J＝24.6 Hz), 162.7 (d,
J＝246.0 Hz), 148.7, 141.0 (d, J＝5.2 Hz), 138.0 (dd,
J＝7.2, 27.7 Hz), 132.1 (d, J＝2.7 Hz), 130.3 (d, J＝8.1
Hz), 126.1, 125.5 (d, J＝2.5 Hz), 125.0 (d, J＝17.9 Hz),
1298
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1295—1304

(NHC) Palladium Complex-Catalyzed Asymmetric Fluorination and Amination of Oxindoles
121.9 (dd, J＝3.1, 5.9 Hz), 116.6 (d, J＝21.4 Hz), 115.8
(d, J＝1.6 Hz), 113.7 (dd, J＝6.6, 23.4 Hz), 92.1 (dd,
J＝2.1, 187.8 Hz), 85.2, 28.0; IR (CH2Cl2) ν: 3319,
2959, 2926, 2854, 1785, 1735, 1591, 1445, 1161, 1149,
788 cm ; MS (ESI) m/z (%): 713.2 (2M ＋Na, 100).
HRMS (ESI) calcd for C38H34N2O6F4Na 713.2251,
found 713.2256.
(S)-tert-Butyl 3-fluoro-5-methoxy-2-oxo-3-p-tolyl-
indoline-1-carboxylate (8k) A known compound,[24]
a colorless oil, 91.0 mg, 98% yield. [a]2D0 ＋59.2 (c
1.15, CHCl3), 49% ee [HPLC conditions: Chiracel OD-
H column, hexane/2-propanol＝100∶2, flow rate＝0.3
－
＋
1
mL/min, wavelength＝254 nm, tminor＝18.48 min and
1
t
major＝19.26 min]; H NMR (400 MHz, CDCl3, TMS)
(S)-tert-Butyl 3-fluoro-2-oxo-3-p-tolylindoline-1-
carboxylate (8g) A known compound,[24] a colorless
oil, 83.6 mg, 98% yield. [a]2D0 ＋13.1 (c 1.10, CHCl3),
34% ee [HPLC conditions: Chiracel AD-H column,
hexane/2-propanol＝299∶1, flow rate＝0.8 mL/min,
δ: 7.92 (dd, J＝1.2, 8.8 Hz, 1H), 7.27—7.24 (m, 2H),
7.20—7.18 (m, 2H), 7.04—7.00 (m, 1H), 6.90 (t, J＝2.4
Hz, 1H), 3.79 (s, 3H), 2.36 (s, 3H), 1.60 (s, 9H); 19F
NMR (376 MHz, CDCl3, CF3CO2H) δ: －145.3 (s).
(S)-tert-Butyl-3-fluoro-3-(4-fluorophenyl)-5-meth-
wavelength＝254 nm, tminor＝12.90 min and tmajor
＝
oxy-2-oxoindoline-1-carboxylate (8l)
A known
1
15.29 min]; H NMR (400 MHz, CDCl3, TMS) δ: 8.00
(d, J＝8.0 Hz, 1H), 7.53—7.48 (m, 1H), 7.38—7.36 (m,
1H), 7.29—7.24 (m, 3H), 7.20—7.18 (m, 2H), 2.35 (s,
3H), 1.61 (s, 9H); 19F NMR (376 MHz, CDCl3,
CF3CO2H) δ: －144.6 (s).
compound,[24] a colorless oil, 88.2 mg, 94% yield. [a]2D0
＋14.1 (c 0.24, CHCl3), 38% ee [HPLC conditions:
Chiracel OD-H column, hexane/2-propanol＝299∶1,
flow rate＝0.8 mL/min, wavelength＝254 nm, tminor
＝
1
14.88 min and tmajor＝33.56 min]; H NMR (400 MHz,
CDCl3, TMS) δ: 7.93 (dd, J＝0.8, 8.8 Hz, 1H), 7.36 (dd,
J＝5.2, 8.4 Hz, 2H), 7.10—7.02 (m, 3H), 6.90 (t, J＝2.0
Hz, 1H), 3.81 (s, 3H), 1.61 (s, 9H); 19F NMR (376 MHz,
CDCl3, CF3CO2H) δ: － 111.50 — － 111.58 (m),
－143.8 (s).
( ＋ )-tert-Butyl 3-fluoro-3-(4-fluorophenyl)-2-
oxoindoline-1-carboxylate (8h)
A known com-
pound,[24] a white solid, 82.0 mg, 95% yield. [a]2D0
＋16.0 (c 0.94, CHCl3), 22% ee [HPLC conditions:
Chiracel OD-H column, hexane/2-propanol＝100∶2,
flow rate＝0.5 mL/min, wavelength＝254 nm, tminor
＝
( ＋ )-tert-Butyl 3,5-difluoro-2-oxo-3-p-tolylindo-
line-1-carboxylate (8m) A colorless oil, 85.3 mg,
95% yield. [a]2D0 ＋31.5 (c 0.79, CHCl3), 40% ee
[HPLC conditions: Chiracel AD-H column, hexane/
2-propanol＝100∶2, flow rate＝0.5 mL/min, wave-
length＝254 nm, tmajor＝10.61 min and tminor＝11.27
1
9.37 min and tmajor＝10.97 min]; H NMR (400 MHz,
CDCl3, TMS) δ: 8.01 (d, J＝8.4 Hz, 1H), 7.53 (t, J＝
8.0 Hz, 1H), 7.38—7.34 (m, 3H), 7.31—7.27 (m, 1H),
7.08 (t, J＝8.4 Hz, 2H), 1.62 (s, 9H); 19F NMR (376
MHz, CDCl3, CF3CO2H) δ: －111.5 (d), －142.9 (d).
(S)-tert-Butyl 3-fluoro-5-methyl-2-oxo-3-p-tolylin-
1
min]; H NMR (400 MHz, CDCl3, TMS) δ: 8.03—
doline-1-carboxylate (8i) A known compound,[24]
a
7.99 (m, 1H), 7.25—7.18 (m, 5H), 7.11—7.08 (m, 1H),
2.36 (s, 3H), 1.60 (s, 9H); 19F NMR (376 MHz, CDCl3,
CF3CO2H) δ: －116.1 (s), －145.6 (s); 13C NMR (100
MHz, CDCl3, TMS) δ: 169.9 (d, J＝25.9 Hz), 160.1 (d,
J＝244.3 Hz), 148.9, 139.9 (d, J＝2.7 Hz), 136.8 (dd, J
＝1.8, 4.9 Hz,), 132.1 (d (J＝27.6 Hz), 129.4, 127.2 (dd,
J＝8.1, 17.8 Hz), 126.1 (d, J＝6.2 Hz), 118.5 (dd, J＝
3.3, 22.8 Hz), 113.5 (d, J＝24.8 Hz), 113.4, 92.3 (d, J＝
188.3 Hz), 85.2, 28.0, 21.2; IR (CH2Cl2) ν: 3358, 2924,
2852, 2369, 2341, 1785, 1731, 1488, 1384, 1295, 1155,
colorless oil, 80.1 mg, 90% yield. [a]2D0 ＋68.5 (c 0.91,
CHCl3), 45% ee [HPLC conditions: Chiracel OD-H
column, hexane/2-propanol＝100∶2, flow rate＝0.3
mL/min, wavelength＝254 nm, tminor＝15.62 min and
1
t
major＝18.60 min]; H NMR (400 MHz, CDCl3, TMS)
δ: 7.86 (d, J＝8.4 Hz, 1H), 7.30—7.17 (m, 6H), 2.36 (s,
6H), 1.60 (s, 9H); 19F NMR (376 MHz, CDCl3,
CF3CO2H) δ: －144.9 (s).
( ＋ )-tert-Butyl 3-fluoro-3-(4-fluorophenyl)-5-
methyl-2-oxoindoline-1-carboxylate (8j) A colorless
oil, 85.3 mg, 95% yield. IR (CH2Cl2) ν: 3133, 2361,
－
＋
1
764, 750 cm ; MS (ESI) m/z (%): 741.3 (2M ＋Na,
100). HRMS (ESI) calcd for C40H38N2O6F4Na 741.2564,
found 741.2571.
－
1
1785, 1736, 1655, 1630, 1400 cm . [a]2D0 ＋35.0 (c
1.45, CHCl3), 28% ee [HPLC conditions: Chiracel OD-
H column, hexane/2-propanol＝299∶1, flow rate＝0.8
(＋ )-tert-Butyl 3,5-difluoro-3-(4-fluorophenyl)-2-
oxoindoline-1-carboxylate (8n) A colorless oil, 86.3
mg, 95% yield. [a]D20 ＋14.1 (c 1.88, CHCl3), 20% ee
[HPLC conditions: Chiracel AD-H column, hexane/
2-propanol＝100∶2, flow rate＝0.5 mL/min, wave-
length＝254 nm, tmajor＝11.58 min and tminor＝13.57
mL/min, wavelength＝254 nm, tminor＝13.61 min and
1
t
major＝21.24 min]; H NMR (400 MHz, CDCl3, TMS)
δ: 7.88 (d, J＝8.4 Hz, 1H), 7.37—7.31 (m, 3H), 7.17 (s,
1H), 7.08 (t, J＝8.4 Hz, 2H), 2.37 (s, 3H), 1.61 (s, 9H);
19F NMR (376 MHz, CDCl3, CF3CO2H) δ: －111.7 (d),
143.2 (d); 13C NMR (100 MHz, CDCl3, TMS) δ: 170.1
(d, J＝24.0 Hz), 163.5 (dd, J＝1.9, 247.7 Hz), 148.9,
138.5 (d, J＝5.6 Hz), 135.3 (d, J＝3.1 Hz), 132.6 (d,
J＝2.6 Hz), 131.5 (dd, J＝2.7, 28.6 Hz), 128.5 (dd, J＝
5.3, 8.0 Hz), 126.5, 125.0 (d, J＝17.4 Hz), 115.7, 115.6
(d, J＝21.5 Hz), 92.3 (d, J＝185.5 Hz), 85.0, 28.0, 21.0;
MS (ESI) m/z (%): 741 (2M＋＋Na, 100). HRMS (ESI)
calcd for C40H38N2O6F4Na 741.2564, found 741.2575.
1
min]; H NMR (400 MHz, CDCl3, TMS) δ: 8.03 (dd,
J＝4.0, 8.8 Hz, 1H), 7.37—7.33 (m, 2H), 7.23—7.21
(m, 1H), 7.12—7.08 (m, 3H), 1.61 (s, 9H); 19F NMR
(376 MHz, CDCl3, CF3CO2H) δ: －111.0 (s), －115.7
(s), －144.1 (s); 13C NMR (100 MHz, CDCl3, TMS) δ:
169.6 (d, J＝25.1 Hz), 163.6 (dd, J＝1.9, 248.3 Hz),
160.1 (dd, J＝3.3, 244.9 Hz), 148.8, 136.9 (dd, J＝2.3,
5.2 Hz), 130.8 (dd, J＝3.2, 28.8 Hz), 128.4 (dd, J＝5.9,
8.3 Hz), 126.7 (dd, J＝8.0, 17.6 Hz), 118.8 (dd, J＝2.8,
Chin. J. Chem. 2012, 30, 1295—1304
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1299

Zhang et al.
FULL PAPER
23.1 Hz), 117.4 (d, J＝6.6 Hz), 115.8 (d, J＝21.9 Hz),
113.5 (d, J＝24.6 Hz), 91.9 (d, J＝189.7 Hz), 85.4, 27.9;
IR (CH2Cl2) ν: 3585, 2918, 2852, 2366, 2337, 1784,
1738, 1511, 1488, 1150, 811, 732 cm ; MS (ESI) m/z
(%): 749.2 (2M＋＋Na, 100). HRMS (ESI) calcd for
C38H32N2O6F6Na 749.2062, found 749.2068.
(－)-tert-Butyl 3-fluoro-2-oxo-3-o-tolylindoline-1-
carboxylate (8o) A colorless oil, 75.1 mg, 88% yield.
[a]2D0 －2.0 (c 1.85, CHCl3), 21% ee [HPLC conditions:
Chiracel OD-H column, hexane/2-propanol＝299∶1,
Hz), 138.3, 135.5 (d, J＝27.1 Hz), 131.7 (d, J＝4.0 Hz),
131.2 (d, J＝1.6 Hz), 129.7, 128.4, 126.2, 125.9 (d, J＝
18.6 Hz), 125.3 (d, J＝3.2 Hz), 123.8 (d, J＝5.9 Hz),
115.6, 92.8 (d, J＝185.6 Hz), 85.0, 53.4, 28.0, 21.3; IR
(CH2Cl2) ν: 3312, 2924, 2847, 2353, 2324, 1784, 1736,
1607, 1481, 1150, 843, 772, 725 cm ; MS (ESI) m/z
(%): 733 (2M＋ ＋Na, 100). HRMS (ESI) calcd for
C42H44N2O6F2Na 733.3065, found 733.3073.
(＋)-tert-Butyl 3-benzyl-3-fluoro-2-oxoindoline-1-
carboxylate (8r) A known compound,[48] a colorless
oil, 68.3 mg 80% yield. [a]2D0 ＋7.8 (c 0.50, CHCl3),
6% ee [HPLC conditions: Chiracel Oj-H column,
hexane/2-propanol＝99∶1, flow rate＝0.7 mL/min,
－
1
－
1
flow rate＝0.5 mL/min, wavelength＝254 nm, tminor
＝
1
23.00 min and tmajor＝27.12 min]; H NMR (400 MHz,
CDCl3, TMS) δ: 7.97 (d, J＝8.8 Hz, 1H), 7.59—7.57
(m, 1H), 7.49—7.46 (m, 1H), 7.29—7.27 (m, 2H),
7.19—7.12 (m, 3H), 2.01 (s, 3H), 1.64 (s, 9H); 19F
NMR (376 MHz, CDCl3, CF3CO2H) δ: －143.1 (s);
13C NMR (100 MHz, CDCl3, TMS) δ: 169.8 (d, J＝
23.2 Hz), 148.9, 141.0 (d, J＝5.8 Hz), 134.9 (d, J＝4.0
Hz), 133.9 (d, J＝25.7 Hz), 131.85 (d, J＝4.9 Hz),
131.78 (d, J＝2.1 Hz), 129.2, 126.2, 126.1, 125.9 (d,
J＝2.0 Hz), 125.8 (d, J＝1.9 Hz), 125.3 (d, J＝3.3 Hz),
115.5 (d, J＝2.3 Hz), 93.4 (d, J＝182.4 Hz), 85.1, 28.0,
19.9 (d, J＝2.0 Hz); IR (CH2Cl2) ν: 2979, 2928, 2363,
wavelength＝254 nm, tminor＝17.87 min and tmajor
＝
1
27.50 min]; H NMR (400 MHz, CDCl3, TMS) δ: 7.74
(d, J＝8.4 Hz, 1H), 7.35 (t, J＝8.0 Hz, 1H), 7.23—7.17
(m, 3H), 7.12 (t, J＝8.0 Hz, 1H), 7.04—7.00 (m, 3H),
3.57 (dd, J＝9.6, 13.2 Hz, 1H), 3.24 (dd, J＝13.6, 22.4
Hz, 1H), 1.60 (s, 9H); 19F NMR (376 MHz, CDCl3,
CF3CO2H) δ: －150.3 (s).
(－)-1-Benzyl-3-fluoro-3-phenylindolin-2-one (8s)
A colorless oil, 68.2 mg, 86% yield. [a]2D0 －57.0 (c
0.30, CHCl3), 23% ee [HPLC conditions: Chiracel
OD-H column, hexane/2-propanol ＝ 299 ∶ 1, flow
rate＝1.0 mL/min, wavelength＝254 nm, tminor＝12.94
min and tmajor＝15.89 min]; 1H NMR (400 MHz, CDCl3,
TMS) δ: 7.42—7.38 (m, 5H), 7.34—7.27 (m, 7H), 7.10
(t, J＝8.0 Hz, 1H), 6.79 (d, J＝7.6 Hz, 1H), 4.97 (d, J＝
15.6 Hz, 1H), 4.85 (d, J＝15.2 Hz, 1H); 19F NMR (376
MHz, CDCl3, CF3CO2H) δ: －152.9 (s); 13C NMR (100
MHz, CDCl3, TMS) δ: 172.5 (d, J＝24.0 Hz), 143.7 (d,
J＝4.8 Hz), 135.9 (d, J＝26.8 Hz), 135.0, 131.4 (d, J＝
2.7 Hz), 129.2 (d, J＝1.8 Hz), 128.8, 128.6, 127.8,
126.9 (d, J＝17.1 Hz), 126.1, 125.8 (d, J＝5.2 Hz),
123.5 (d, J＝2.6 Hz), 109.9, 93.2 (d, J＝186.6 Hz), 43.9;
IR (CH2Cl2) ν: 3648, 2925, 2855, 2360 2341, 1716,
－
1
2354, 1786, 1737, 1149, 750 cm ; MS (ESI) m/z (%):
＋
705 (2M ＋ Na, 100). HRMS (ESI) calcd for
C40H40N2O6F2Na 705.2752, found 705.2770.
( ＋ )-tert-Butyl 3-fluoro-2-oxo-3-m-tolylindoline-
1-carboxylate (8p) A colorless oil, 82.0 mg, 96%
yield. [a]2D0 ＋24.5 (c 0.24, CHCl3), 44% ee [HPLC
conditions: Chiracel OD-H column, hexane/2-propanol＝
100∶2, flow rate＝0.5 mL/min, wavelength＝254 nm,
1
t
minor＝9.30 min and tmajor＝10.32 min]; H NMR (400
MHz, CDCl3, TMS) δ: 8.00 (d, J＝8.0 Hz, 1H), 7.50 (t,
J＝8.0 Hz, 1H), 7.37—7.35 (m, 1H), 7.28—7.18 (m,
4H), 7.10 (d, J＝8.0 Hz, 1H), 2.35 (s, 3H), 1.62 (s, 9H);
19F NMR (376 MHz, CDCl3, CF3CO2H) δ: －145.4 (s);
13C NMR (100 MHz, CDCl3, TMS) δ: 170.2 (d, J＝
25.2 Hz), 148.9, 140.9 (d, J＝4.9 Hz.), 138.5, 135.6 (d,
J＝26.4 Hz), 131.8 (d, J＝3.8 Hz), 130.3 (d, J＝1.3 Hz),
128.5, 126.7 (d, J＝5.9 Hz), 126.2, 125.7 (d, J＝17.8
Hz), 125.3 (d, J＝2.5 Hz), 123.3 (d, J＝6.0 Hz), 115.6,
92.7 (d, J＝186.7 Hz), 85.0, 28.0, 21.4; IR (CH2Cl2) ν:
3320, 2919, 2361, 2345, 1784, 1736, 1344, 1269, 1251,
－
1
1540, 1506, 1472, 750 cm ; MS (ESI) m/z (%): 318.1
(M＋, 100). HRMS (ESI) calcd for C21H17NOF 318.1294,
found 318.1293.
3-Fluoro-1-methyl-3-phenylindolin-2-one (8t)
A
colorless oil, 48.3 mg, 80% yield. [a]2D0 0 (c 0.73,
CHCl3), 0% ee [HPLC conditions: Chiracel OD-H
column, hexane/2-propanol＝299∶1, flow rate＝1.0
－
1
＋
1150, 776, 727 cm ; MS (ESI) m/z (%): 364 (M ＋Na,
37). HRMS (ESI) calcd for C20H20NO3FNa 364.1325,
found 364.1327.
mL/min, wavelength＝254 nm, tminor＝14.20 min and
1
t
major＝24.27 min]; H NMR (400 MHz, CDCl3, TMS)
δ: 7.40—7.27 (m, 7H), 7.09 (td, J＝0.8, 7.6 Hz, 1H),
6.91 (d, J＝8.0 Hz, 1H), 3.25 (s, 3H), 1.60 (s, 9H); 19F
NMR (376 MHz, CDCl3, CF3CO2H) δ: －152.9 (s).
13C NMR (100 MHz, CDCl3, TMS) δ: 172.3 (d, J＝24.1
Hz), 144.6 (d, J＝5.5 Hz), 135.8 (d, J＝26.9 Hz), 131.5
(d, J＝3.8 Hz), 129.1 (d, J＝1.4 Hz), 128.5, 126.7 (d,
J＝17.0 Hz), 126.0, 125.8 (d, J＝6.9 Hz), 123.5 (d, J＝
2.5 Hz), 108.8, 93.1 (d, J＝187.2 Hz), 26.4; IR (CH2Cl2)
ν: 3058, 2932, 1716, 1612, 1495, 1448, 1419, 1344, 811,
(＋)-tert-Butyl 3-(3,5-dimethylphenyl)-3-fluoro-2-
oxoindoline-1-carboxylate (8q) A colorless oil, 85.3
mg, 96% yield. [a]D20 ＋24.5 (c 0.24, CHCl3), 35% ee
[HPLC conditions: Chiracel OD-H column, hexane/
2-propanol＝299∶1, flow rate＝0.5 mL/min, wave-
length＝254 nm, tminor＝19.36 min and tmajor＝23.96
1
min]; H NMR (400 MHz, CDCl3, TMS) δ: 8.01 (d, J
＝8.4 Hz, 1H), 7.50 (t, J＝8.0 Hz, 1H), 7.36—7.35 (m,
1H), 7.28—7.25 (m, 1H), 7.02 (s, 1H), 6.94 (s, 2H),
2.29 (s, 6H), 1.62 (s, 9H); 19F NMR (376 MHz, CDCl3,
CF3CO2H) δ: －145.8 (s); 13C NMR (100 MHz, CDCl3,
TMS) δ: 170.3 (d, J＝24.7 Hz), 149.0, 140.9 (d, J＝4.9
－
＋
1
751, 697 cm ; MS (ESI) m/z (%): 280.1 (M ＋K, 100).
HRMS (ESI) calcd for C15H12NOFK 280.0540, found
280.0539.
1300
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1295—1304

(NHC) Palladium Complex-Catalyzed Asymmetric Fluorination and Amination of Oxindoles
General procedure for the asymmetric α-amination
reaction of oxindole (6a)
Results and Discussion
Initial examinations using N-Boc-protected-3-phenyl-
oxindole 6a (0.25 mmol) as the substrate for enantio-
selective fluorination in the presence of chiral C2-sym-
metric N-heterocyclic carbene (NHC) palladium diaquo
complex 5b (3 mol%, 0.0075 mmol) and 4 Å MS (20
mg) in the presence of various fluorination reagents 7
(0.375 mmol) in acetone were aimed at determining the
optimal conditions and the results of these experiments
are summarized in Table 1. The electrophilic N-fluoro-
benzenesulfonimide (NFSI) 7a and 1-chloromethyl-4-
fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoro-
borate) (selectfluor) 7c could afford the desired product
8a in good yields in the presence of NHC-Pd-complex
5b (Table 1, Entries 2 and 4). Using NSFI as the fluori-
nation reagent could also afford 8a in 99% yield with no
ee value in the absence of catalyst 5b and even in the
presence of catalyst 5b, 8a was obtained in 99% yield
with no ee value (Table 1, Entries 1 and 2). Notably, the
nucleophilic diethylaminosulfur trifluoride (DAST) 7b
did not give the desired product 8a (Table 1, Entry 3).
Using selectfluor as fluorination reagent afforded 8a in
＞99% yield and 40% ee in the presence of NHC-Pd-
complex 5b (Table 1, Entry 4). Increasing or decreasing
the employed amounts of selectfluor did not improve
reaction outcomes (Table 1, Entries 4—7). When select-
fluor was added in three portions, the desired product 8a
was formed in ＞99% yield and 39% ee (Table 1, Entry
8).
NHC-Pd (II) catalyst 5b (3 mol%, 7.5 μmol), oxin-
dole 6a (0.25 mmol) and 20 mg activated 4 Å molecule
sieves were dissolved in THF (1.0 mL) in a flame-dried
Schlenk tube equipped with a septum and stirring bar
and the mixture was stirred under argon at －20 ℃ for
10 min. After that, the (E)-di-tert-butyl diazene-1,2-
dicarboxylate 9 (0.375 mmol) was added into the mix-
ture and the resulting solution was stirred for 24 h. Then
the reaction mixture was concentrated under reduced
pressure, and the residue was purified by flash chroma-
tography on silica gel (eluent: EtOAc/petroleum ether＝
1/4) to yield the corresponding pure product 10.
(－)-Di-tert-butyl 1-(1-(tert-butoxycarbonyl)-2-
oxo-3-phenylindolin-3-yl)hydrazine-1,2-dicarboxy-
late (10) A colorless oil, 117.4 mg, 87% yield. [a]D20
－19.5 (c 0.73, CHCl3), 30% ee [HPLC conditions:
Chiracel AD-H column, hexane/2-propanol＝90∶10,
flow rate＝1.0 mL/min, wavelength＝254 nm, tminor
＝
1
12.55 min and tmajor＝17.81 min]; H NMR (400 MHz,
CDCl3, TMS) δ: 8.25 (d, J＝7.6 Hz, 1H), 7.90 (d, J＝
8.4 Hz, 1H), 7.55—7.54 (m, 2H), 7.37—7.30 (m, 5H),
6.30 (brs, 1H), 1.60 (s, 9H), 1.30 (s, 9H), 1.19 (s, 9H);
13C NMR (100 MHz, CDCl3, TMS) δ: 174.1, 154.8,
153.1, 149.1, 138.8, 132.9, 129.7, 129.3, 128.81, 128.77,
128.2, 126.4, 124.4, 114.8, 84.2, 83.1, 80.9, 72.5, 28.1,
27.8, 27.7; IR (CH2Cl2) ν: 3295, 2978, 2930, 1788, 1748,
1729, 1707, 1504, 1480, 1603, 1394, 1370, 1322, 1307,
－
1
1251, 1151, 1061, 753, 730 cm ; MS m/z (%): 439.2
([M－Boc＋H]＋ 0.2), 253.1 (12), 209.1 (100), 180.1
(57), 57.1 (15). HRMS (EI) calcd for C24H29N3O5
439.2107, found 439.2110.
With these tentatively optimized reaction conditions
in hand, we next attempted to examine the catalyst, sol-
vent and temperature effects under identical conditions
as shown in Table 2. Catalyst 5a (3 mol%) had the
Table 1 Optimization of the reaction conditions in the asymmetric fluorination of oxindolesa
Ph
F
Ph
(S)-N-Bn-NHC-Pd(II) 5b, (3 mol%)
O
+
7 (x equiv.)
O
N
o
N
4 A MS, acetone
Boc
Boc
6a
8a
Entry
x
Time/h
Yieldb/%
eec/%
7
1d
7a, NFSI
7a, NFSI
1.5
1.5
1.5
1.5
1.0
2.0
0.5
1.5
24
24
24
24
24
24
24
24
99
99
0
2
0
3e
4
7b, DAST
n.r.
n.d.
7c, Selectfluor
7c, Selectfluor
7c, Selectfluor
7c, Selectfluor
7c, Selectfluor
＞99
＞99
＞99
48
40 (S)
30 (S)
28 (S)
39 (S)
39 (S)
5
6
7
8f
＞99
a Reaction conditions: oxindole 6a (0.25 mmol), 7 (0.375 mmol), NHC-Pd(II) 5b (3 mol%, 0.0075 mmol), 4 Å MS (20 mg), acetone (1.0
mL), and the reaction was carried out at 20 ℃. b Isolated yields. c The ee value was determined by HPLC using a Chiralcel OD-H column
(see the Supporting Information). The absolute configuration of the products was assigned by comparison of the sign of optical rotation
with those of the literature compounds. d Oxindole 6a (0.25 mmol), 7a (0.375 mmol), 4 Å MS (20 mg), acetone (1.0 mL), and the reaction
was carried out at 20 ℃ in the absence of catalyst. e No reaction. f Oxindole 6a (0.25 mmol), 7c (0.375 mmol) added in to three portions,
NHC-Pd(II) 5b (3 mol%, 0.0075 mmol), 4 Å MS (20 mg), acetone (1.0 mL), and the reaction was carried out at 20 ℃.
Chin. J. Chem. 2012, 30, 1295—1304
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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1301

Zhang et al.
FULL PAPER
similar catalytic ability as that of 5d (3 mol%), giving
the desired product 8a in excellent yield (＞99%) and
35% ee after 24 h (Table 2, Entries 1 and 3). Other
NHC-Pd complex 5c and complex 5e, which has an axi-
ally chiral H8-binaphthyl scaffold, were as effective as
catalyst 5a in above reaction (Table 2, Entries 2 and 4).
Furthermore, using chiral NHC-Pd catalyst 5b, we also
examined the solvent effects in this asymmetric reaction
in 1,2-dichloroethane (DCE), CH3CN, tetrahydrofuran
(THF), 1,4-dioxane, isopropanol (IPA), ethyl acetate
(EA), toluene, dichloromethane and chlorobenzene. We
found that no improvement could be observed in these
solvents (Table 2, Entries 5—13). Using NHC-Pd com-
plex 5b as the catalyst, we found that lowering the reac-
tion temperature could improve the reaction outcome,
affording desired product 8a in ＞99% yield and 56%
ee at －20 ℃ (Table 2, Entries 14—18).
Under the optimized reaction conditions, we next
examined the substrate scope with various oxindoles
and the results are summarized in Table 3. As can be
seen from Table 3, all reactions proceeded smoothly to
give the corresponding products 8 in good yields and
moderate ee values under the optimal conditions (Table
3). Whether R1 is an electron-donating or -withdrawing
group, the reactions proceeded smoothly to give the
corresponding products 8b—8f in excellent yields and
42%—59% ee values (Table 3, Entries 1—5). However,
when R2 are electron-rich or -deficient aromatic rings,
the corresponding products 8g—8n were obtained in
excellent yields along with lower ee values (20%—49%
ee), perhaps due to the combined electronic properties
of R1 and R2 groups (Table 3, Entries 6—13). When R2
is o-MeC6H4, m-MeC6H4, or m,m-dimethylC6H3, the
corresponding products 8o, 8p and 8q were obtained in
good yields also along with lower ee values (21%—
44% ee), presumably due to the steric effect (Table 3,
Entries 14—16). When R2 is an aliphatic group (R2＝
Bn), the reaction also proceeded efficiently to afford the
corresponding product 8r in 80% yield but along with
6% ee (Table 3, Entry 17). Changing the N-Boc-pro-
tecting group to N-Bn or N-Me protecting group pro-
vided the corresponding products 8s and 8t in 86% yield
along with 23% ee and 80% yield with no chiral induc-
tion, respectively, suggesting that the carbonyl group in
the N-Boc-protecting group plays a significant role in
this reaction (Table 3, Entries 18 and 19). Furthermore,
NHC-Pd catalyst 5b was also used in the asymmet-
ricα-amination reaction of oxindole 6a with (E)-di-tert-
butyl diazene-1,2-dicarboxylate (9). It was found that
the corresponding product 10 was obtained in good
Table 2 Optimization of the reaction conditions in the enantioselective fluorination of oxindolesa
Ph
F
Ph
catalyst (3 mol%)
O
+
O
Boc
selectfluor
o
N
N
4 A MS (20 mg), solvent, temperature
7c (1.5 equiv.)
Boc
6a
8a
Entry
1
Catalyst
5a
Solvent
Temp/℃
20
Time/h
24
24
36
24
24
24
24
24
24
24
24
36
24
24
24
24
48
48
Yieldb/%
＞99
96
eec/%
35 (S)
25 (S)
35 (S)
30 (S)
20 (S)
0
Acetone
Acetone
Acetone
Acetone
DCE
2
5c
20
3
5d
5e
20
＞99
80
4
20
5
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
20
85
6
CH3CN
DCM
20
＞99
75
7
20
30 (S)
13 (S)
0
8
THF
20
20
9
1,4-Dioxane
IPA
20
70
10
11
12
13
14
15
16
17
18
20
20
15 (S)
41 (S)
11 (S)
n.d.
EA
20
＞99
80
Toluene
Chlorobenzene
Acetone
Acetone
Acetone
Acetone
Acetone
20
20
trace
＞99
＞99
＞99
＞99
＞99
0
40 (S)
56 (S)
46 (S)
50 (S)
43 (S)
－20
－25
－30
－35
a
Reaction conditions: oxindole 6a (0.25 mmol), selectfluor 7c (0.375 mmol), NHC-Pd(II) 5 (3 mol%, 0.0075 mmol), 4 Å MS (20 mg),
and solvent (1.0 mL). b Isolated yields. c The ee value was determined by HPLC using a Chiralcel OD-H column (see the Supporting In-
formation). The absolute configuration of the products was assigned by comparison of the sign of optical rotation with those of the litera-
ture compounds.
1302
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1295—1304

(NHC) Palladium Complex-Catalyzed Asymmetric Fluorination and Amination of Oxindoles
Table 3 Enantioselective fluorination of oxindoles under the optimal conditionsa
R2
F
*
R2
R1
R1
catalyst 5b (3 mol%)
selectfluor
7c (1.5 equiv.)
O
+
O
o
4 A MS (20 mg), acetone, -20 o
C
N
N
R3
6 (1.0 equiv.)
R3
8
Entry
1
Oxindoles 6 (R1/R2/R3)
6b (Me/C6H5/Boc)
Time/h
24
24
24
24
24
24
24
24
24
24
24
24
24
48
24
24
48
48
48
Yieldb/%
96
eec/%
8b, 47 (S)
8c, 44 (S)
8d, 59 (＋)
8e, 42 (＋)
8f, 48 (＋)
8g, 34 (＋)
8h, 22 (＋)
8i, 45 (S)
2
6c (OMe/C6H5/Boc)
6d (F/C6H5/Boc)
97
3
98
4
6e (H/β-naphthyl/Boc)
6f (H/m-FC6H4/Boc)
6g (H/p-MeC6H4/Boc)
6h (H/p-FC6H4/Boc)
6i (Me/p-MeC6H4/Boc)
6j (Me/p-FC6H4/Boc)
6k (OMe/p-MeC6H4/Boc)
6l (OMe/p-FC6H4/Boc)
6m (F/p-MeC6H4/Boc)
6n (F/p-FC6H4/Boc)
6o (H/o-MeC6H4/Boc)
6p (H/m-MeC6H4/Boc)
6q (H/m,m-dimethylC6H3/Boc)
6r (H/Bn/Boc)
95
5
92
6
98
7
95
8
90
9
95
8j, 28 (＋)
8k, 49 (S)
8l, 38 (S)
10
11
12
13
14
15
16
17
18
19
98
94
95
8m, 40 (＋)
8n, 20 (＋)
8o, 21 (－)
8p, 44 (＋)
8q, 35 (＋)
8r, 6 (＋)
8s, 23 (－)
8t, 0
95
88
96
96
80
6s (H/Ph/Bn)
86
6t (H/Ph/Me)
80
a
Reaction conditions: oxindoles 6 (0.25 mmol), selcetfluor 7c (0.375 mmol), NHC-Pd(II) 5b (3 mol%, 0.0075 mmol) and 4 Å MS (20
mg). b Isolated yields. c The ee value was determined by HPLC using a Chiralcel column (see the Supporting Information). The absolute
configuration of the products was assigned by comparison of the sign of optical rotation with those of the literature compounds.
Scheme 3 A plausible transition state for the enantioselectivity
yield but with 30% ee value under the standard condi-
tions (Scheme 2).
*
OTf -
The possible transition state of this asymmetric fluo-
rination of 3-substituted oxindole can be explained as
the approach of selectfluor toward the tetracoordinated
Pd(II) complex and 3-substituted oxindole as illustrated
in Scheme 3. According to the previous work reported
Si-face
N
N
+
Pd
N
N
O
O
O
Ph
N
Scheme 2 Asymmetric α-amination reaction of oxindole 6a
Ph
Re
-fa
ce
catalyst 5b (3 mol%)
+
N
Boc
O
Boc
N
o
4 A MS (20 mg), THF, -20 oC
N
se
lec
6a
tfluo
r
9
Boc
by Sodeoka using NHC-Pd(II)(OTFA)2 complex as the
catalyst,[48] the Si-face of the putative Pd enolate would
be blocked by one of the aryl groups of the ligand and
t-Bu group of Boc protecting group might locate at the
Si-face to avoid the steric repulsion with the aryl groups
of the ligand. As a result, the enolized 3-substituted ox-
indoles could react with selectfluor from the Re face to
form the (S)-products in accordance with the experi-
mental results. A more detailed investigation on the re-
action mechanism using DFT calculation is undergoing
Boc
HN
Ph
N
Boc
*
O
N
Boc
10
yield = 87%, ee = 30%
Chin. J. Chem. 2012, 30, 1295—1304
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1303

Zhang et al.
FULL PAPER
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Conclusions
In conclusion, chiral C2-symmetric N-heterocyclic
carbene (NHC) palladium diaquo complex 5b was
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lective fluorination of oxindoles to give the correspond-
ing adducts in moderate enantioselectivities along with
good to excellent yields. Efforts are underway to eluci-
date the mechanistic details of this asymmetric addition
reaction in the presence of chiral NHC-Pd(II) catalyst
and to disclose the exact structure of the active species
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Acknowledgement
We thank the Shanghai Municipal Committee of
Science and Technology (No. 11JC1402600), National
Basic Research Program of China [No. (973)-
2010CB833302], the Fundamental Research Funds for
the Central Universities and the National Natural Sci-
ence Foundation of China for financial support (Nos.
21072206, 20872162, 20672127, 20732008, 21121062
and 20702013).
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Chin. J. Chem. 2012, 30, 1295—1304