An Unexpected inversion of enantioselectivity in a copper-catalyzed intramolecular desymmetric aryl C-N coupling reaction

Article abstract of DOI:10.1055/s-0033-1338638

Enantioselective formation of indolines was achieved through desymmetrization of α,α-bis(2-iodobenzyl)glycines under the catalysis of copper(I) iodide and (2S,3aS,7aS)-octahydro-1H-Aindole-2-carboxylic acid. An unexpected inversion of enantioselectivity was observed when achiral additives such as 4-(N,N-dimethylamino)pyridine were added which work together with the ligand. The configuration-reversed products were obtained in moderate yields as well as moderate ee values. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338638

SPECIAL TOPIC
▌1917
sApencialUtopnicexpected Inversion of Enantioselectivity in a Copper-Catalyzed
Intramolecular Desymmetric Aryl C–N Coupling Reaction
Inversion of Enantioselectivity in Asymmetric N-Arylation
Jiangguang Liu,a Jiajie Yan,a,1 Dongguang Qin,a,b Qian Caia
a
Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, No. 190 Kaiyuan Avenue, Guangzhou Science Park,
Guangzhou 510530, P. R. of China
Fax +86(20)32015266; E-mail: cai_qian@gibh.ac.cn
b
ABA Chemicals Corporation, Suite 18, Ningxia Road, Shanghai 200063, P. R. of China
Received: 20.02.2014; Accepted: 15.04.2014
oxide, which are comparable results to those of copper(I)
iodide and BINOL, as outlined in our previous report.6a
With the further optimization of L-proline-type ligands,
we found that under the catalysis of copper(I) iodide and
Abstract: Enantioselective formation of indolines was achieved
through desymmetrization of α,α-bis(2-iodobenzyl)glycines under
the catalysis of copper(I) iodide and (2S,3aS,7aS)-octahydro-1H-
indole-2-carboxylic acid. An unexpected inversion of enantioselec-
tivity was observed when achiral additives such as 4-(N,N-dimeth- a commercially available ligand, (2S,3aS,7aS)-octahydro-
ylamino)pyridine were added which work together with the ligand.
The configuration-reversed products were obtained in moderate
yields as well as moderate ee values.
1H-indole-2-carboxylic acid (L4), the desired product 2a
was obtained in 78% ee. This catalytic system is much
less effective than our previously reported copper(I) io-
dide/BINOL-derived ligand systems, and further efforts
Key words: asymmetric desymmetrization, indolines, copper ca-
talysis, N-arylation, inversion
to improve the enantioselectivity by modifying the ligand
structure or reaction conditions were unsuccessful. How-
ever, an unexpected inversion of enantioselectivity was
observed in these reactions when bases or additives such
as 4-(N,N-dimethylamino)pyridine (DMAP) or potassium
acetate were added. Herein, we disclose the details of our
findings.
Asymmetric syntheses, including organocatalytic, metal-
catalyzed or enzyme-catalyzed reactions, are of funda-
mental significance in organic chemistry because they
provide methods for the efficient formation of enantio-
merically enriched compounds.2 The enantioselectivity in
asymmetric synthesis depends on many factors including
the temperature, solvents, chiral ligands, metal catalysts
and substrate structures. These influencing factors may
vary in different types of reactions or even for each indi-
vidual compound in the same type of reaction. Unexpect-
ed results may show up occasionally under certain
experimental conditions.
As shown in Table 1, with the reaction of 1a as a model
case, the optimization of proline-type ligands led to the
discovery of L4, which afforded the desired product 2a in
93% yield and 78% ee with potassium phosphate as the
base in dimethyl sulfoxide at room temperature (Table 1,
entry 4). No improvement of the enantioselectivity was
observed upon lowering the reaction temperature or by
changing the solvent (Table 1, entries 5–9).
Transition-metal-catalyzed (e.g., Pd or Cu) coupling reac-
tions of aryl halides with nucleophiles have become im-
portant methods for the formation of aryl carbon–
heteroatom bonds.3,4 Recent advances in enantioselective
aryl carbon–heteroatom coupling reactions5,6 have opened
new doors in this field. In the course of developing enan-
tioselective aryl carbon–heteroatom bond-forming meth-
ods, we found that asymmetric desymmetrization7 of α,α-
bis(2-iodobenzyl)glycines afforded the desired indoline
products in excellent enantioselectivity under the cataly-
sis of copper(I) iodide and BINOL-derived chiral li-
gands.6a In fact, several other types of copper ligands,
such as L-proline and (1R,2R)-N1,N2-dimethylcyclohex-
ane-1,2-diamine,6b also exhibit effects similar to BINOL.
For example, the reaction of ethyl 2-amino-2-(2-iodoben-
zyl)-3-(2-iodophenyl)propanoate (1a) affords indoline
product 2a in 95% yield and 41% ee (R) under the cataly-
sis of copper(I) iodide and L-proline (L1) in dimethyl sulf-
The screening of bases revealed that potassium phosphate
seems to be the best choice for high enantioselectivity. To
our surprise, an inversion of enantioselectivity (–57% ee)
was observed when potassium acetate was used as the
base (Table 1, entry 13). This is very interesting since we
have found only sporadic literature reports of solvent or
achiral additive mediated inversion of enantioselectivi-
ty.8,9 We speculated that the acetate anion may act as a li-
gand together with our chiral ligand L4 to coordinate with
copper(I), and reverse the chiral configuration. This
prompted us to test a variety of organic bases and addi-
tives which may coordinate with copper (Table 1, entries
14–18). A slightly better result was obtained when DMAP
was used as the base, albeit in lower yield (Table 1, entry
18). Higher yield was obtained by adding potassium phos-
phate together with DMAP as the base, but in a slightly
lower enantioselectivity (Table 1, entry 19). The ligand
effect of the base was further confirmed when 2,6-di-tert-
butylpyridine was employed as the base. This base can not
coordinate with the copper salt due to the presence of the
bulky substituents; thus, the reaction furnished the normal
product in 77% ee, albeit in a lower yield (Table 1, entry
SYNTHESIS 2014, 46, 1917–1923
Advanced online publication: 09.05.2014
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0
3
9
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7
8
8
1
1
4
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DOI: 10.1055/s-0033-1338638; Art ID: ss-2014-c0121-st
© Georg Thieme Verlag Stuttgart · New York

1918
J. Liu et al.
SPECIAL TOPIC
15). Finally, the configuration-reversed product was ob- potassium phosphate as the base (method A), the normal
tained in 71% yield and –69% ee with potassium phos- products were obtained in good yields and high ee values.
phate and DMAP as the additive, in the mixed solvent of When DMAP was used as an additive (method B), the
dimethyl sulfoxide and N,N-dimethylformamide (1:1) af- configuration-reversed products were obtained in moder-
ter 24 hours at 0 °C (Table 1, entry 20).
ate yields as well as moderate ee values. A slightly better
enantioselectivity was observed with method A when the
size of the ester group was increased. For example, the
ethyl ester product 2a was obtained in 93% yield and 78%
With the optimized conditions in hand, we then explored
the reaction scope with a series of ester-bearing sub-
strates; the results are shown in Table 2. Firstly, with only
Table 1 Screening of the Reaction Conditions for the Copper(I) Iodide/Proline-Type Ligand Promoted Coupling of 1aa
I
I
I
CO2Et
NH2
CuI, L*
CO2Et
N
H
1a
2a
H
HO
CO2H
HO
CO2H
CO2H
CO2H
N
H
N
N
N
H
H
H
H
L1
L2
L3
L4
Entry
Ligand
Conditions
Yieldb (%)
eec (%)
1
2
L1
L2
L3
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
L4
K3PO4, DMSO, r.t., 3 h
K3PO4, DMSO, r.t., 3 h
K3PO4, DMSO, r.t., 3 h
K3PO4, DMSO, r.t., 3 h
K3PO4, i-PrOH, r.t., 24 h
K3PO4, NMP, 0 °C, 24 h
K3PO4, DMF, –15 °C, 24 h
95
88
95
93
0
41
29
3
58
4
78
5
–
6
10
30
87
35
95
32
15
81
90
7
71
7
70
8
K3PO4, DMSO–DMF (1:1), 0 °C, 24 h
77
9
K3PO4, DMSO–1,4-dioxane (1:1), 0 °C, 24 h
Cs2CO3, DMSO, r.t., 6 h
75
10
11
12
13
14
15
16
17
18
19d
20d
70
KOH, DMSO, r.t., 24 h
34
t-BuOK, DMSO, r.t., 24 h
25
KOAc, DMSO, r.t., 24 h
–57
54
Et3N, DMSO, r.t., 24 h
2,6-di-tert-butylpyridine, DMSO, r.t., 45 h
DBU, DMSO, r.t., 24 h
77
47
85
31
82
71
–11
–56
–60
–54
–69
BnNH2, DMSO, r.t., 24 h
DMAP, DMSO, r.t., 24 h
DMAP, K3PO4, DMSO, r.t., 24 h
DMAP, K3PO4, DMSO–DMF (1:1), 0 °C, 24 h
a Reaction conditions: 1a (0.5 mmol, 1.0 equiv), CuI (0.075 mmol, 15 mol%), ligand (0.15 mmol, 30 mol%), base (1.0 mmol, 2.0 equiv), solvent
(1 mL).
b Isolated yield.
c Determined by chiral HPLC analysis.
d DMAP (0.5 mmol, 1.0 equiv), K3PO4 (0.5 mmol, 1.0 equiv).
Synthesis 2014, 46, 1917–1923
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Inversion of Enantioselectivity in Asymmetric N-Arylation
1919
ee value, while the bulkier isopropyl and tert-butyl ester erated and all such substrates delivered the corresponding
products were isolated in 90% yield and 79% ee (for 2b) products in high ee values, though the reactants bearing
and in 98% yield and 84% ee (for 2c), respectively (Table electron-withdrawing groups on the aryl ring only gave
2, entries 1, 3 and 5). Similar results were observed in the the desired products in moderate yields (Table 2, entries
case of 2d (81% ee) and 2e (83% ee) (Table 2, entries 7 11–16). For practical applications, excellent ee values of
and 9). However, a different tendency was observed with the coupling products could be obtained through a simple
method B: the ee values of the configuration-reversed recrystallization, such as in the case of 2j (Table 2, entries
products were reduced when the size of the ester group 19 and 20). Finally, the absolute configuration of these
was increased (Table 2, entries 2, 4 and 6; entries 8 and coupling products was determined by a comparison with
10). Different substituents on the aryl ring were well tol- our previously reported data.10
Table 2 Substrate Scopea
I
I
I
I
CO2R1
R2
R2
method A
method B
R2
R2
R2
R2
CO2R1
CO2R1
N
H
N
H
NH2
1
(S)-2
(R)-2
Entry Method Product
Yieldb eec
Entry Method Product
Yieldb eec
(%)
(%)
(%)
(%)
1
2
A
B
93
78
11
12
A
B
49
73
I
I
NO2
CO2Et
CO2Et
71
–69
40
–67
N
N
H
O2N
H
2f
2a
2b
2c
I
I
3
4
5
6
7
8
A
B
A
B
A
B
90
67
98
65
93
73
79
–65
84
13
14
15
16
17
18
A
B
A
B
A
B
86
71
78
57
96
67
73
–65
74
Br
CO2i-Pr
CO2Et
Br
N
H
N
H
2g
I
I
CO2Me
CO2t-Bu
CO2Et
–61
81
–61
78
N
N
H
MeO2C
H
2h
I
I
F
MeO
CO2Et
CO2t-Bu
OMe
–68
–57
N
N
F
H
H
2d
2i
I
I
82
9
A
B
91
71
83
19
20
A
B
99
72
(99)d
F
CO2t-Bu
CO2t-Bu
–62
N
H
N
F
10
–55
H
(–96)d
2e
2j
a Reaction conditions: 1 (0.5 mmol, 1.0 equiv), CuI (0.075 mmol, 15 mol%), L4 (0.15 mmol, 30 mol%); for method A: K3PO4 (1.0 mmol, 2.0
equiv), DMSO (1.0 mL), r.t., 2–4 h; for method B: K3PO4 (0.5 mmol, 1.0 equiv), DMAP (0.5 mmol, 1.0 equiv), DMSO–DMF (1:1, 1.0 mL),
0 °C, 20–24 h.
b Isolated yield.
c Determined by chiral HPLC analysis.
d After recrystallization from methanol.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1917–1923

1920
J. Liu et al.
SPECIAL TOPIC
unfavorable
I
H2
N
I
N
H
H
Cu
I
RO
O
(R)
O
O
N
RO2C
H
favorable
Nu:
unfavorable
I
H2
N
I
N
H
H2
N
Cu
I
I
N
H
RO
H
Cu
O
H
O
(S)
O
O
RO
O
O
Nu
RO2C
N
I
H
Nu:
favorable
Figure 1 Plausible transition states
1
All products were characterized by their H and 13C NMR spectra
which were recorded on a Bruker AV 400 or 500 MHz spectrome-
ter. Mass spectrometric analyses were performed on an Agilent
1956B single quadrupole mass spectrometer. High-resolution mass
spectra (HRMS) were obtained on a QSTAR Elite ESI-LC/MS/MS
spectrometer. Optical rotations were measured on a Perkin-Elmer
341 polarimeter. Enantiomeric ratios were determined by chiral
HPLC using a Chiralpak AD-H column or a Chiralcel OD-H col-
umn with hexane and i-PrOH as solvents. Commercially obtained
reagents were used without further purification.
Based on the literature11 and our experimental observa-
tions, we propose a plausible mode of action of the chiral
catalyst and achiral additives. As shown in Figure 1, cop-
per(I) iodide coordinates with the substrate and the chiral
ligand to form a planar complex. The two aryls may ap-
proach and interact with copper(I) from both the top and
the bottom side of the plane. When no additive is added,
it is more favorable for the copper(I) to interact and acti-
vate the aryl halide from the bottom side of the plane due
to steric reasons, leading to the formation of the (R)-prod-
uct. However, when a suitable achiral additive such as
DMAP is added, it occupies the bottom position and coor-
dinates with the copper, forcing the copper to interact and
activate the aryl halide only from the top side of the plane,
thus delivering a product with the reversed configuration.
Enantioselective Formation of 2-(2-Iodobenzyl)indoline-2-car-
boxylates; General Procedure
Method A
A mixture of an α,α-bis(2-iodobenzyl)glycine 1 (0.5 mmol),
(2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (L4; 25.4 mg,
0.15 mmol), CuI (14.3 mg, 0.075 mmol) and K3PO4 (212 mg, 1.0
mmol) in freshly dried DMSO (1.0 mL) was stirred at r.t. After re-
action completion (monitored by TLC), H2O (5.0 mL) and EtOAc
In summary, we have developed an enantioselective intra-
molecular aryl C–N coupling reaction through desymme- (5.0 mL) were added to the mixture. The organic phase was separat-
ed and the aqueous phase was extacted with EtOAc (3 × 5.0 mL).
The combined organic phase was washed with H2O and brine, dried
over Na2SO4 and concentrated under reduced presure. The residue
was loaded on a silica gel column and purified by flash chromatog-
trization of α,α-bis(2-iodobenzyl)glycines under the
catalysis of copper(I) iodide and a proline-type ligand.
This led to the formation of chiral indoline products with
good yields and high ee values when dimethyl sulfoxide
raphy (EtOAc–petroleum ether, 1:5 to 1:10) to afford the configu-
as the solvent and potassium phosphate as the base were
employed. An inversion of enantioselectivity was ob-
served when 4-(N,N-dimethylamino)pyridine was added
which works together with the same commercially avail-
able ligand; in such cases, the configuration-reversed
products were obtained in moderate yields as well as mod-
erate ee values in the mixed solvent system of dimethyl
sulfoxide and N,N-dimethylformamide. This method is
valuable for organic synthesis as it provides an additional
option for asymmetric coupling. Further exploration of
this reaction and its application is underway in our labora-
tory.
ration-reserved product. The enantiomeric excess was determined
by chiral HPLC analysis.
Method B
A mixture of an α,α-bis(2-iodobenzyl)glycine 1 (0.5 mmol),
(2S,3aS,7aS)-octahydro-1H-indole-2-carboxylic acid (L4; 25.4 mg,
0.15 mmol), CuI (14.3 mg, 0.075 mmol), K3PO4 (212 mg, 0.5
mmol) and DMAP (61 mg, 0.5 mmol) in a mixed solvent of DMSO
and DMF (1:1, 1.0 mL) was stirred at 0 °C for 20–24 h. Then, H2O
(5.0 mL) and EtOAc (5.0 mL) were added to the mixture. The or-
ganic phase was separated and the aqueous phase was extacted with
EtOAc (3 × 5.0 mL). The combined organic phase was washed with
H2O and brine, dried over Na2SO4 and concentrated under reduced
presure. The residue was loaded on a silica gel column and purified
by flash chromatography (EtOAc–petroleum ether, 1:5 to 1:10) to
Synthesis 2014, 46, 1917–1923
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SPECIAL TOPIC
Inversion of Enantioselectivity in Asymmetric N-Arylation
1921
afford the configuration-reversed product. The enantiomeric excess
was determined by chiral HPLC analysis.
2 H), 3.48 (d, J = 16.0 Hz, 1 H), 3.37 (d, J = 14.0 Hz, 1 H), 3.31 (d,
J = 14.0 Hz, 1 H), 3.04 (d, J = 16.0 Hz, 1 H), 1.25 (t, J = 6.4 Hz, 3
H).
Ethyl 2-(2-Iodobenzyl)indoline-2-carboxylate (2a)
Method A: yield: 189 mg (93%); 78% ee (R).
13C NMR (125 MHz, CDCl3): δ = 174.8, 164.2, 160.2, 150.8, 135.2,
131.4, 126.7, 126.5, 124.8, 121.8, 115.3, 105.3, 101.3, 97.6, 72.3,
62.0, 46.6, 38.6, 14.1.
Method B: yield: 177 mg (71%); 69% ee (S).
ESI-MS: m/z = 444.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C18H17F2INO2: 444.0266; found:
HPLC [Chiralpak AD-H (hexane–i-PrOH, 87:13; 1.0 mL/min)]:
tR (R) = 6.9 min, tR (S) = 10.9 min.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.0 Hz, 1 H), 7.25–
7.32 (m, 2 H), 7.01–7.06 (m, 2 H), 6.90–6.93 (m, 1 H), 6.67–6.72
(m, 2 H), 4.52 (br s, 1 H), 4.17 (m, 2 H), 3.56 (d, J = 16.0 Hz, 1 H),
3.42 (d, J = 13.6 Hz, 1 H), 3.35 (d, J = 13.6 Hz, 1 H), 3.14 (d,
J = 16.0 Hz, 1 H), 1.22 (t, J = 7.2 Hz, 3 H).
444.0259.
tert-Butyl 6-Fluoro-2-(4-fluoro-2-iodobenzyl)indoline-2-car-
boxylate (2e)
Method A: yield: 214 mg (91%); 83% ee (R).
13C NMR (125 MHz, CDCl3): δ = 174.9, 149.0, 139.8, 139.4, 131.0,
128.7, 128.1, 127.5, 126.5, 124.4, 119.1, 109.8, 102.4, 71.6, 61.8,
47.6, 39.5, 14.0.
ESI-MS: m/z = 408.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C18H19INO2: 408.0455; found:
Method B: yield: 167 mg (71%); 55% ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 90:10; 1.0 mL/min)]:
tR (R) = 5.9 min, tR (S) = 9.4 min.
(R)-2e: [α]D20 +61.9 (c 1.0, CH2Cl2); 83% ee.
1H NMR (400 MHz, CDCl3): δ = 7.57 (dd, J = 8.0, 2.8 Hz, 1 H),
7.30 (m, 1 H), 7.00 (m, 1 H), 6.88 (m, 1 H), 6.35 (m, 2 H), 4.52 (br
s, 1 H), 3.39 (d, J = 16.0 Hz, 1 H), 3.32 (s, 2 H), 2.98 (d, J = 16.0
Hz, 1 H), 1.44 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 174.2, 163.1, 160.8, 151.0, 135.3,
131.3, 126.4, 124.6, 121.9, 115.1, 105.1, 101.8, 97.6, 82.5, 72.7,
46.3, 38.4, 27.9.
408.0453.
Isopropyl 2-(2-Iodobenzyl)indoline-2-carboxylate (2b)
Method A: yield: 189 mg (90%); 79% ee (R).
Method B: yield: 141 mg (67%); 65% ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 90:10; 1.0 mL/min)]:
tR (R) = 6.7 min, tR (S) = 12.3 min.
ESI-MS: m/z = 472.2 [M + H]+.
HRMS: m/z [M + H]+ calcd for C20H21F2INO2: 472.0580; found:
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.0 Hz, 1 H), 7.24–
7.32 (m, 2 H), 7.00–7.05 (m, 2 H), 6.89–6.93 (m, 1 H), 6.65–6.72
(m, 2 H), 5.02 (heptet, J = 6.4 Hz, 1 H), 3.53 (d, J = 16.0 Hz, 1 H),
3.39 (d, J = 14.0 Hz, 1 H), 3.35 (d, J = 14.0 Hz, 1 H), 3.12 (d,
J = 16.0 Hz, 1 H), 1.22 (d, J = 6.4 Hz, 3 H), 1.18 (d, J = 6.4 Hz, 3
H).
472.0572.
Ethyl 2-(2-Iodo-4-nitrobenzyl)-6-nitroindoline-2-carboxylate
(2f)
Method A: yield: 120 mg (49%); 73% ee (R).
13C NMR (125 MHz, CDCl3): δ = 174.7, 149.4, 139.8, 139.7, 131.0,
128.6, 128.0, 127.5, 126.7, 124.4, 119.0, 109.8, 102.7, 71.5, 69.4,
47.5, 39.4, 21.7.
ESI-MS: m/z = 422.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C19H21INO2: 422.0611; found:
Method B: yield: 99 mg (40%); 67% ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 80:20; 1.0 mL/min)]:
tR (R) = 16.6 min, tR (S) = 21.6 min.
1H NMR (400 MHz, CDCl3): δ = 8.70 (s, 1 H), 8.14 (d, J = 8.4 Hz,
1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.42 (s, 1
H), 7.12 (d, J = 8.0 Hz, 1 H), 4.81 (br s, 1 H), 4.23 (m, 2 H), 3.66
(d, J = 17.2 Hz, 1 H), 3.50 (s, 2 H), 3.14 (d, J = 17.2 Hz, 1 H), 1.28
(t, J = 7.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 173.8, 149.9, 148.5, 146.9, 146.1,
134.5, 133.7, 131.2, 124.4, 122.8, 115.3, 104.1, 101.6, 71.7, 62.5,
47.2, 38.8, 14.1.
422.0603.
tert-Butyl 2-(2-Iodobenzyl)indoline-2-carboxylate (2c)
Method A: yield: 213 mg (98%); 84% ee (R).
Method B: yield: 141 mg (65%); 61% ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 90:10; 1.0 mL/min)]:
tR (R) = 5.5 min, tR (S) = 10.3 min.
1H NMR (400 MHz, CDCl3): δ = 7.83 (d, J = 8.0 Hz, 1 H), 7.38 (m,
1 H), 7.24 (m, 1 H), 7.00 (m, 2 H), 6.91 (m, 1 H), 6.68 (m, 2 H), 3.49
(d, J = 16.4 Hz, 1 H), 3.37 (s, 2 H), 3.08 (d, J = 16.4 Hz, 1 H), 1.42
(s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 174.2, 149.1, 139.7, 130.9, 128.5,
128.0, 127.4, 127.0, 124.3, 119.4, 110.2, 103.0, 82.2, 72.0, 47.3,
39.4, 27.9.
ESI-MS: m/z = 498.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C18H17IN3O6: 498.0156; found:
498.0147.
Ethyl 5-Bromo-2-(5-bromo-2-iodobenzyl)indoline-2-carboxyl-
ate (2g)
Method A: yield: 243 mg (86%); 73% ee (R).
Method B: yield: 201 mg (71%); 65% ee (S).
ESI-MS: m/z = 436.1 [M + H]+.
HRMS: m/z [M + H]+ calcd for C20H23INO2: 436.0768; found:
HPLC [Chiralpak AD-H (hexane–i-PrOH, 80:20; 1.0 mL/min)]:
tR (R) = 7.2 min, tR (S) = 16.0 min.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 8.4 Hz, 1 H), 7.40 (d,
J = 2.0 Hz, 1 H), 7.05–7.14 (m, 3 H), 6.53 (d, J = 8.0 Hz, 1 H), 4.48
(br s, 1 H), 4.18 (m, 2 H), 3.53 (d, J = 16.4 Hz, 1 H), 3.35 (d,
J = 14.0 Hz, 1 H), 3.29 (d, J = 14.0 Hz, 1 H), 3.09 (d, J = 16.4 Hz,
1 H), 1.26 (t, J = 6.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 174.4, 148.3, 141.3, 141.0, 133.8,
131.9, 130.4, 128.8, 127.4, 122.4, 111.2, 110.9, 100.2, 71.8, 62.1,
47.3, 39.2, 14.0.
436.0757.
Ethyl 6-Fluoro-2-(4-fluoro-2-iodobenzyl)indoline-2-carboxyl-
ate (2d)
Method A: yield: 206 mg (93%); 81% ee (R).
Method B: yield: 162 mg (73%); 68% ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 90:10; 1.0 mL/min)]:
tR (R) = 7.4 min, tR (S) = 12.7 min.
1H NMR (400 MHz, CDCl3): δ = 7.56 (dd, J = 8.0, 2.4 Hz, 1 H),
7.24 (m, 1 H), 7.00 (m, 1 H), 6.93 (m, 1 H), 6.36 (m, 2 H), 4.19 (m,
ESI-MS: m/z = 563.9 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1917–1923

1922
J. Liu et al.
SPECIAL TOPIC
HRMS: m/z [M + H]+ calcd for C18H17Br2INO2: 563.8665; found:
563.8660.
Acknowledgment
The authors are grateful to the 100-Talent Program of CAS and to
the National Natural Science Foundation (Grant 21272234) for their
financial support. We also thank Prof. Fayang Qiu at the Guangz-
hou Institutes of Biomedicine and Health, Chinese Academy of Sci-
ences for helpful discussions.
2-Ethyl 6-Methyl 2-[2-Iodo-4-(methoxycarbonyl)benzyl]in-
doline-2,6-dicarboxylate (2h)
Method A: yield: 204 mg (78%); 74% ee (R).
Method B: yield: 149 mg (57%); 61% ee (S).
HPLC [Chiralcel OD-H (hexane–i-PrOH, 87:13; 1.0 mL/min)]:
tR (S) = 15.8 min, tR (R) = 19.6 min.
Supporting Information for this article is available online
1H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H), 7.91 (d, J = 7.6 Hz,
1 H), 7.42 (d, J = 8.0 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.29 (s, 1
H), 7.07 (d, J = 8.0 Hz, 1 H), 4.18 (m, 2 H), 3.93 (s, 3 H), 3.86 (s, 3
H), 3.60 (d, J = 16.8 Hz, 1 H), 3.45 (d, J = 14.0 Hz, 1 H), 3.40 (d,
J = 14.0 Hz, 1 H), 3.14 (d, J = 16.8 Hz, 1 H), 1.23 (t, J = 7.2 Hz, 3
H).
13C NMR (125 MHz, CDCl3): δ = 174.4, 167.2, 165.3, 149.2, 144.2,
140.8, 131.9, 130.7, 130.4, 129.9, 129.0, 124.1, 121.4, 110.3, 101.9,
71.5, 62.1, 52.3, 52.0, 47.5, 39.2, 14.0.
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References
(1) Current address: Department of Chemistry, Uppsala
University, Box 576, SE-751 23 Uppsala, Sweden.
(2) (a) Corey, E. J.; Kurti, L. Enantioselective Chemical
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ESI-MS: m/z = 524.2 [M + H]+.
HRMS: m/z [M + H]+ calcd for C22H23INO6: 524.0565; found:
524.0558.
tert-Butyl 2-(2-Iodo-5-methoxybenzyl)-5-methoxyindoline-2-
carboxylate (2i)
Method A: yield: 238 mg (96%); 78% ee (R).
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Method B: yield: 166 mg (67%); 57% ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 90:10; 1.0 mL/min)]:
tR (R) = 10.7 min, tR (S) = 14.0 min.
(R)-2i: [α]D20 +37.4 (c 1.0, CH2Cl2); 78% ee.
1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J = 7.2 Hz, 1 H), 7.02 (d,
J = 3.2 Hz, 1 H), 6.59 (m, 3 H), 6.50 (dd, J = 8.4, 3.2 Hz, 1 H), 3.73
(s, 3 H), 3.71 (s, 3 H), 3.46 (d, J = 16.0 Hz, 1 H), 3.10 (s, 2 H), 3.04
(d, J = 16.0 Hz, 1 H), 1.42 (s, 9 H).
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13C NMR (125 MHz, CDCl3): δ = 174.7, 159.6, 153.7, 143.5, 140.7,
139.8, 128.5, 117.1, 114.6, 112.5, 111.0, 110.6, 91.5, 82.1, 72.2,
55.9, 55.3, 47.4, 39.8, 27.9.
ESI-MS: m/z = 496.2 [M + H]+.
HRMS: m/z [M + H]+ calcd for C22H27INO4: 496.0979; found:
496.0972.
Tetrahedron Lett. 2009, 50, 4170. (f) Rossen, K.; Pye, P. J.;
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tert-Butyl 2-(2-Iodo-5-methylbenzyl)-5-methylindoline-2-car-
boxylate (2j)
Method A: yield: 229 mg (99%); 82% ee (R).
Method B: yield: 167 mg (72%); 62% ee (S).
HPLC [Chiralpak AD-H (hexane–i-PrOH, 95:5; 1.0 mL/min)]:
tR (R) = 5.8 min, tR (S) = 9.1 min.
(R)-2j: [α]D20 +44.7 (c 1.0, CH2Cl2); 99% ee [after recrystallization
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from methanol].
1H NMR (400 MHz, CDCl3): δ = 7.70 (d, J = 8.0 Hz, 1 H), 7.17 (d,
J = 1.6 Hz, 1 H), 6.85 (s, 1 H), 6.82 (d, J = 8.0 Hz, 1 H), 6.71 (dd,
J = 8.0, 1.6 Hz, 1 H), 6.55 (d, J = 8.0 Hz, 1 H), 3.44 (d, J = 16.0 Hz,
1 H), 3.31 (s, 2 H), 3.05 (d, J = 16.0 Hz, 1 H), 2.24 (s, 3 H), 2.22 (s,
3 H), 1.43 (s, 9 H).
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13C NMR (125 MHz, CDCl3): δ = 174.6, 147.5, 139.7, 139.5, 137.9,
131.8, 129.5, 128.3, 127.8, 127.2, 125.0, 109.7, 98.9, 81.9, 72.2,
47.6, 39.8, 28.0, 20.8, 20.7.
ESI-MS: m/z = 464.2 [M + H]+.
HRMS: m/z [M + H]+ calcd for C22H27INO2: 464.1081; found:
464.1080.
Synthesis 2014, 46, 1917–1923
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Inversion of Enantioselectivity in Asymmetric N-Arylation
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1917–1923