Asymmetric Chlorination of Cyclic β-Keto Esters and N -Boc Oxindoles Catalyzed by an Iron(III)-BPsalan Complex

Article abstract of DOI:10.1055/s-0036-1590955

An iron(III)-BPsalan complex was found to efficiently catalyze the asymmetric chlorination reaction of cyclic β-keto esters and N -Boc oxindoles, affording the corresponding chlorinated products in high yield and up to 92% ee with NCS as chlorination reag

Full text of DOI:10.1055/s-0036-1590955

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
paper
A
en
Y.-H. Luo et al.
Paper
Synthesis
Asymmetric Chlorination of Cyclic β-Keto Esters and N-Boc
Oxindoles Catalyzed by an Iron(III)-BPsalan Complex
Yong-Heng Luoa
O
O
Yuan-Ji Pingb
Zong-Rui Lib
Xin Gub
Zhen-Jiang Xu*b
Chi-Ming Che*b,c
O
O
R
R
OR1
OR1
Cl
up to 92% ee
N
O
N
O
10 examples
R1
Fe
Cl
up to 99% yield
NCS + 1a + AgClO4
tBu
tBu
R1
Cl
tBu
tBu
O
R
O
N
R
N
1a
a School of Chemical and Environmental Engineering, Shanghai
Institute of Technology, 100 Haiquan Road, Shanghai, P. R. of
China
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis,
Shanghai Institute of Organic Chemistry, 354 Feng Lin Road,
Shanghai 200032, P. R. of China
Boc
10 examples
Boc
up to 91% ee
up to 99% yield
xuzhenjiang@sioc.ac.cn
c Department of Chemistry and State Key Laboratory of Syn-
thetic Chemistry, The University of Hong Kong, Pokfulam
Road, Hong Kong, SAR, P. R. of China
cmche@hku.hk
Received: 29.08.2017
Accepted after revision: 12.10.2017
Published online: 09.11.2017
highly efficient asymmetric fluorination and hydroxylation
reaction of β-keto esters and N-Boc oxindoles.8,9 Herein we
report the application of these iron complexes as efficient
catalysts in the asymmetric chlorination of β-keto esters
and N-Boc oxindoles to give the corresponding chlorinated
products in excellent yield and up to 92% ee under mild re-
action conditions.
DOI: 10.1055/s-0036-1590955; Art ID: ss-2017-h0556-op
Abstract An iron(III)-BPsalan complex was found to efficiently catalyze
the asymmetric chlorination reaction of cyclic β-keto esters and N-Boc
oxindoles, affording the corresponding chlorinated products in high
yield and up to 92% ee with NCS as chlorination reagent under mild re-
action conditions.
Initially the catalytic chlorination reactions were ex-
plored with cyclic β-keto ester 2a (0.15 mmol) as the model
substrate and N-chlorosuccinimide (NCS, 1.2 equiv) as a
chlorination reagent, in the presence of 5 mol% of the iron
complexes and 5 mol% AgClO4 in CH2Cl2 (1 mL) with 4Å MS
(100 mg) at room temperature. All the iron complexes 1a–g
showed high activity in the chlorination reactions, the in
situ generated cationic complexes efficiently prompted the
reactions to afford the α-chlorinated product 3a in high
yields, while the ee values of 3a were significantly affected
by the R1 and R2 substituents in the iron complexes (Table
1). When complex 1a with two tert-butyl substituents was
used as catalyst, 3a was obtained in 95% yield and 85% ee
(Table 1, entry 1). To our surprise, when the previously best
catalyst complex 1b in asymmetric fluorination and hy-
droxylation reaction9 was used as catalyst, both the yield
and ee value of 3a dropped (entry 2). When complex 1c
with two Br substituents was used, a much lower ee value
of 45% was obtained (entry 3). When R2 was changed to ste-
rically less hindered F and Cl, even lower ee values were ob-
tained (entries 4, 5). Changing R1 to phenyl led to a moder-
ate 70% ee (entry 6), while when the sterically more hin-
dered adamantanyl group was incorporated only racemic
product was obtained (entry 7).
Key words iron catalysis, BPsalan ligand, asymmetric chlorination, cy-
clic β-keto ester, N-Boc oxindole, asymmetric bromination
α-Chlorinated carbonyl compounds are important
structure motifs found in various biologically active natural
products and can be used as valuable synthetic intermedi-
ates with numerous applications.1,2 The direct chlorination
of carbonyl compounds with either metal complexes or or-
ganocatalysts as catalyst is the most straightforward meth-
od for the construction of α-chlorinated carbonyl com-
pounds.3 In the past decades, a panel of metal and organo
catalysts have been developed and applied in the asymmet-
ric electrophilic chlorination of 1,3-dicarbonyl derivatives
such as β-keto esters4 and N-Boc oxindoles,5 which led to
enantiomer-enriched chlorinated products bearing one ter-
tiary or quaternary stereocenter. Despite the recent prog-
ress in this area, it is still of great interest to develop new
catalytic system with readily available, cheap, and nontoxic
catalyst to meet the need of sustainable and green catalysis.
Iron is environmentally benign and one of the most earth-
abundant transition metals and its application in C–H func-
tionalization has been receiving growing interest.6 In our
endeavor to develop practical iron-catalyzed organic reac-
tions,7 recently we have reported the synthesis of a series of
novel Fe(III)-Bpsalan complexes and their application in
With 1a as catalyst, various chlorination reagents were
tested in the asymmetric chlorination reaction (Scheme 1).
The results revealed that NCS and its analogue N-chloro-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
Y.-H. Luo et al.
Paper
Synthesis
Table 1 Screening of Catalystsa
N
O
N
O
O
O
cat. (5 mol%)
AgClO4 (5 mol%)
O
O
Fe
Cl
R2
R2
NCS (1.2 equiv)
CH2Cl2, RT
4 Å MS
OtBu
OtBu
Cl
R1
R1
2a
3a
1
Entry
Cat.
R1
R2
tBu
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
tBu
tBu
Br
95
86
93
98
93
99
95
85
74
45
11
7
Br
Br
F
tBu
tBu
Ph
Cl
Br
Br
70
0
1g
Ad
a Reaction conditions: substrate (0.15 mmol), catalyst (5 mol%), AgClO4 (5 mol%), and NCS (1.2 equiv) were stirred in CH2Cl2 with 4Å MS at room temperature
under an argon atmosphere.
b Isolated yield.
c Determined by chiral HPLC.
phthalimide were the best to afford 3a in excellent yield
and high ee (85% and 82% ee, respectively), while the other
chlorination reagents were less selective to afford 3a with
Table 2 Optimization of Reaction Conditionsa
only low to moderate ee. As NCS is cheap and readily avail-
able, we chose NCS as the chlorination reagent in the subse-
quent investigation.
O
O
1a (5 mol%)
silver salt (5 mol%)
O
O
NCS (1.2 equiv)
solvent, temp
4 Å MS
OtBu
OtBu
Cl
3a
2a
O
O
1a (5 mol%)
O
AgClO4 (5 mol%)
O
Entry
Solvent
Silver salt
AgClO4
Temp (°C)
Yield (%)b
ee (%)c
Cl source (1.2 equiv)
CH2Cl2, RT
4 Å MS
OtBu
OtBu
Cl
1
2
CH2Cl2
toluene
CHCl3
MeCN
Et2O
25
25
25
25
25
25
25
25
25
25
25
25
0
95
89
99
99
99
99
99
91
94
99
98
97
98
99
90
85
40
34
70
72
7
3a
2a
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
AgClO4
–
O
3
O
O
Cl
Cl
Cl
Cl
Cl
4
N
Cl
N
Cl
5
O
Cl
O
6
THF
95% yield
85% ee
99% yield
82% ee
99% yield
47% ee
7d
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
18
5
O
O
Cl
Cl
O
Cl
9
AgOTf
NaBArF
AgOAc
NaOPiv
AgClO4
AgClO4
AgClO4
83
70
4
N
N
N
N
OCl
10
11
12
13
14
15
O
N
Cl
O
Cl
94% yield
54% ee
97% yield
16% ee
93% yield
71% ee
16
90
92
78
Scheme 1 Screening of various chlorination reagents
–20
–40
The effect of solvent and additive in the chlorination re-
action were also explored. As can be seen from Table 2, the
chlorination reaction underwent well in all the common or-
ganic solvents screened to afford 3a in high yield, but only
dichloromethane gave the best ee of 85% and the other sol-
a Reaction conditions: substrate (0.15 mmol), cat. (5 mol%), silver salt (5
mol%), and NCS (1.2 equiv) were stirred in CH2Cl2 with 4Å MS at the indi-
cated temperature under an argon atmosphere.
b Isolated yield.
c Determined by chiral HPLC.
d Without 4Å MS.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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Y.-H. Luo et al.
Paper
Synthesis
vents such as toluene, chloroform, acetonitrile, diethyl
ether, or THF gave only low to moderate ee (Table 2, entries
1–6). It is noteworthy that the addition of 4Å MS was essen-
tial for achieving a high ee value for 3a: when the reaction
was carried out without 4Å MS, the ee value of 3a dropped
significantly to 18% (entry 7). And the addition of silver
salts was also critical for better chirality induction. When
the reaction was done without addition of silver salts, al-
most racemic 3a was obtained (entry 8). This may be at-
tributed to the higher activity of the cationic in situ formed
active catalyst upon addition of silver salts with non-coor-
dination counter anion, which suppressed the non-selective
background reaction. This is supported by the fact that sil-
ver salt with non-coordinative counter anion gave better
results than that of silvers salts with coordinative counter
anion (entries 1, 9, 10 vs entries 11, 12) and AgClO4 gave the
best result. Lowering the reaction temperature to –20 °C
further improved the ee value of 3a to 92% (entry 14).
With the established optimized reactions conditions at
hand, the asymmetric chlorination of various cyclic β-keto
esters 2a–j was investigated; the corresponding products
3a–j are depicted in Table 3. In contrast to the Fe(III)-
BPsalan complexes catalyzed asymmetric fluorination reac-
tion of cyclic β-keto esters, the substituents on the phenyl
ring can affect the ee value of the chlorinated product sig-
nificantly. Cyclic β-keto ester 2b with the electron-donating
methyl group underwent the reaction smoothly to afford
3b in 97% yield and 86% ee (Table 3, entry 2), while 3c,d
with electron-withdrawing Cl group led to relative lower ee
(entries 3, 4). It is interesting that substrates 3e,f with
strong electron-donating methoxy group also led to only
moderate ee (entries 5, 6). This might be attributed to the
possible coordination of the methoxy group to the catalyst,
thus led to lower ee of the chlorination product. The size of
the ester group also played important role in the reaction
and the sterically more hindered ester group led to higher
ee than the smaller ones (entry 1 vs entries 7, 8). The six-
membered ring cyclic β-keto ester 2i also underwent the
reaction well to afford 3i in 84% yield and 76% ee (entry 9).
Cyclic β-keto ester 2j was also suitable substrate for the
chlorination reaction to afford the product 3j in high yield
and 83% ee (entry 10). Noncyclic β-keto ester 2k was inac-
tive to the reaction and only trace amount of product was
formed after 24 hours (entry 11).
substituted oxindole 4a underwent the reaction smoothly
to afford the chlorinated product in quantitative yield and
90% ee. 3-Aryl-substituted oxindole derivatives 4b–f were
also efficiently chlorinated to afford 5b–f in good yields and
moderate to good ee. It is noteworthy that 3-benzyl-substi-
tuted oxindoles 4g–i were also suitable substrates in the
asymmetric chlorination reaction to afford the products
5g–i in 47–73% yields and 70–91% ee. 3-Methyl-substituted
substrate 4j was less efficient in the asymmetric chlorina-
tion reaction to afford 5j in much lower yield and ee.
In addition to the chlorination reaction, we also tried
one example of bromination reaction of cyclic -keto ester
2a catalyzed by iron complex 1a with AgClO4 as additive
and NBS as a bromination reagent (Scheme 3). The bromi-
R1
R1
1a (5 mol%)
AgClO4 (5 mol%)
R2
Cl
R2
O
O
NCS (1.2 equiv)
CH2Cl2, –20 °C
4Å MS
N
N
Boc
Boc
4
5
F
Cl
Cl
Cl
O
N
O
O
Boc
N
N
Boc
Boc
5a: 99% yield
5b: 95% yield
5c: 92% yield
90% ee
73% ee
71% ee
F
Cl
Cl
Cl
F
O
O
N
O
N
Boc
N
Boc
F
Boc
5f: 54% yield
77% ee
5d: 99% yield
5e: 86% yield
56% ee
72% ee
X
Cl
Cl
O
Cl
N
O
O
N
Boc
N
Boc
Boc
5g: 73% yield
5h: X = OMe, 47% yield,70% ee
5i: X = F, 56% yield, 85% ee
5j: 29% yield
47% ee
91% ee
With the successful application of iron complex 1a in
asymmetric chlorination of cyclic β-keto esters, we turned
our attention to the asymmetric chlorination of N-Boc oxin-
doles, as the corresponding chiral chlorinated products
could be useful intermediates for the synthesis of 3,3′-
disubstituted chiral oxindole derivatives, which are import-
ant structure motifs found in natural products and pharma-
ceuticals. To our delight, various N-Boc oxindole derivatives
4a–j were suitable substrates under the same reaction con-
ditions to afford the corresponding chlorinated products in
high yields and moderate to high ee (Scheme 2). 3-Phenyl-
Scheme 2 Iron complex 1a-catalyzed asymmetric chlorination of N-
Boc oxindoles
1a (5 mol%)
AgClO4 (5 mol%)
NBS (1.2 equiv)
O
O
*
O
O
OtBu
OtBu
CH2Cl2, –20 °C
4Å MS
Br
2a
6a
89% yield
25% ee
Scheme 3 Asymmetric bromination reaction of cyclic β-keto ester 2a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
Y.-H. Luo et al.
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Synthesis
Table 3 Iron Complex 1a-Catalyzed Asymmetric Chlorination of β-Keto Estersa
N
O
N
O
1a (5 mol%)
AgClO4 (5 mol%)
EWG2
EWG1
EWG2
EWG1
Cl
Fe
Cl
tBu
tBu
R
R
NCS (1.2 equiv)
CH2Cl2, –20 °C
4 Å MS
tBu
tBu
2
3
1a
Entry
Product
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
3a: R1 = H, R2 = H
3b: R1 = Me, R2 = H
3c: R1 = Cl, R2 = H
3d: R1 = H, R2 = Cl
99
97
99
93
97
99
81
92
86
64
79
66
77
53
O
R1
R2
O
OtBu
Cl
3e: R1 = OMe, R2 = H
3f: R1 = OMe, R2 = OMe
3g: R = Me
O
O
8
3h: R = Et
91
48
OR
Cl
O
O
OtBu
9
3i
84
76
Cl
O
O
O
10
11
3j
83
83
–
OtBu
O
Cl
3k
<5%
Ph
OtBu
Cl
a Reaction conditions: substrate (0.15 mmol), catalyst (5 mol%), AgClO4 (5 mol%), and NCS (1.2 equiv) were stirred in CH2Cl2 with 4Å MS at –20 °C under an
argon atmosphere.
b Isolated yield.
c Determined by chiral HPLC or GC.
nated product 6a was obtained in 89% yield albeit with a
lower ee of 25%, maybe due to the strong background reac-
tion.
BPsalan could also catalyze the asymmetric bromination re-
action of cyclic β-keto ester and the optimization of the this
reaction is currently underway in our laboratory.
A plausible mechanism for the iron(III)-BPsalan com-
plex catalyzed asymmetric chlorination reaction is pro-
posed and depicted in Scheme 4. Similar to that of the pre-
viously reported fluorination reaction, iron complex 1a was
converted in situ into an active cationic intermediate upon
addition of AgClO4, which subsequently coordinate to the
substrate to form the ‘chiral-at-iron’ intermediate and fur-
ther reaction with NCS to give the desired enantiomer en-
riched chlorination product.
In conclusion, we have developed an efficient and prac-
tical iron(III)-BPsalan complex catalyzed asymmetric chlo-
rination of both cyclic β-keto ester and N-Boc oxindole de-
rivatives. The corresponding chlorinated products were ob-
tained in high yields and moderate to good ee under mild
reaction conditions with cheap NCS as chlorination reagent.
Moreover, preliminary result revealed that the iron(III)-
All manipulations were carried out using standard Schlenk line or
dry-box techniques under an argon atmosphere. All reactions were
carried out with anhydrous solvents unless otherwise noted. Solvents
were dried and freshly distilled under an argon atmosphere. Flash
chromatography (FC) was performed with Merck silica gel 60 (230–
400 mesh). 1H and 13C NMR spectra were recorded on a Varian Mercu-
ry 300 (300 MHz) or Agilent 400 (400 MHz) spectrometer. 1H and 13
C
NMR spectra were referenced internally to residual protio-solvent
(1H) or solvent (13C) resonances and are reported relative to TMS.
Chemical shifts (δ values) were reported in parts per million (ppm),
and the residual solvent peak was used as an internal reference. Stan-
dard abbreviations are used to indicate multiplicity. Coupling con-
stants were reported in hertz (Hz). Low-resolution mass spectra were
obtained with Agilent GC-MS 5975C and Agilent 1100 LC-MSD SL.
High-resolution mass spectra (HRMS) were measured on an Agilent
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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Y.-H. Luo et al.
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Synthesis
+
N
O
N
O
N
O
N
O
AgClO4
Fe
Cl
Fe
tBu
tBu
tBu
tBu
tBu
tBu
tBu
tBu
1a
O
O
O
O
+
OR
Cl
N
OR
O
N
Fe
NCS
O
O
O
OtBu
Scheme 4 Plausible mechanism of the asymmetric chlorination catalyzed by 1a
Technologies 6224 TOF LC/MS spectrometer. HRMS/LRMS were ob-
tained in ESI/EI mode. Chiral HPLC analysis was performed on a DI-
ONEX UltiMate 3000, No. 8074238, ThermoScientific. Chiral GC anal-
ysis was performed on an Agilent GC 7820 equipment. Optical rota-
MS (ESI): m/z = 284.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C14H19ClNO3 ([M + NH4]+): 284.1048;
+
found: 284.1051.
tions were measured on an Autopol
I polarimeter. (R,R)-2,2′-
tert-Butyl (S)-2-Chloro-6-methyl-1-oxo-2,3-dihydro-1H-indene-2-
Bipyrrolidine was synthesized according to the literature proce-
dures.10,11 All iron complexes and β-keto esters were synthesized ac-
cording to the literature procedures.9 All N-Boc oxindoles were syn-
thesized according to the literature procedures.5d,9 NCS and NBS were
purchased from commercial sources and used as received without
further purification. All other reagents were commercially available
and used as received. The absolute configurations of products were
assigned by comparing HPLC data and optical rotations with those of
the known compound reported in the literature, or by analogy.
carboxylate (3b)4l
Yield: 41 mg (97%); pale yellow oil; [α]D25 +21.9 (c = 1.00, CH2Cl2).
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (9:1), 0.7 mL/min, 214
nm, tR (major) = 6.9 min, tR (minor) = 7.2 min; 86% ee.
1H NMR (CDCl3, 400 MHz): δ = 7.64 (s, 1 H, ArH), 7.50 (d, J = 7.7 Hz, 1
H, ArH), 7.36 (d, J = 7.8 Hz, 1 H, ArH), 3.96 (d, J = 17.6 Hz, 1 H, CH2),
3.48 (d, J = 17.6 Hz, 1 H, CH2), 2.43 (s, 3 H, CH3), 1.43 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 298.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C15H21ClNO3 ([M + NH4]+): 298.1204;
found: 298.1202.
+
Asymmetric Chlorination of Cyclic β-Keto Esters and N-Boc Oxin-
doles Catalyzed by Iron Complex 1a; General Procedure
A mixture of iron complex 1a (5 mol%, 0.0075 mmol), AgClO4 (5 mol%,
0.0075 mmol), and 4Å molecular sieves (100 mg) in CH2Cl2 (1 mL) un-
der an argon atmosphere was stirred at r.t. for 1 h. After cooling the
reaction to –20 °C, the β-keto ester or N-Boc oxindole (0.15 mmol)
was added and stirred for 20 min, then NCS or NBS (1.2 equiv, 0.18
mmol) was added in one portion at once. The reaction mixture was
stirred until completion (monitored by TLC, hexane/EtOAc 5:1). The
mixture was filtered and the filtrate was concentrated under vacuum
and the product was isolated by flash column chromatography (hex-
ane/EtOAc 5:1).
tert-Butyl (+)-2,6-Dichloro-1-oxo-2,3-dihydro-1H-indene-2-car-
boxylate (3c)
Yield: 45 mg (99%); pale yellow oil; [α]D25 +13.2 (c = 1.00, CH2Cl2).
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (9:1), 0.7 mL/min, 214
nm, tR (major) = 7.1 min, tR (minor) = 6.7 min; 64% ee.
1H NMR (CDCl3, 400 MHz): δ = 7.81 (s, 1 H, ArH), 7.69–7.60 (d, J = 8.1
Hz, 1 H, ArH), 7.43 (d, J = 8.1 Hz, 1 H, ArH), 3.98 (d, J = 17.8 Hz, 1 H,
CH2), 3.49 (d, J = 17.8 Hz, 1 H, CH2), 1.44 [s, 9 H, C(CH3)3].
13C NMR (CDCl3, 100 MHz): δ = 194.4, 165.5, 148.8, 136.3, 134.9,
134.4, 127.5, 125.5, 84.8, 69.0, 43.2, 27.8.
MS (ESI): m/z = 318.0 [M + NH4]+.
tert-Butyl (S)-2-Chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxyl-
ate (3a)4h
33
+
Yield: 40 mg (99%); colorless solid; mp 76–78 °C; [α]D +29.4 (c =
HRMS (ESI): m/z calcd for C14H18Cl2NO3 ([M + NH4]+): 318.0658;
1.00, CH2Cl2).
found: 318.0657.
HPLC: Daicel Chiralpak OJ-H, hexane/i-PrOH (95:5), 0.7 mL/min, 254
nm, tR (major) = 13.7 min, tR (minor) = 17.0 min; 92% ee.
1H NMR (CDCl3, 400 MHz): δ = 7.85 (d, J = 7.6 Hz, 1 H, ArH), 7.68 (t, J =
7.3 Hz, 1 H, ArH), 7.46 (m, J = 8.9 Hz, 2 H, ArH), 4.02 (d, J = 17.7 Hz, 1
H, CH2), 3.54 (d, J = 17.7 Hz, 1 H, CH2), 1.43 [s, 9 H, C(CH3)3].
tert-Butyl (S)-2,5-Dichloro-1-oxo-2,3-dihydro-1H-indene-2-car-
boxylate (3d)4l
Yield: 42 mg (93%); pale yellow oil; [α]D25 +20.7 (c = 1.00, CH2Cl2).
HPLC: Daicel Chiralpak ID-3, hexane/i-PrOH (95:5), 0.7 mL/min, 214
nm, tR (major) = 5.3 min, tR (minor) = 5.8 min; 79% ee.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

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Y.-H. Luo et al.
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Synthesis
1H NMR (CDCl3, 400 MHz): δ = 7.79 (d, J = 8.2 Hz, 1 H, ArH), 7.48 (s, 1
H, ArH), 7.44 (d, J = 8.2 Hz, 1 H, ArH), 4.00 (d, J = 17.9 Hz, 1 H, CH2),
3.51 (d, J = 17.9 Hz, 1 H, CH2), 1.44 [s, 9 H, C(CH3)3].
tert-Butyl (S)-2-Chloro-1,2,3,4-tetrahydro-1-oxonaphthalene-2-
carboxylate (3i)4o
Yield: 35 mg (84%); pale yellow oil; [α]D26 +9.8 (c = 1.00, CH2Cl2).
MS (ESI): m/z = 318.0 [M + NH4]+.
HPLC: Daicel Chiralpak ID-3, hexane/i-PrOH (95:5), 0.7 mL/min, 214
nm, tR (major) = 5.9 min, tR (minor) = 6.7 min; 76% ee.
+
HRMS (ESI): m/z calcd for C14H18Cl2NO3 ([M + NH4]+): 318.0658;
1H NMR (CDCl3, 400 MHz): δ = 8.08 (d, J = 7.6 Hz, 1 H, ArH), 7.53 (t, J =
7.2 Hz, 1 H, ArH), 7.35 (t, J = 7.2 Hz, 1 H, ArH), 7.27 (d, J = 7.1 Hz, 1 H,
ArH), 3.25 (m, 1 H, CH2), 3.10–2.86 (m, 2 H, CH2), 2.50 (m, 1 H, CH2),
1.46 [s, 9 H, C(CH3)3].
found: 318.0659.
tert-Butyl (S)-2-Chloro-6-methoxy-1-oxo-2,3-dihydro-1H-indene-
2-carboxylate (3e)4l
Yield: 43 mg (97%); pale yellow oil; [α]D33 +10.5 (c = 1.00, CH2Cl2).
MS (ESI): m/z = 298.1 [M + NH4]+.
+
HRMS (ESI): m/z calcd for C15H21ClNO3 ([M + NH4]+): 298.1204;
found: 298.1204.
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (9:1), 0.7 mL/min, 214
nm, tR (major) = 8.1 min, tR (minor) = 7.7 min; 66% ee.
1H NMR (CDCl3, 400 MHz): δ = 7.36 (d, J = 8.0 Hz, 1 H, ArH), 7.27 (m, 2
H, ArH), 3.93 (d, J = 17.4 Hz, 1 H, CH2), 3.86 (s, 3 H, OCH3), 3.46 (d, J =
17.4 Hz, 1 H, CH2), 1.43 [s, 9 H, C(CH3)3].
tert-Butyl (S)-1-Chloro-2-oxocyclopentanecarboxylate (3j)4f
Yield: 27 mg (83%); colorless oil; [α]D26 +4.1 (c = 1.00, CH2Cl2).
MS (ESI): m/z = 314.1 [M + NH4]+.
GC: cp-chiralsil-DEX CB, T1 = 90 °C, t1 = 70 min, v1 = 5 °C/min, T2 = 120
°C, t2 = 10 min, v2 = 20 °C /min, T3 = 200 °C, t3 = 5 min, tR (major) = 60.2
min, tR (minor) = 61.9 min; 83% ee.
HRMS (ESI): m/z calcd for C15H21ClNO4 ([M + NH4]+): 314.1154;
+
found: 314.1154.
1H NMR (CDCl3, 400 MHz): δ = 2.71 (m, 1 H, CH2), 2.59–2.46 (m, 1 H,
tert-Butyl (S)-2-Chloro-5,6-dimethoxy-1-oxo-2,3-dihydro-1H-in-
CH2), 2.38 (m, 2 H, CH2), 2.11 (m, 2 H, CH2), 1.49 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 236.1 [M + NH4]+.
dene-2-carboxylate (3f)4f
Yield: 48 mg (99%); pale yellow oil; [α]D33 +20.1 (c = 1.00, CH2Cl2).
+
HRMS (ESI): m/z calcd for C10H19ClNO3 ([M + NH4]+): 236.1048;
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (9:1), 0.7 mL/min, 214
nm, tR (major) = 14.7 min, tR (minor) = 13.5 min; 77% ee.
found: 236.105.
1H NMR (CDCl3, 400 MHz): δ = 7.23 (s, 1 H, ArH), 6.89 (s, 1 H, ArH),
4.00 (s, 3 H, OCH3), 3.93 (s, 3 H, OCH3), 3.93 (d, J = 20 Hz, 1 H, CH2),
3.45 (d, J = 17.5 Hz, 1 H, CH2), 1.44 [s, 9 H, C(CH3)3].
tert-Butyl (R)-3-Chloro-2-oxo-3-phenylindoline-1-carboxylate
(5a)5d
Yield: 51 mg (99%); pale yellow oil; [α]D27 –77.8 (c = 0.96, CH2Cl2).
MS (ESI): m/z = 344.1 [M + NH4]+.
HPLC: Daicel Chiralpak OJ-H, hexane/i-PrOH (9:1), 1.0 mL/min, 254
nm, tR (major) = 8.7 min, tR (minor) = 7.0 min; 90% ee.
+
HRMS (ESI): m/z calcd for C16H23ClNO5 ([M + NH4]+): 344.1259;
1H NMR (CDCl3, 300 MHz): δ = 8.00 (d, J = 8.1 Hz, 1 H, ArH), 7.57–7.23
found: 344.126.
(m, 8 H, ArH), 1.63 [s, 9 H, C(CH3)3].
Methyl (S)-2-Chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate
MS (ESI): m/z = 361.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C19H22ClN2O3 ([M + NH4]+): 361.1313;
(3g)4n
+
Yield: 27 mg (81%); pale yellow oil; [α]D25 +33.5 (c = 1.00, CH2Cl2).
found: 361.1312.
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (9:1), 0.7 mL/min, 214
nm, tR (major) = 10.9 min, tR (minor) = 11.5 min; 53% ee.
1H NMR (CDCl3, 400 MHz): δ = 7.86 (d, J = 7.6 Hz, 1 H, ArH), 7.71 (t, J =
7.4 Hz, 1 H, ArH), 7.48 (t, J = 8.4 Hz, 2 H, ArH), 4.11 (d, J = 17.8 Hz, 1 H,
CH2), 3.82 (s, 3 H, OCH3), 3.57 (d, J = 17.8 Hz, 1 H, CH2).
tert-Butyl (R)-3-Chloro-2-oxo-3-p-tolylindoline-1-carboxylate
(5b)5d
Yield: 51 mg (95%); pale yellow oil; [α]D27 –53.2 (c = 0.85, CH2Cl2).
HPLC: Daicel Chiralpak OJ-H, hexane/i-PrOH (9:1), 1.0 mL/min, 254
nm, tR (major) = 12.3 min, tR (minor) = 6.8 min; 73% ee.
1H NMR (CDCl3, 300 MHz): δ = 8.00 (d, J = 8.1 Hz, 1 H, ArH), 7.51–7.35
(m, 4 H, ArH), 7.29 (t, J = 7.6 Hz, 1 H, ArH), 7.18 (d, J = 7.8 Hz, 2 H,
ArH), 2.35 (s, 3 H, CH2), 1.63 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 242.0 [M + NH4]+.
+
HRMS (ESI): m/z calcd for C11H13ClNO3 ([M + NH4]+): 242.0578;
found: 242.0578.
Ethyl (S)-2-Chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate
MS (ESI): m/z = 375.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C20H24ClN2O3 ([M + NH4]+): 375.147;
(3h)4o
+
Yield: 32 mg (91%); colorless oil; [α]D33 +30.5 (c = 1.00, CH2Cl2).
found: 375.147.
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (9:1), 0.7 mL/min, 214
nm, tR (major) = 12.0 min, tR (minor) = 12.7 min; 48% ee.
1H NMR (CDCl3, 400 MHz): δ = 7.86 (d, J = 7.6 Hz, 1 H, ArH), 7.71 (t, J =
7.3 Hz, 1 H, ArH), 7.48 (t, J = 8.9 Hz, 2 H, ArH), 4.27 (q, J = 7.0 Hz, 2 H,
CH2Me), 4.10 (d, J = 17.8 Hz, 1 H, ArCH2), 3.57 (d, J = 17.8 Hz, 1 H,
ArCH2), 1.27 (t, J = 7.1 Hz, 3 H, CH3).
tert-Butyl (R)-3-Chloro-3-(4-fluorophenyl)-2-oxoindoline-1-car-
boxylate (5c)5d
Yield: 50 mg (92%); colorless oil; [α]D26 –75.6 (c = 1.00, CH2Cl2).
1H NMR (CDCl3, 300 MHz): δ = 7.99 (d, J = 8.2 Hz, 1 H, ArH), 7.58–7.37
(m, 4 H, ArH), 7.35–7.23 (m, 1 H, ArH), 7.04 (t, J = 8.6 Hz, 2 H, ArH),
1.62 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 256.0 [M + NH4]+.
+
HRMS (ESI): m/z calcd for C12H15ClNO3 ([M + NH4]+): 256.0735;
HPLC: Daicel Chiralpak OJ-H, hexane/i-PrOH (9:1), 0.3 mL/min, 254
nm, tR (major) = 28.1 min, tR (minor) = 25.2 min; 71% ee.
found: 256.0737.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
Y.-H. Luo et al.
Paper
Synthesis
MS (ESI): m/z = 279.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C19H21ClFN2O3 ([M + NH4]+): 379.1219;
HPLC: Daicel Chiralpak OD-H, hexane/i-PrOH (96:4), 0.7 mL/min, 214
nm, tR (major) = 7.8 min, tR (minor) = 8.8 min; 70% ee.
+
found: 379.1218.
1H NMR (CDCl3, 400 MHz): δ = 7.66 (d, J = 8.1 Hz, 1 H, ArH), 7.30 (dt,
J = 15.5, 7.6 Hz, 2 H, ArH), 7.19 (t, J = 7.5 Hz, 1 H, ArH), 6.85 (d, J = 8.3
Hz, 2 H, ArH), 6.64 (d, J = 8.4 Hz, 2 H, ArH), 3.71 (s, 3 H, OCH3), 3.52 (q,
J = 13.5 Hz, 2 H, CH2), 1.59 [s, 9 H, C(CH3)3].
tert-Butyl (R)-3-Chloro-5-methyl-2-oxo-3-phenylindoline-1-car-
boxylate(5d)5d
13C NMR (CDCl3, 100 MHz): δ = 172.0, 159.0, 148.6, 139.0, 131.7,
130.5, 127.7, 125.1, 125.0, 124.8, 115.3, 113.6, 84.9, 65.5, 55.2, 45.3,
28.1.
Yield: 53 mg (99%); pale yellow oil; [α]D27 –0.2 (c = 0.725, CH2Cl2).
HPLC: Daicel Chiralpak IC-3, hexane/i-PrOH (99:1), 0.7 mL/min, 214
nm, tR (major) = 19.3 min, tR (minor) = 17.8 min; 72% ee.
1H NMR (CDCl3, 300 MHz): δ = 7.87 (d, J = 8.2 Hz, 1 H, ArH), 7.59–7.46
(m, 2 H, ArH), 7.42–7.30 (m, 3 H, ArH), 7.29–7.19 (m, 2 H, ArH), 2.38
(s, 3 H, CH3), 1.63 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 405.1 [M + NH4]+.
+
HRMS (ESI): m/z calcd for C21H26ClN2O4 ([M + NH4]+): 405.1573;
found: 405.1576.
MS (ESI): m/z = 375.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C20H24ClN2O3 ([M + NH4]+): 375.147;
tert-Butyl (–)-3-Chloro-3-(4-fluorobenzyl)-2-oxoindoline-1-car-
boxylate (5i)
Yield: 32 mg (56%); pale yellow oil; [α]D27 –9.8 (c = 1.00, CH2Cl2).
+
found: 375.1468.
HPLC: Daicel Chiralpak OD-H, hexane/i-PrOH (96:4), 0.7 mL/min, 214
nm, tR (major) = 6.5 min, tR (minor) = 7.0 min; 85% ee.
tert-Butyl (R)-3-Chloro-7-fluoro-2-oxo-3-phenylindoline-1-car-
boxylate (5e)5d
1H NMR (CDCl3, 400 MHz): δ = 7.67 (d, J = 8.1 Hz, 1 H, ArH), 7.31 (dd,
J = 22.0, 10.2 Hz, 2 H, ArH), 7.20 (t, J = 7.5 Hz, 1 H, ArH), 6.96–6.86 (m,
2 H, ArH), 6.80 (t, J = 8.2 Hz, 2 H, ArH), 3.55 (q, J = 13.4 Hz, 2 H, CH2),
1.59 [s, 9 H, C(CH3)3].
13C NMR (CDCl3, 100 MHz): δ = 171.8, 163.5, 148.5, 139.0, 132.2 (d, J =
8.1 Hz), 130.6, 128.9, 127.3, 124.9 (d, J = 8.1 Hz), 115.4, 115.2, 115.0,
85.1, 65.3, 45.3, 28.1.
Yield: 47 mg (86%); pale yellow oil; [α]D27 –52.3 (c = 0.84, CH2Cl2).
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (96:4), 0.7 mL/min, 214
nm, tR (major) = 8.7 min, tR (minor) = 9.4 min; 56% ee.
1H NMR (CDCl3, 300 MHz): δ = 7.57–7.45 (m, 2 H, ArH), 7.43–7.31 (m,
3 H, ArH), 7.30–7.14 (m, 3 H, ArH), 1.60 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 379.1 [M + NH4]+.
+
HRMS (ESI): m/z calcd for C19H21ClFN2O3 ([M + NH4]+): 379.1219;
19F NMR (CDCl3, 282 MHz): δ = –114.91 to –115.20 (m).
MS (ESI): m/z = 393.1 [M + NH4]+.
found: 379.1217.
HRMS (ESI): m/z calcd for C20H23ClFN2O3 ([M + NH4]+): 393.1376;
found: 393.1374.
+
tert-Butyl (R)-3-Chloro-5-fluoro-3-(4-fluorophenyl)-2-oxoindo-
line-1-carboxylate (5f)5d
Yield: 31 mg (54%); yellow oil; [α]D27 –75.0 (c = 1.00, CH2Cl2).
tert-Butyl (–)-3-Chloro-3-methyl-2-oxoindoline-1-carboxylate
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (96:4), 0.7 mL/min, 214
nm, tR (major) = 7.2 min, tR (minor) = 6.1 min; 77% ee.
1H NMR (CDCl3, 300 MHz): δ = 8.00 (dd, J = 8.8, 4.4 Hz, 1 H, ArH),
7.54–7.41 (m, 2 H, ArH), 7.22–7.10 (m, 2 H, ArH), 7.06 (t, J = 8.6 Hz, 2
H, ArH), 1.61 [s, 9 H, C(CH3)3].
(5j)5d
Yield: 12 mg (29%); pale yellow oil; [α]D27 –32.6 (c = 0.15, CHCl3).
HPLC: Daicel Chiralpak OJ-H, hexane/i-PrOH (95:5), 0.5 mL/min, 220
nm, tR (major) = 11.31 min, tR (minor) = 10.15 min; 47% ee.
1H NMR (CDCl3, 400 MHz): δ = 7.88 (d, J = 8.3 Hz, 1 H, ArH), 7.46 (dd,
J = 7.5, 0.9 Hz, 1 H, ArH), 7.38 (td, J = 8.0, 1.4 Hz, 1 H, ArH), 7.22 (dd, J =
7.6, 0.9 Hz, 1 H, ArH), 1.95 (s, 3 H, CH3), 1.65 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 397.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C19H20ClF2N2O3 ([M + NH4]+): 397.1125;
+
found: 397.1122.
13C NMR (CDCl3, 100 MHz): δ = 172.4, 149.0, 138.3, 130.6, 129.9,
125.3, 123.9, 115.6, 85.2, 62.0, 28.1, 26.6.
MS (ESI): m/z = 299.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C14H20ClN2O3+ (M + NH4+): 299.1157; found:
299.1151.
tert-Butyl (R)-3-Chloro-3-benzyl-2-oxoindoline-1-carboxylate
(5g)5d
Yield: 39 mg (73%); yellow oil; [α]D27 –6.6 (c = 1.00, CH2Cl2).
HPLC: Daicel Chiralpak AD-H, hexane/i-PrOH (96:4), 0.7 mL/min, 214
nm, tR (major) = 7.0 min, tR (minor) = 6.6 min; 91% ee.
1H NMR (CDCl3, 300 MHz): δ = 7.65 (d, J = 8.1 Hz, 1 H, ArH), 7.31 (dd,
J = 17.8, 7.9 Hz, 2 H, ArH), 7.24–7.04 (m, 4 H, ArH), 6.94 (d, J = 6.6 Hz, 2
H, ArH), 3.58 (q, J = 13.3 Hz, 2 H, CH2), 1.58 [s, 9 H, C(CH3)3].
tert-Butyl 2-Bromo-2,3-dihydro-1-oxo-1H-indene-2-carboxylate
(6a)12
Yield: 42 mg (89%); colorless oil; [α]D26 +6.2 (c = 1.00, CH2Cl2).
HPLC: Daicel Chiralpak OJ-H, hexane/i-PrOH (95:5), 0.7 mL/min, 254
nm, tR (major) = 17.0 min, tR (minor) = 21.1 min; 25% ee.
1H NMR (CDCl3, 300 MHz): δ = 7.86 (d, J = 7.8 Hz, 1 H, ArH), 7.69 (t, J =
7.4 Hz, 1 H, ArH), 7.46 (m, 2 H, ArH), 4.13 (d, J = 18.1 Hz, 1 H, CH2),
3.66 (d, J = 18.1 Hz, 1 H, CH2), 1.46 [s, 9 H, C(CH3)3].
MS (ESI): m/z = 375.1 [M + NH4]+.
HRMS (ESI): m/z calcd for C20H24ClN2O3 ([M + NH4]+): 375.147;
+
found: 375.1468.
tert-Butyl (–)-3-Chloro-3-(4-methoxybenzyl)-2-oxoindoline-1-
carboxylate (5h)
Yield: 27 mg (47%); pale yellow oil; [α]D26 –10.1 (c = 1.00, CH2Cl2).
MS (ESI): m/z = 328.0 [M + NH4]+.
+
HRMS (ESI): m/z calcd for C14H19BrNO3 ([M + NH4]+): 328.0543;
found: 328.054.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
Y.-H. Luo et al.
Paper
Synthesis
Hirashima, S.; Nakashima, K.; Maeda, C.; Yoshida, A.; Koseki, Y.;
Miura, T. Chem. Pharm. Bull. 2016, 64, 1781. (o) Kang, Y. K.; Kim,
H. H.; Koh, K. O.; Kim, D. Y. Tetrahedron Lett. 2012, 53, 3811.
(5) For selected examples of asymmetric chlorination of N-Boc
oxindoles, see: (a) Wang, D.; Jiang, J.-J.; Zhang, R.; Shi, M. Tetra-
hedron: Asymmetry 2011, 22, 1133. (b) Zhao, M. X.; Zhang, Z.
W.; Chen, M. X.; Tang, W. H.; Shi, M. Eur. J. Org. Chem. 2011,
3001. (c) Zheng, W. H.; Zhang, Z. H.; Kaplan, M. J.; Antilla, J. C.
J. Am. Chem. Soc. 2011, 133, 3339. (d) Gao, X.; Han, J.; Wang, L.
Org. Lett. 2015, 17, 4596.
Funding Information
We thank the National Natural Science Foundation of China (NSFC
21472216) and the Croucher Funding Scheme for Joint laboratories
for financial support.
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Supporting Information
(6) For reviews of iron catalysis, see: (a) Bolm, C.; Legros, J.; Le Paih,
J.; Zani, L. Chem. Rev. 2004, 104, 6217. (b) Correa, A.; Mancheño,
O. G.; Bolm, C. Chem. Soc. Rev. 2008, 37, 1108. (c) Enthaler, S.;
Junge, K.; Beller, M. Angew. Chem. Int. Ed. 2008, 47, 3317.
(d) Fürstner, A. Angew. Chem. Int. Ed. 2009, 48, 1364. (e) Sun, C.-
L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293. (f) Gopalaiah, K.
Chem. Rev. 2013, 113, 3248. (g) Bauer, I.; Knölker, H.-J. Chem.
Rev. 2015, 115, 3170. (h) Shang, R.; Llies, L.; Nakamura, E. Chem.
Rev. 2017, 117, 9086.
(7) For selected recent examples, see: (a) Zang, C.; Liu, Y.; Xu, Z.-J.;
Tse, C.-W.; Guan, X.; Wei, J.; Huang, J.-S.; Che, C.-M. Angew.
Chem. Int. Ed. 2016, 55, 10253. (b) Liu, Y.; Chen, G.-Q.; Tse, C.-
W.; Guan, X.; Xu, Z.-J.; Huang, J.-S.; Che, C.-M. Chem. Asian J.
2015, 10, 100. (c) Du, Y.-D.; Tse, C.-W.; Xu, Z.-J.; Liu, Y.-G.; Che,
C.-M. Chem. Commun. 2014, 50, 12669. (d) Liu, P.; Wong, E. L.-
M.; Yuen, A. W.-H.; Che, C.-M. Org. Lett. 2008, 10, 3275. (e) Liu,
Y.; Che, C.-M. Chem. Eur. J. 2010, 16, 10494. (f) Chow, T. W.-S.;
Wong, E. L.-M.; Guo, Z.; Liu, Y.; Huang, J.-S.; Che, C.-M. J. Am.
Chem. Soc. 2010, 132, 13229. (g) Chen, G.-Q.; Xu, Z.-J.; Liu, Y.;
Zhou, C.-Y.; Che, C.-M. Synlett 2011, 1174. (h) Chen, G.-Q.; Xu,
Z.-J.; Zhou, C.-Y.; Che, C.-M. Chem. Commun. 2011, 47, 10963.
(i) Liu, Y.; Guan, X.; Wong, E. L.-M.; Liu, P.; Huang, J.-S.; Che, C.-
M. J. Am. Chem. Soc. 2013, 135, 7194.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590955.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H