Highly enantioselective hydrogenation of N-unprotected indoles using (S)-C10-BridgePHOS as the chiral ligand

Article abstract of DOI:10.1016/j.tet.2013.06.016

(S)-C₁₀-BridgePHOS was successfully applied to a highly efficient Pd-catalyzed enantioselective hydrogenation of substituted indoles. The methodology was suitable for the hydrogenation of indoles substituted at the 2-, 3- and 2,3-positions. Products were obtained in quantitative conversion and up to 98% ee. The role the 2-position substituent plays in the hydrogenation process has been proposed. The methodology could be used as an alternative method to synthesize extremely important chiral indolines from N-unprotected indoles.

Full text of DOI:10.1016/j.tet.2013.06.016

Accepted Manuscript
Highly enantioselective hydrogenation of N-unprotected indoles using (S)-C10-
BridgePHOS as the chiral ligand
Chao Li, Jianzhong Chen, Guanghong Fu, Delong Liu, Yangang Liu, Wanbin Zhang
PII:
S0040-4020(13)00934-4
10.1016/j.tet.2013.06.016
TET 24492
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 13 April 2013
Revised Date: 25 May 2013
Accepted Date: 3 June 2013
Please cite this article as: Li C, Chen J, Fu G, Liu D, Liu Y, Zhang W, Highly enantioselective
hydrogenation of N-unprotected indoles using (S)-C10-BridgePHOS as the chiral ligand, Tetrahedron
(2013), doi: 10.1016/j.tet.2013.06.016.
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Highly enantioselective hydrogenation of N-
unprotected indoles using (S)-C10-
BridgePHOS as the chiral ligand
Leave this area blank for abstract info.
Chao Lia,§, Jianzhong Chenb,§, Guanghong Fub, Delong Liua, Yangang Liua and Wanbin Zhanga,b
a School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China

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1
Tetrahedron
journal homepage: www.elsevier.com
Highly enantioselective hydrogenation of N-unprotected indoles using (S)-C10-
BridgePHOS as the chiral ligand
Chao Lia,§, Jianzhong Chenb,§, Guanghong Fub, Delong Liua, Yangang Liua, and Wanbin Zhanga,b,
a School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
(S)-C10-BridgePHOS was successfully applied to a highly efficient Pd-catalyzed enantioselective
hydrogenation of substituted indoles. The methodology was suitable for the hydrogenation of
indoles substituted at the 2-, 3- and 2,3-positions. Products were obtained in quantitative
conversion and up to 98% ee. The role the 2-position substituent plays in the hydrogenation
process has been proposed. The methodology could be used as an alternative method to
synthesize extremely important chiral indolines from N-unprotected indoles.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
(S)-C10-BridgePHOS
Pd-catalyzed enantioselective hydrogenation
Chiral indoline
N-unprotected indole
1. Introduction
Since the discovery of BINAP,1 many excellent chelating
diphosphines possessing atropisomeric biaryl scaffolds such as
MeO-BIPHEP,2 SEGPHOS3 etc, have been developed (Fig. 1)4.
Traditionally, the axial chirality of these atropisomeric ligands
relied on the steric hindrance of the ortho substituents of the
biaryl skeleton. These substituents limit the rotation of the two
benzene rings around the axis, thus affecting the range of the
dihedral angles the ligand can adopt, a significant factor which
influences asymmetric control.2–5 Recently, our group developed
a new class of atropisomeric diphosphine ligands (BridgePHOS
ligands) based on our previous research of axial ligands,6 in
which a bridge of variable length at the 5,5'-positions restricts the
movement of the biaryl system.7 The reduced steric hindrance
resulting from the ortho hydrogen atoms, allows for a greater
degree of control of the dihedral angles compared to traditional
atropisomeric ligands. The largest bite angle of the ligand was
obtained using a bridge of n=10 (C10-BridgePHOS), which gave
Fig. 1 Some atropisomeric ligands
products in quantitative yields and up to 99% ee when subjected
to Pd-catalyzed asymmetric hydrogenations of α-phthalimide
ketones. In order to investigate the applicability of this ligand in
asymmetric reactions, it was applied to Pd-catalyzed asymmetric
hydrogenation reactions of N-unprotected indoles.
Chiral indolines especially fused ring indolines are important
structural motifs which are commonly used in the chemical and
pharmaceutical industry.8 A number of methods have been
successfully developed to synthesize enantioenriched indoline
intermediates. These methods include dynamic kinetic
resolution,9 asymmetric catalysis10 and chiral pool synthesis11
———
§ These authors contributed equally
Corresponding author. Tel./fax: +86-21-5474-3265; e-mail: wanbin@sjtu.edu.cn (W. Zhang)

ACCEPTED MANUSCRIPT
2
Tetrahedron
amongst others.12 Except for the aforementioned reactions,
asymmetric hydrogenation is considered to be the most efficient
and rapid approach to preparing chiral indoline molecules. these
types of reactions provide a high degree of enantioselectivity
with low catalyst loadings, and reduce the amount of unwanted
byproducts in the transformation process.13 Recent studies have
predominantly focused on the reduction of N-protected indoles
utilizing chiral Ru, Rh, and Ir catalysts.14 However, Zhang and
Zhou reported the asymmetric hydrogenation of N-unprotected
indoles using a Pd-catalyst.15 We envisioned that our C10-
BridgePHOS ligand could be utilized in the above protocol,
providing the desired products in high yields and
enantioselectivities. Herein, we report our work concerning the
highly enantioselective Pd-catalyzed hydrogenation of N-
unprotected indoles using (S)-C10-BridgePHOS as the chiral
ligand (Scheme 1).
8
D-CSA
L-CSA
>95
85
90(S,S)
75(S,S)
9
a
Conditions: 1l (0.15 mmol), Pd(OCOCF3)2 (0.8 mg, 2.0 mol%), (S)-C10-
BridgePHOS (2.0 mg, 2.4 mol%), additive (1 equiv.), CH2Cl2 (1 mL), 24 h,
b
1
c
35 ℃, 60 bar H2 pressure. Determined by H NMR analysis. Determined
by chiral HPLC analysis.
determined by comparison of the specific rotations with the literature data.15a
d
The absolute configuration of product was
Further investigations focused on the effect of solvent (Table
2). TFE was first tested and gave full conversion and good
enantioselectivity (entry 1). The use of THF and DMF resulted in
poor catalytic behavior because of coordination of the solvent to
the chiral catalyst (entries 2 and 3). CH2Cl2 gave the desired
product in quantitative conversion with good enantiomeric excess
(entry 4). Considering both CH2Cl2 and TFE were suitable for
this reaction, a mixed solvent system consisting of CH2Cl2 and
TFE (in a 1:1 ratio) was tested, providing the best results (entry
5). Therefore, this solvent system was used in subsequent
reactions.
Table 2 The effect of the solvent, pressure and temperature on
the reactiona
Scheme 1 Asymmetric hydrogenation of indole derivatives
2. Results and discussion
Initial experiments were performed on the substrate 2,3,4,9-
tetrahydro-1H-carbazole (1l), due to its significance in the
chemical and pharmaceutical industry. A catalytic system of
Pd(OCOCF3)2 and (S)-C10-BridgePHOS under an atmosphere of
H2 (60 bar) in CH2Cl2 at 35 ℃ was used.8 As shown in Table 1,
no reaction occurred in the absence of additives (entry 1), and
only a trace amount of product was obtained with PhCO2H as an
additive (entry 2). The application of a strongly acidic additive,
TFA, proved to be successful in this transformation, with both
reactivity and enantioselectivity increasing appreciably (entry 3).
The acidity of the additive had a significant impact on the
outcome of the reaction. Organic sulfonic acids, such as MsOH,
TfOH, para-Cl-PhSO3H and TsOH·H2O, were examined, and
almost all the reactions proceeded smoothly in good conversions
with preferable enantioselectivities (entries 4-7). Finally, chiral
D-camphorsulfonic acid (D-CSA) was used, resulting in a large
increase in enantioselectivity (entry 8). However, the enantiomer
of D-CSA, L-CSA, is inferior to its enantioisomer (entry 9), most
likely because of the mismatch in chirality between the ligand
and additive. Therefore D-CSA was selected as the additive in
subsequent reactions.
Entry
Solvent
Conv.(%)b E.e.(%)c,d
1
TFE
>95
<5
87(S,S)
NA
2
THF
3
DMF
<5
NA
4
CH2Cl2
>95
>95
91
90(S,S)
93(S,S)
92(S,S)
91(S,S)
93(S,S)
93(S,S)
5
CH2Cl2/TFE(1/1)
CH2Cl2/TFE (1/1)
CH2Cl2/TFE (1/1)
CH2Cl2/TFE (1/1)
CH2Cl2/TFE (1/1)
6e
7f
8g
>95
>95
89
9h
a
Conditions: 1l (0.15 mmol), Pd(OCOCF3)2 (0.8 mg, 2.0 mol%), (S)-C10-
BridgePHOS (2.0 mg, 2.4 mol%), D-CSA (1 equiv.), solvent (1 mL), 24 h, 35
b
1
c
℃, 60 bar H2 pressure. Determined by H NMR analysis. Determined by
chiral HPLC analysis.
determined by comparison of the specific rotations with the literature data.15a e
d
The absolute configuration of product was
f
Reaction was carried out in 50 bar H2 pressure. Reaction was carried out in
70 bar H2 pressure. g Reaction was carried out at 60 ℃. h Reaction was carried
Table 1 The effect of the additive on the reactiona
out under room temperature.
H2 pressure and reaction temperature had a marginal effect on
the enantioselectivity but
a significant effect on reaction
conversion. Lower H2 pressure and reaction temperature both led
to a decrease in reaction activity (entries 6 and 9). Higher H2
pressure and temperature showed little effect on both the reaction
activity and the enantioselectivity (entries 7 and 8). Therefore,
the following reaction was carried out using (S)-C10-BridgePHOS
as the chiral ligand in the presence of D-CSA, CH2Cl2/TFE (1/1,
1 mL) at 35 ℃ under 60 bar H2 pressure.
Entry
Additive
no
Conv.(%)b E.e.(%)c,d
1
2
3
4
5
6
7
NR
<5
NA
PhCO2H
TFA
NA
48
23(S,S)
86(S,S)
85(S,S)
86(S,S)
87(S,S)
With the optimal reaction condition in hand, applicability of
this catalytic system was investigated on a series of N-
unprotected indoles (Table 3). At first, the effect of R2 for 2-
substituted substrates on the reaction was investigated. The
enantioselectivities of the products were improved by replacing
the Me group with a Bn substituent (entries 1 and 2). A Bn group
MsOH
>95
65
TfOH
p-Cl-PhSO3H
TsOH·H2O
>95
>95

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3
possessing a para-fluro or methyl group did not siginficantly
affect the reaction outcome (entries 3 and 4). Replacing the Bn
group with naphthylmethyl derivaties had little effect on catalytic
behavior. Products with up to 96% ee were obtained (entries 5
and 6). The substituted group R1 on the phenyl ring of the indoles
was also examined. To our delight, addition of a Me group to the
7-position of the indoles gave excellent enantioselectivities (up to
98% ee) and quantitative conversions of products (entries 7-9).
Substrate scope was also expanded to 2,3-disubstituted
indoles, because the corresponding products, 2,3-disubstituted
indolines (especially those with fused ring), are commonly found
in alkaloids and other natural products. A substrate with a Me
group

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4
Tetrahedron
Table 3 Asymmetric hydrogenation of a series of N-unprotected indolesa
Entry
1
R1
R2
R3
H
Product
2a
2b
2c
Conv.(%)b
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
E.e.(%)c,d
88(S)
H
Me
2
H
Bn
H
95(S)
3
H
4-FC6H4CH2-
4-MeC6H4CH2-
1-Naphthylmethyl
2-Naphthylmethyl
Bn
H
94(S)
4
H
H
2d
2e
95(S)
5
H
H
96(S)
6
7e
8e
9e
H
H
2f
94(S)
7-Me
7-Me
7-Me
H
H
2g
2h
2i
97(S)
4-FC6H4CH2-
4-MeC6H4CH2-
Me
H
97(S)
H
98(S)
10
11
12
13
14
15
16
17
18e
19e
Me
2j
90(S,S)
59(S,S)
93(S,S)
90(S,S)
89(S,S)
88(S,S)
84(S,S)
95(S,S)
66(S)
H
-(CH2)3-
-(CH2)4-
-(CH2)5-
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
H
2k
2l
H
H
2m
2n
2o
2p
2q
2r
5-F
5-Me
5-MeO
7-Me
H
Me
Bn
H
H
2s
51(S)
a Conditions: 1a-1s (0.15 mmol), Pd(OCOCF3)2 (0.8 mg, 2.0 mol%), (S)-C10-BridgePHOS (2.0 mg, 2.4 mol%), D-CSA (1 equiv.), CH2Cl2/TFE (1/1, 1 mL), 24
b
c
d
h, 35 ℃, 60 bar H2 pressure. Determined by 1H NMR analysis. Determined by chiral HPLC analysis. The absolute configuration of the products were
determined by comparison of the specific rotations with the literature data.15a e Reaction is carried out for 36 h.
at the 2 and 3-position was subjected to our reaction conditions
and the reaction proceeded smoothly to give the desired product
in quantitative conversion and 90% ee (entry 10). Our attention
then turned to the 2,3-disubstituted fused ring indolines, of which
a synthesis has not been widely reported. The reduction of five to
seven fused ring indoles were investigated first, with products
being obtained with up to 93% ee (entries 11-13). Interestingly,
both electron donating and withdrawing R1 substituents at the 5-
position on the phenyl ring of the indole substrates, decreased the
enantioselectivities of the reactions (entries 14-16). However, a
methyl group at the 7-position of the indoles provided better
enantioselectivity (95% ee, entry 17). Finally, reactions of 3-
substituted indoles were investigated and only moderate
enantioselectivities were obtained, albeit with full conversion of
the substrates to the products. (entries 18 and 19).
species via protonation of the C=C double bond. The iminium
species can then be reduced via a hydride anion to give two
possible enantiomers. If 2-substituted or 2,3-substituted indoles
wrere used, reaction of the intermediate imminium ion with the
hydride anion becomes more difficult because of the steric
hindrance imposed by the group at the 2-positon. This results in
the equilibrium rate of the formation of the iminium intermediate
from the indole being much faster than the hydrogenation process
(k1≫ k2). Good to excellent enantioselectivity was then observed
for the hydrogenation of the intermediate iminium during the
enantioselectivity-determining step. If the R group is replaced by
a H atom, the rate of hydride addition to the C=N double bond of
the intermediate iminium species increases because of
a
reduction in steric hindrance. Additionally, the difference
between K2 and K3 also decreases for the increased reaction rate.
The two combined aspects result in only moderate
enantioselectivities for the whole reaction process.
The results mentioned above show that substrates possessing
substituents at the 2-position or 2,3-position, reacted very well in
our catalytic system. Substrates with groups at the 3-position
gave medium enantioselectivities. It appears that groups at the 2-
position play a significant role in the asymmetric hydrogenation.
Considering the reaction pathway and mechanism, a dynamic
kinetic resolution hydrogenation process is proposed, which has
been studied by Zhou and Zhang. Herein, we propose a more
detailed description (Scheme 2).
The indole first reacts with the acidic additive to give iminium
Scheme 2 Proposed reaction pathway

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5
3. Conclusion
4.2.3 (-)-(S)-2-(4 -Flurobenzyl)indoline (2c). As a colorless oil.
1H NMR (400 MHz, CDCl3): δ 7.24–7.16 (m, 2H), 7.10 (d, J =
6.4 Hz, 1H), 7.06–7.01 (m, 3H), 6.72 (td, J = 7.6, 0.8 Hz, 1H),
6.60 (d, J = 7.6 Hz, 1H), 4.11–4.02 (m, 1H), 3.71 (brs, 1H), 3.14
(dd, J = 15.2, 8.4 Hz, 1H), 2.94–2.74 (m, 3H); 13C NMR (100
MHz, CDCl3): δ 163.1, 160.6, 149.8, 134.8, 134.7, 130.8, 130.7,
128.8, 127.7, 125.1, 119.5, 115.7, 115.5, 110.0, 61.3, 41.8, 35.9;
HRMS (ESI+Tof) Calculated for C15H15NF [M+H]+ 228.1189,
found 228.1163; [α]D = –17.4 (c = 0.14, benzene); HPLC
conditions: The enantiomeric excess was determined by HPLC
(Chiralcel OD-H), Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃,
To summarize, we have applied the axially chiral diphosphine
(S)-C10-BridgePHOS ligand to a highly efficient Pd-catalyzed
enantioselective hydrogenation of substituted indoles. The
methodology is suitable for the hydrogenation of indoles
substituted at the 2-, 3- and 2,3-positions. Products were obtained
in quantitative conversion and up to 98% ee. The role the 2-
position substituent plays in the hydrogenation process has been
proposed. Further work to improve the reaction for indoles
substituted at the 3-position is ongoing.
20
1.0 mL / min, t1 = 17.9 min (minor), t2 = 21.1 min (major), 94%
ee.
4. Experimental section
4.1 General
4.2.4 (-)-(S)-2-(4 -Methylbenzyl)indoline (2d).15a As a pale
1
All the moisture and air sensitive reactions were carried out
under nitrogen or argon. All organic solvents were dried and
freshly distilled before use with standard methods. Purification of
the products were accomplished by flash chromatography on
silica gel (100-200 mesh). Identification of compounds were
yellow oil. H NMR (400 MHz, CDCl3): δ 7.23–7.13 (m, 3H),
7.12 (d, J = 7.6 Hz, 1H), 7.05 (td, J = 7.4, 0.8 Hz, 1H), 6.74 (td, J
= 7.4, 0.8 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 4.15–4.04 (m, 1H),
3.78 (brs, 1H), 3.17 (dd, J = 15.4, 8.6 Hz, 1H), 2.95–2.79 (m, 3H),
2.39 (s, 3H); [α]D20 = –82.3 (c = 1.00, CHCl3); HPLC conditions:
The enantiomeric excess was determined by HPLC (Chiralcel
OD-H), Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min,
t1 = 12.1 min (minor), t2 = 13.3 min (major), 95% ee.
1
recorded on Varian Mercury Plus 400 with H NMR(400 MHz)
and 13C NMR(100 MHz). Specific rotation was measured on the
Rudolph Autopol VI Automatic Polarimeter. HRMS was
measured on UMS Q-Tof (ESI) Premier.
4.2.5 (-)-(S)-2-(1-Naphtylmethyl)indoline (2e).15a As
a pale
1
4.2 General procedure for Pd-catalyzed asymmetric
hydrogenation
yellow oil. H NMR (400 MHz, CDCl3): δ 8.07 (d, J = 7.2 Hz,
1H), 7.93–7.88 (m, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.58–7.49 (m,
2H), 7.46 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 6.8 Hz, 1H), 7.13 (d, J
= 7.2 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H),
6.57 (d, J = 7.6 Hz, 1H), 4.32–4.21 (m, 1H), 3.89 (brs, 1H), 3.41–
3.26 (m, 2H), 3.21 (dd, J = 16.0, 8.8 Hz, 1H), 2.93 (dd, J = 15.6,
6.8 Hz, 1H); [α]D20 = –40.9 (c = 1.50, CHCl3); HPLC conditions:
The enantiomeric excess was determined by HPLC (Chiralcel
(S)-C10-BridgePHOS (2.0 mg, 2.4 mol%) and Pd(OCOCF3)2
(0.8 mg, 2 mol%) were placed into an oven dried flask under a
nitrogen atmosphere, and degassed fresh dry acetone (2 mL) was
added. The mixture was stirred at rt for 1 h. Then acetone was
removed under vacuum and a solvent system of CH2Cl2/TFE (1/1,
1 mL) was added to the mixture to afford the catalyst solution.
The substrate 1 (0.15 mmol) and additive (1 equiv.) were placed
in a reaction tube under nitrogen and the above catalyst solution
was added to the tube. The mixture was then degassed and
transferred to a stainless steel autoclave in a glove box. After
exchanging the gas 3 times, the hydrogenation was carried out at
35 ℃ under 60 bar H2. After several hours, the reaction mixture
was concentrated under reduced pressure. After alkalization with
saturated NaHCO3, the percentage conversion of product was
determined by 1H NMR analysis of the crude product. The
organic residue was purified by flash chromatography with ethyl
acetate/petrol ether (1 : 50) to give pure product 2. Enantiomeric
excess was determined using a Daicel Chiralcel column with
hexane/i-propyl alcohol as the eluent.
OD-H), Hexane / i-PrOH 90 : 10, UV 254 nm, 25 ℃, 0.8 mL /
min, t1 = 14.9 min (minor), t2 = 19.5 min (major), 96% ee.
4.2.6 (-)-(S)-2-(2-Naphtylmethyl)indoline (2f). As a pale yellow
1
oil. H NMR (400 MHz, CDCl3): δ 7.88–7.78 (m, 3H), 7.68 (s,
1H), 7.53–7.43 (m, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 7.2
Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.71 (t, J = 7.2 Hz, 1H), 6.57 (d,
J = 7.6 Hz, 1H), 4.26–4.09 (m, 1H), 3.88 (brs, 1H), 3.18 (dd, J =
15.6, 8.4 Hz, 1H), 3.04 (ddd, J = 22.0, 13.2, 7.2 Hz, 2H), 2.86
(dd, J = 15.6, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 150.7,
136.8, 133.8, 132.4, 128.6, 128.5, 127.9, 127.7, 127.6, 126.4,
125.8, 125.1, 61.1, 43.1, 36.2; HRMS (ESI+Tof) Calculated for
20
C19H18N [M+H]+ 260.1441, found 260.1439; [α]D = –50.4 (c =
0.16, benzene); HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralcel OD-H), Hexane / i-PrOH 90 : 10,
4.2.1 (-)-(S)-2-Methylindoline (2a).15a As a pale yellow oil. H
1
NMR (400 MHz, CDCl3): δ 7.10 (d, J = 7.2 Hz, 1H), 7.04 (t, J =
7.6 Hz, 1H), 6.72 (t, J = 7.2 Hz, 1H), 6.63 (d, J = 7.6 Hz, 1H),
4.09–3.93 (m, 1H), 3.76 (brs, 1H), 3.17 (dd, J = 15.4, 8.6 Hz, 1H),
UV 254 nm, 25 ℃, 1.0 mL / min, t1 = 11.1 min (minor), t2 = 13.9
min (major), 94% ee.
20
4.2.7 (-)-(S)-7-Methyl-2-benzylindoline (2g). As a pale yellow oil.
1H NMR (400 MHz, CDCl3): δ 7.39–7.34 (m, 2H), 7.32–7.23 (m,
3H), 6.99 (d, J = 7.2 Hz, 1H), 6.89 (d, J = 7.2 Hz, 1H), 6.68 (t, J
= 7.4 Hz, 1H), 4.20–4.04 (m, 1H), 3.66 (brs, 1H), 3.19 (dd, J =
15.4, 8.6 Hz, 1H), 2.96–2.81 (m, 3H), 2.11 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 149.2, 139.3, 129.3, 128.9, 128.5, 127.9,
126.7, 122.5, 119.0, 118.8, 61.0, 43.0, 36.4, 17.1; HRMS
(ESI+Tof) Calculated for C16H18N [M+H]+ 224.1439, found
2.66 (dd, J = 15.4, 7.8 Hz, 1H), 1.31 (d, J = 6.0 Hz, 3H); [α]D = –
10.78 (c = 0.18, benzene); HPLC conditions: The enantiomeric
excess was determined by HPLC (Chiralpak IC-3), Hexane / i-PrOH
98 : 2, UV 254 nm, 25 ℃, 0.5 mL / min, t1 = 14.5 min (minor), t2 =
20.3 min (major), 88% ee.
4.2.2 (-)-(S)-2-Benzylindoline (2b).15a As a pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 7.34 (t, J = 7.2 Hz, 2H), 7.28–7.21
(m, 3H), 7.10 (d, J = 7.6 Hz, 1H), 7.02 (t, J = 7.6 Hz, 1H), 6.73
20
224.1421; [α]D = –24.6 (c = 0.18, benzene); HPLC conditions:
(td, J = 7.2, 0.8 Hz, 1H), 6.64 (d, J = 7.6 Hz, 1H), 4.17–4.06 (m,
The enantiomeric excess was determined by HPLC (Chiralpak
IA), Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1
= 6.8 min (minor), t2 = 7.8 min (major), 97% ee.
20
1H), 3.15 (dd, J = 15.8, 8.4 Hz, 1H), 2.97–2.76 (m, 3H); [α]D
=
–78.9 (c = 1.00, CHCl3); HPLC conditions: The enantiomeric
excess was determined by HPLC (Chiralcel AD-H), Hexane / i-
PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1 = 12.2 min
(minor), t2 = 15.3 min (major), 95% ee.
4.2.8 (-)-(S)-7-Methyl-2-(4 -flurobenzyl)indoline (2h). As a pale
1
red oil. H NMR (400 MHz, CDCl3): δ 7.23–7.16 (m, 2H), 7.07–
7.00 (m, 2H), 6.97 (d, J = 7.2 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H),

ACCEPTED MANUSCRIPT
6
Tetrahedron
6.67 (t, J = 7.2 Hz, 1H), 4.13–4.00 (m, 2H), 3.64 (brs, 1H), 3.16
(dd, J = 15.6, 8.4 Hz, 1H), 2.93–2.75 (m, 3H), 2.10 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 163.0, 160.6, 149.1, 135.0, 134.9,
130.8, 130.7, 128.5, 127.7, 122.5, 119.0, 118.8, 115.7, 115.5,
61.0, 42.1, 36.3, 17.0; HRMS (ESI+Tof) Calculated for
C16H17NF [M+H]+ 242.1345, found 242.1334; [α]D20 = –22.2 (c =
0.21, benzene); HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralcel OD-H), Hexane / i-PrOH 99 : 1,
UV 254 nm, 25 ℃, 1.0 mL / min, t1 = 17.5 min (minor), t2 = 19.7
min (major), 97% ee.
(q, J = 6.6 Hz, 1H), 1.74–1.69 (m, 2H), 1.68–1.48 (m, 3H), 1.44–
1.30 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 158.5, 156.2,
146.9, 146.8, 135.6, 135.5, 113.1, 112.9, 111.0, 110.7, 110.5,
20
110.4, 60.4, 41.4, 29.3, 27.0, 22.6, 21.8; [α]D = –8.6 (c = 0.41,
benzene); HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralpak IC-3), Hexane / i-PrOH 99 : 1,
UV 254 nm, 25 ℃, 0.5 mL / min, t1 = 12.2 min (minor), t2 = 18.7
min (major), 89% ee.
4.2.15
(-)-(4aS,9aS)-5-Methyl-2,3,4,4a,9,9a-hexahydro-1H-
carbazole (2o).18 As a pale yellow oil. 1H NMR (400 MHz,
CDCl3): δ 6.94–6.90 (m, 1H), 6.88–6.82 (m, 1H), 6.60 (d, J = 7.6
Hz, 1H), 3.77–3.64 (m, 1H), 3.08 (q, J = 6.6 Hz, 1H), 2.28 (s,
3H), 1.82–1.74 (m, 2H), 1.69–1.50 (m, 3H), 1.45–1.30 (m, 3H);
13C NMR (100 MHz, CDCl3): δ 148.5, 134.0, 128.3, 127.5, 124.1,
110.3, 60.0, 41.2, 29.4, 27.1, 22.7, 22.0, 21.2; [α]D20 = –17.5 (c =
0.40, benzene); HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralpak IC-3), Hexane / i-PrOH 90 : 10,
UV 254 nm, 25 ℃, 1.0 mL / min, t1 = 4.6 min (minor), t2 = 8.3
min (major), 88% ee.
4.2.9 (-)-(S)-7-Methyl-2-(4 -methylbenzyl)indoline (2i). As a
pale yellow oil. H NMR (400 MHz, CDCl3): δ 7.22–7.10 (m,
1
4H), 6.99 (d, J = 7.2 Hz, 1H), 6.93–6.85 (m, 1H), 6.68 (t, J = 7.4
Hz, 1H), 4.14–4.02 (m, 1H), 3.73 (brs, 1H), 3.19 (dd, J = 15.6,
8.4 Hz, 1H), 2.93–2.77 (m, 3H), 2.38 (s, 3H), 2.12 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ 149.2, 136.2, 136.1, 129.5, 129.2,
128.5, 127.9, 122.5, 118.9, 118.7, 61.0, 42.5, 36.4, 21.3, 17.1;
HRMS (ESI+Tof) Calculated for C17H20N [M+H]+ 238.1596,
20
found 238.1565; [α]D = –64.5 (c = 0.50, benzene); HPLC
conditions: The enantiomeric excess was determined by HPLC
(Chiralpak IE), Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 0.5
mL / min, t1 = 11.6 min (major), t2 = 12.3 min (minor), 98% ee.
4.2.16
(-)-(4aS,9aS)-5-Methoxy-2,3,4,4a,9,9a-hexahydro-1H-
carbazole (2p). As a pale yellow oil. 1H NMR (400 MHz, CDCl3):
δ 6.73–6.71 (m, 1H), 6.63–6.56 (m, 2H), 3.76 (s, 3H), 3.74–3.67
(m, 1H), 3.09 (q, J = 6.4 Hz, 1H), 1.80–1.70 (m, 2H), 1.69–1.49
(m, 3H), 1.45–1.30 (m, 3H); 13C NMR (100 MHz, CDCl3): δ
153.7, 144.6, 135.5, 111.6, 110.8, 110.5, 60.2, 56.1, 41.6, 29.4,
27.1, 22.7, 22.0; HRMS (ESI+Tof) Calculated for C13H18NO
4.2.10 (-)-(S,S)-cis-2,3-Dimethylindoline (2j).15a As a colorless
oil. 1H NMR (400 MHz, CDCl3): δ 7.07 (d, J = 7.2 Hz, 1H), 7.02
(t, J = 7.6 Hz, 1H), 6.74 (t, J = 7.6 Hz, 1H), 6.64 (d, J = 7.6 Hz,
1H), 4.01–3.88 (m, 1H), 3.35–3.19 (m, 1H), 1.18 (d, J = 7.2 Hz,
20
20
2H), 1.15 (d, J = 6.4 Hz, 2H); [α]D = –15.6 (c = 0.40, CHCl3);
[M+H]+ 204.1388, found 204.1351; [α]D = –22.9 (c = 0.38,
HPLC conditions: The enantiomeric excess was determined by
HPLC (Chiralcel OJ-H), Hexane / i-PrOH 99 : 1, UV 254 nm, 25
℃, 1.0 mL / min, t1 = 21.8 min (major), t2 = 28.9 min (major),
90% ee.
benzene); HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralpak IC-3), Hexane / i-PrOH 90 : 10,
UV 254 nm, 25 ℃, 1.0 mL / min, t1 = 9.3 min (minor), t2 = 12.9
min (major), 84% ee.
4.2.11
(-)-(3aS,8bS)-1,2,3,3a,4,8b-
4.2.17
(-)-(4aS,9aS)-7-Methyl-2,3,4,4a,9,9a-hexahydro-1H-
Hexahydrocyclopenta[b]indole (2k).16 As a pale red oil. 1H NMR
(400 MHz, CDCl3): δ 7.05 (d, J = 7.2 Hz, 1H), 7.00 (t, J = 7.6 Hz,
1H), 6.70 (td, J = 7.2, 0.8 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H),
4.42–4.34 (m, 1H), 3.74–3.82 (m, 1H), 1.89–2.01 (m, 1H), 1.82–
carbazole (2q).15a As a pale blue oil. 1H NMR (400 MHz, CDCl3):
δ 6.96 (d, J = 7.6 Hz, 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.70 (t, J =
7.4 Hz, 1H), 3.79–3.68 (m, 1H), 3.12 (q, J = 6.4 Hz, 1H), 2.15 (s,
3H), 1.81–1.71 (m, 2H), 1.69–1.51 (m, 3H), 1.44–1.30 (m, 3H);
20
20
1.59 (m, 4H), 1.58–1.51 (m, 1H); [α]D = –25.4 (c = 0.20,
[α]D = –18.0 (c = 0.70, CHCl3); HPLC conditions: The
CHCl3); HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralpak IC-3), Hexane / i-PrOH 95 : 5,
UV 254 nm, 25 ℃, 0.5 mL / min, t1 = 10.6 min (minor), t2 = 13.6
min (major), 59% ee.
enantiomeric excess was determined by HPLC (Chiralpak IC-3),
Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1 = 5.4
min (minor), t2 = 6.3 min (major), 95% ee.
1
4.2.18 (-)-(S)-3-Methylindoline (2r).15e As a pale yellow oil. H
4.2.12 (-)-(2S,3S)-5,6,7,8,8a,9-Hexahydro-4bH-carbazole (2l).15a
NMR (400 MHz, CDCl3): δ 7.13–7.08 (m, 1H), 7.07–7.01 (m,
1H), 6.75 (td, J = 7.4, 0.8 Hz, 1H), 6.68–6.63 (m, 1H), 3.71 (t, J
= 8.6 Hz, 1H), 3.48 (brs, 1H), 3.42–3.32 (m, 1H), 3.12 (t, J = 8.6
1
As a pale yellow oil. H NMR (400 MHz, CDCl3): δ 7.13–7.07
(m, 1H), 7.03 (tdd, J = 7.6, 1.2, 0.8 Hz, 1H), 6.75 (td, J = 7.2, 0.8
Hz, 1H), 6.68 (d, J = 8.0 Hz, 1H), 3.77–3.70 (m, 1H), 3.11 (q, J =
6.6 Hz, 1H), 1.74–1.81 (m, 2H), 1.48–1.70 (m, 3H), 1.30–1.45
20
Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H); [α]D = –13.4 (c = 0.25,
CHCl3); HPLC conditions: The enantiomeric excess was
determined by HPLC (Chiralpak IC-3), Hexane / i-PrOH 95 : 5,
UV 254 nm, 25 ℃, 0.5 mL / min, t1 = 12.3 min (minor), t2 = 14.4
min (major), 66% ee.
20
(m, 3H); [α]D = –28.2 (c = 1.10, CHCl3); HPLC conditions: The
enantiomeric excess was determined by HPLC (Chiralpak IC-3),
Hexane / i-PrOH 98 : 2, UV 254 nm, 25 ℃, 1.0 mL / min, t1 = 6.5
min (minor), t2 = 11.9 min (major), 93% ee.
4.2.19 (-)-(S)-3-Benzylindoline (2s).16 As a pale yellow oil. 1H
NMR (400 MHz, CDCl3): δ 7.35–7.29 (m, 2H), 7.24 (dd, J = 8.8,
7.2 Hz, 3H), 7.05 (t, J = 7.6 Hz, 1H), 6.98 (d, J = 7.6 Hz, 1H),
6.76–6.62 (m, 2H), 3.67–3.57 (m, 1H), 3.55 (t, J = 8.6 Hz, 1H),
3.29 (dd, J = 8.6, 6.4 Hz, 1H), 3.12 (dd, J = 13.8, 6.0 Hz, 1H),
2.83 (dd, J = 13.8, 8.8 Hz, 1H); [α]D20 = –24.0 (c = 0.70, CHCl3);
HPLC conditions: The enantiomeric excess was determined by
HPLC (Chiralcel AD-H), Hexane / i-PrOH 90 : 10, UV 254 nm,
25 ℃, 0.5 mL / min, t1 = 14.4 min (minor), t2 = 16.8 min (major),
51% ee.
4.2.13
(-)-(2S,3S)-5,5a,6,7,8,9,10,10a-
1
Octahydrocyclohepta[b]indole (2m).15a As a pale yellow oil. H
NMR (400 MHz, CDCl3): δ 7.06–6.97 (m, 2H), 6.72 (td, J = 7.4,
1.0 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 4.10–4.01 (m, 1H), 3.47 (td,
J = 10.4, 3.6 Hz, 1H), 2.01–1.92 (m, 1H), 1.91–1.66 (m, 6H),
20
1.46–1.28 (m, 3H); [α]D = –31.7 (c = 0.50, CHCl3); HPLC
conditions: The enantiomeric excess was determined by HPLC
(Chiralpak IC-3), Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 0.5
mL / min, t1 = 16.4 min (minor), t2 = 24.7 min (major), 90% ee.
4.2.14
(-)-(4aS,9aS)-5-Fluoro-2,3,4,4a,9,9a-hexahydro-1H-
Acknowledgments
carbazole (2n).17 As a colorless oil. 1H NMR (400 MHz, CDCl3):
δ 6.80 (ddd, J = 8.4, 2.6, 1.0 Hz, 1H), 6.72–6.66 (m, 1H), 6.55
(dd, J = 8.4, 4.4 Hz, 1H), 3.76–3.70 (m, 1H), 3.47 (brs, 1H), 3.08
This work was partly supported by the National Nature
Science Foundation of China (No. 21172143, 21172145 and

ACCEPTED MANUSCRIPT
7
H.; Xie, F.; Ma, Z.; Liu, Y.; Zhang, W. Org. Biomol. Chem. 2012, 10,
5137–5142; (q) Liu, Y.; Zhang, W. Angew. Chem., Int. Ed. 2013, 52,
2203-2206.
21232004), Science and Technology Commission of Shanghai
Municipality (No. 09JC1407800), Nippon Chemical Industrial
Co. Ltd and the Instrumental Analysis Center of Shanghai Jiao
Tong University. We thank Prof. Tsuneo Imamoto and Dr.
Masashi Sugiya for helpful discussions.
7
8
Wang, C.; Yang, G.; Zhuang, J.; Zhang, W. Tetrahedron Lett. 2010, 51,
2044-2047.
(a) Southon, I. W.; Buckingham, J. in Diction-ary of Alkaloids Chapman
and Hall, New York, 1989; (b) Neuss, N. in The Alkaloids (Eds.: Brossi,
A.; Suffness, M.), Academic Press, San Diego, 1990, p. 229; (c) Gueritte,
F.; Fahy, J. in Anti-cancer Agents from Natural Products (Eds.: Cragg, G.
M.; Kingstom, D. G. I.; Newman, D. J.), CRC Press, Boca Raton 2005, p.
123; (d) Modern Alkaloids (Eds.: Fattorusso, E.; Taglialatela-Scafati, O.),
Wiley-VCH, Weinheim 2008, and references therein.
Supporting data
Supplementary data associated with this article can be found
in online version at doi:
9
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2006, 128, 5955–5965; (f) Shintani, R.; Yashio, K.; Nakamura, T.;
Okamoto, K.; Shimada, T.; Hayashi, T. J. Am. Chem. Soc. 2006, 128,
2772–2773 and references therein.
6
For our previous research on axial chiral ligands, see: (a) Wang, F.;
Zhang, Y. J.; Wei, H.; Zhang, J.; Zhang, W. Tetrahedron Lett. 2007, 48,
4083–4086; (b) Wang, F.; Zhang, Y. J.; Yang, G.; Zhang, W.
Tetrahedron Lett. 2007, 48, 4179–4182; (c) Zhang, Y. J.; Wang, F.;
Zhang, W. J. Org. Chem. 2007, 72, 9208–9213; (d) Wei, H.; Zhang, Y. J.;
Wang, F.; Zhang, W. Tetrahedron: Asymmetry 2008, 19, 482–488; (e)
Wei, H.; Zhang, Y. J.; Dai, Y.; Zhang, J.; Zhang, W. Tetrahedron Lett.
2008, 49, 4106–4109; (f) Wang, F.; Yang, G.; Zhang, Y. J.; Zhang, W.
Tetrahedron 2008, 64, 9413–9416; (g) Fang, F.; Xie, F.; Yu, H.; Zhang,
H.; Yang, B.; Zhang, W. Tetrahedron 2009, 50, 6672–6675; (h) Zhang,
Y. J.; Wei, H.; Zhang, W. Tetrahedron 2009, 65, 1281–1286; (i) Tian, F.;
Yao, D.; Zhang, Y. J.; Zhang, W. Tetrahedron 2009, 65, 9609–9615; (j)
Zhang, H.; Fang, F.; Xie, F.; Yu, H.; Yang, G.; Zhang, W. Tetrahedron
Lett. 2010, 51, 3119–3122; (k) Fang, F.; Zhang, H.; Xie, F.; Yang, G.;
Zhang, W. Tetrahedron 2010, 66, 3593–3598; (l) Tian, F.; Yao, D.; Liu,
Y.; Xie, F.; Zhang, W. Adv. Synth. Catal. 2010, 352, 1841–1845; (m)
Yang, B.; Xie, F.; Yu, H.; Shen, K.; Ma, Z.; Zhang, W. Tetrahedron
2011, 67, 6197–6201; (n) Liu, Q.; Wen, K.; Zhang, Z.; Wu, Z.; Zhang, Y.
J.; Zhang, W. Tetrahedron 2012, 68, 5209–5215; (o) Yu, H.; Xie, F.; Ma,
Z.; Liu, Y.; Zhang, W. Adv. Synth. Catal. 2012, 68, 1941–1947; (p) Yu,
16 Xiao, Y.-C.; Wang, C.; Yao, Y.; Sun, J.; Chen, Y.-C. Angew. Chem., Int.
Ed. 2011, 50, 10661–10664.
17 Hiroshi, I.; Kazuyuki, N. DE Patent 2849158, 1979.
18 Smith, A.; Utley, J. H. P. Chem. Commun. 1965, 18, 427–428.

ACCEPTED MANUSCRIPT
Supporting Information
Highly enantioselective hydrogenation of N-unprotected
indoles using (S)-C10-BridgePHOS as the chiral ligand
Chao Li,a, Jianzhong Chen,b, Guanghong Fu,b Delong Liu,a Yangang Liua,* and
Wanbin Zhanga,b,
*
a School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
b School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai
200240, P. R. China
Contents
1. General Details....................................................................................................................2
2. General Procedure for the Synthesis of Substrate ...........................................................2
3. Reference..............................................................................................................................5
4. HPLC Spectra .....................................................................................................................6
5. NMR Spectra.....................................................................................................................25
1

ACCEPTED MANUSCRIPT
1. General Details
1H NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded on a Varian
MERCURY Plus 400 with TMS as an internal standard. HRMS was performed on
UMS-Q-Tof-Premier in the Analysis Center of Shanghai Jiao Tong University. Melting point was
detected by SGW X-5 micro melting point apparatus. The enantioselectivity was measured by
HPLC with Chiralcel AD-H, OD-H, OJ-H, Chiralpak IC-3, IE or IA column with hexane/i-propyl
alcohol as the eluent. Specific rotation was measured by Rudolph Autopol VI Automatic
Polarimeter. Column chromatography was performed on 100-200 mesh silica gel. All
commercially available substrates were used as received.
2. General Procedure for the Synthesis of Substrates
Method A:
Scheme 1
Sodium hydride (20 mmol) was added to the solution of indole (17 mmol) in DMF (50 mL)
in portions. The mixture was stirred for 30 min and then cooled to 0 ℃. Substituted benzyl
bromide (19 mmol) was added dropwise, and the reaction was kept up at room temperature for 12
h. The reaction was quenched with water and the mixture was extracted with EtOAc (50 mL*3).
The combined organic layer was washed with water, brine, then dried over anhydrous Na2SO4.
After solvent was removed, the residue was purified by column chromatography to get the
intermediate N-benzylindole in 65-87% yield.1
N-benzylindole (4.8 mmol) was added to excess polyphosphoric acid (PPA, 50 mL) at
120-160 ℃ and the mixture was stirred overnight until the system became black entirely. Then
the reidue was poured into ice water and NaHCO3 was added. When the mixture become clear,
2

ACCEPTED MANUSCRIPT
extracted with EtOAc (50 mL*3), and the combined organic layer was washed with saturated
NaHCO3 (aq.), brine, and water. After dried over anhydrous Na2SO4 and removed solvent, the
residue was purified by column chromatography to afford 1b-1i in 32-60% yield.2
Method B:
Scheme 2
Substituted phenyl hydrazine (14 mmol) was solved in the mixture of concentrated
hydrochloric acid and water (50 mL, 1:20) and then ketone (16.8 mmol) was added dropwise at rt.
After that, the mixture was stirred for more than 5 h at 50-60 ℃. When the reaction cooled to rt,
some rice shape solids appeared in the system. The mixture was filtered and the solid was washed
with enough water until neutral. The crude product was recrystallized in hexane to afford 1k-1q in
72-95% yield.3
Substrates scope:
C
3

ACCEPTED MANUSCRIPT
haracterization data of new substrates.
1
2-(2-Naphthylmethyl)indole (1f). As a white solid. m.p. 145–146 ℃. H NMR (400 MHz,
CDCl3): δ 7.80–7.87 (m, 3H), 7.76 (brs, 1H), 7.72 (s, 1H), 7.61–7.58 (m, 1H), 7.52–7.49 (m, 2H),
7.39 (dd, J = 8.4, 1.8 Hz, 1H), 7.25–7.22 (m, 1H), 7.17–7.10 (m, 2H), 6.41 (s, 1H), 4.29 (s, 2H);
13C NMR (100 MHz, CDCl3): δ 137.9, 136.5, 136.2, 133.8, 132.6, 128.9, 128.7, 127.9, 127.8,
127.5, 127.3, 126.5, 125.9, 121.6, 120.2, 119.9, 110.7, 101.4, 35.1; HRMS (ESI+Tof) Calculated
for C19H16N [M+H]+ 258.1283, found 258.1281.
7-Methyl-2-(4-Flurobenzyl)indole (1h). Aa a yellow solid. m.p. 72–73 ℃. 1H NMR (400 MHz,
CDCl3): δ 7.71 (brs, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.25–7.20 (m, 2H), 7.05–6.99 (m, 3H), 6.95 (d,
J = 7.2 Hz, 1H), 6.32–6.30 (m, 1H), 4.12 (s, 2H), 2.43 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
163.2, 160.8, 137.7, 136.2, 134.7, 134.6, 130.6, 130.5, 128.5, 122.4, 120.3, 120.1, 118.1, 115.9,
115.7, 102.2, 34.2, 17.0; HRMS (ESI+Tof) Calculated for C16H15NF [M+H]+ 240.1289, found
240.1280.
7-Methyl-2-(4-methylbenzyl)indole (1i). As a white solid. m.p. 106–107 ℃. 1H NMR (400 MHz,
CDCl3): δ 7.70 (brs, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.17–7.12 (m, 4H), 7.00 (t, J = 7.6 Hz, 1H),
4

ACCEPTED MANUSCRIPT
6.92 (d, J = 7.2 Hz, 1H), 6.34–6.31 (m, 1H), 4.11 (s, 2H), 2.41 (s, 3H), 2.34 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ 137.9, 136.5, 136.1, 135.8, 129.6, 128.9, 128.4, 122.2, 120.1, 119.9, 118.0,
101.9, 34.5, 21.3, 17.0; HRMS (ESI+Tof) Calculated for C17H18N [M+H]+ 236.1439, found
236.1431.
3. Reference
1.Xu, X.-H.; Liu, G.-K.; Azuma, A.; Tokunaga, E.; Shibata, N. Org. Lett. 2011, 13, 4854-4857.
2.Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.; Zhou, Y.-G.; Zhang, X. J. Am. Chem. Soc. 2010,
132, 8909-8911.
3. Ni, H. P.; Hou, Q. J. CN Patent 102249983, 2011.
5

ACCEPTED MANUSCRIPT
4. HPLC Spectra
(-)-(S)-2-Methylindoline (2a):
HPLC conditions: Chiralcel IC-3, Hexane / i-PrOH 98 : 2, UV 254 nm, 25 ℃, 0.5 mL / min, t1 =
14.5 min (minor), t2 = 20.3 min (major)
Figure 1 racemate of 2-Methylindoline
Peak
Retention time/min
14.525
Area%
49.287
50.713
1
2
20.323
Figure 2 (-)-(S)-2-Methylindoline
(2a)
Me
N
H
2a
Peak
Retention time/min
13.623
Area%
5.845
1
2
19.278
94.155
6

ACCEPTED MANUSCRIPT
(-)-(S)-2-Benzylindoline (2b):
HPLC conditions: Chiralcel AD-H, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1
= 12.2 min (minor), t2 = 15.3 min (major)
Figure 3 racemate of 2-Benzylindoline
Peak
Retention time/min
12.241
Area%
49.809
50.191
1
2
15.340
Figure 4 (-)-(S)-2-Benzylindoline (2b)
Peak
Retention time/min
12.143
Area%
97.348
2.652
1
2
15.154
7

ACCEPTED MANUSCRIPT
(-)-(S)-2-(4’-Flurobenzyl)indoline (2c):
HPLC conditions: Chiralcel OD-H, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1
= 17.9 min (minor), t2 = 21.1 min (major)
Figure 5 racemate of 2-(4 -Flurobenzyl)indoline
Peak
Retention time/min
17.934
Area%
49.938
50.062
1
2
21.158
Figure 6 (-)-(S)-2-(4 -Flurobenzyl)indoline (2c)
N
H
F
2c
Peak
Retention time/min
18.266
Area%
97.348
2.652
1
2
11.141
8

ACCEPTED MANUSCRIPT
(-)-(S)-2-(4’-Methylbenzyl)indoline (2d):
HPLC conditions: Chiralcel OD-H, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1
= 12.1 min (minor), t2 = 13.3 min (major).
Figure 7 racemate of 2-(4 -Methylbenzyl)indoline
Peak
Retention time/min
12.135
Area%
49.763
50.237
1
2
13.337
Figure 8 (-)-(S)-2-(4 -Methylbenzyl)indoline
(2d)
Peak
Retention time/min
12.097
Area%
2.874
1
2
13.264
97.126
9

ACCEPTED MANUSCRIPT
(-)-(S)-2-(1-Naphtylmethyl)indoline (2e):
HPLC conditions: Chiralcel OD-H, Hexane / i-PrOH 90 : 10, UV 254 nm, 25 ℃, 0.8 mL / min, t1
= 14.9 min (minor), t2 = 19.5 min (major).
Figure 9 racemate of 2-(1-Naphthylmethyl)indoline
Peak
Retention time/min
14.912
Area%
49.888
50.112
1
2
19.546
Figure 10 (-)-(S)-2-(1-Naphtylmethyl)indoline
(2e)
Peak
Retention time/min
15.597
Area%
2.023
1
2
20.309
97.977
10

ACCEPTED MANUSCRIPT
(-)-(S)-2-(2-Naphtylmethyl)indoline (2f):
HPLC conditions: Chiralcel OD-H, Hexane / i-PrOH 90 : 10, UV 254 nm, 25 ℃, 1.0 mL / min, t1
= 11.1 min (minor), t2 = 13.9 min (major).
Figure 11 racemate of 2-(2-Naphthylmethyl)indoline
Peak
Retention time/min
11.134
Area%
49.942
50.058
1
2
13.877
Figure 12 (-)-(S)-2-(2-Naphtylmethyl)indoline
(2f)
Peak
Retention time/min
11.694
Area%
3.074
1
2
13.614
96.926
11

ACCEPTED MANUSCRIPT
(-)-(S)-7-methyl-2-benzylindoline (2g):
HPLC conditoins: Chiralcel IA, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1 =
6.8 min (minor), t2 = 7.8 min (major).
Figure 13 racemate of 7-Methyl-2-benzylindoline
Peak
Retention time/min
6.820
Area%
50.086
49.914
1
2
7.799
Figure 14 (-)-(S)-7-methyl-2-benzylindoline (2g)
Peak
Retention time/min
7.621
Area%
1.559
1
2
8.554
98.441
12

ACCEPTED MANUSCRIPT
(-)-(S)-7-Methyl-2-(4’-flurobenzyl)indoline (2h):
HPLC conditions: Chiralcel OD-H, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1
= 17.5 min (minor), t2 = 19.7 min (major).
Figure 15 racemate of 7-Methyl-2-(4 -flurobenzyl)indoline
Peak
Retention time/min
17.542
Area%
50.417
49.583
1
2
19.730
Figure 16 (-)-(S)-7-Methyl-2-(4 -flurobenzyl)indoline
(2h)
N
H
Me
F
2h
Peak
Retention time/min
17.784
Area%
98.654
1.346
1
2
20.430
13

ACCEPTED MANUSCRIPT
(-)-(S)-7-Methyl-2-(4’-methylbenzyl)indoline (2i):
HPLC conditions: Chiralcel IE, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 0.5 mL / min, t1 =
11.6 min (major), t2 = 12.3 min (minor).
Figure 17 racemate of 7-Methyl-2-(4 -methylbenzyl)indoline
Peak
Retention time/min
11.570
Area%
49.843
50.157
1
2
12.259
Figure 18 (-)-(S)-7-Methyl-2-(4 -methylbenzyl)indoline (2i)
Peak
Retention time/min
11.987
Area%
1
2
98.985
1.015
12.810
14

ACCEPTED MANUSCRIPT
(-)-(S,S)-cis-2,3-Dimethylindoline (2j):
HPLC conditions: Chiralcel OJ-H, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 1.0 mL / min, t1 =
21.8 min (major), t2 = 28.9 min (major).
Figure 19 racemate of 2,3-Dimethylindoline
Peak
Retention time/min
21.796
Area%
49.976
50.024
1
2
28.921
Figure 20 (-)-(S,S)-cis-2,3-Dimethylindoline
(2j)
Me
Me
N
H
2j
Peak
Retention time/min
21.207
Area%
95.132
4.868
1
2
28.610
15

ACCEPTED MANUSCRIPT
(-)-(3aS,8bS)-1,2,3,3a,4,8b-Hexahydrocyclopenta[b]indole (2k):
HPLC conditions: Chiralcel IC-3, Hexane / i-PrOH 95 : 5, UV 254 nm, 25 ℃, 0.5 mL / min, t1 =
10.6 min (minor), t2 = 13.6 min (major).
Figure 21 racemate of 1,2,3,3a,4,8b-Hexahydrocyclopenta[b]indole
Peak
Retention time/min
10.604
Area%
50.036
49.964
1
2
13.611
Figure 22 (-)-(3aS,8bS)-1,2,3,3a,4,8b-Hexahydrocyclopenta[b]indole
(2k)
N
H
2k
Peak
Retention time/min
10.672
Area%
1
2
20.729
79.271
13.771
16

ACCEPTED MANUSCRIPT
(-)-(2S,3S)-5,6,7,8,8a,9-Hexahydro-4bH-carbazole (2l):
HPLC conditions: Chiralcel IC-3, Hexane / i-PrOH 98 : 2, UV 254 nm, 25 ℃, 1.0 mL / min, t1 =
6.5 min (minor), t2 = 11.9 min (major).
Figure 23 racemate of 5,6,7,8,8a,9-Hexahydro-4bH-carbazole
Peak
Retention time/min
6.552
Area%
50.092
49.908
1
2
11.944
Figure 24 (-)-(2S,3S)-5,6,7,8,8a,9-Hexahydro-4bH-carbazole
(2l)
N
H
2l
Peak
Retention time/min
6.069
Area%
1
2
3.538
10.724
96.462
17

ACCEPTED MANUSCRIPT
(-)-(2S,3S)-5,5a,6,7,8,9,10,10a-Octahydrocyclohepta[b]indole (2m):
HPLC conditions: Chiralcel IC-3, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 0.5 mL / min, t1 =
16.4 min (minor), t2 = 24.7 min (major).
Figure 25 racemate of 5,5a,6,7,8,9,10,10a-Octahydrocyclohepta[b]indole
Peak
Retention time/min
16.428
Area%
50.035
49.965
1
2
24.683
Figure 26 (-)-(2S,3S)-5,5a,6,7,8,9,10,10a-Octahydrocyclohepta[b]indole (2m)
N
H
2m
Peak
Retention time/min
17.110
Area%
4.837
1
2
25.397
95.163
18

ACCEPTED MANUSCRIPT
(-)-(4aS,9aS)-5-Fluoro-2,3,4,4a,9,9a-hexahydro-1H-carbazole (2n):
HPLC conditions: Chiralcel IC-3, Hexane / i-PrOH 99 : 1, UV 254 nm, 25 ℃, 0.5 mL / min, t1 =
12.2 min (minor), t2 = 18.7 min (major).
Figure 27 racemate of 5-Fluoro-2,3,4,4a,9,9a-hexahydro-1H-carbazole
Peak
Retention time/min
12.190
Area%
49.426
50.574
1
2
18.738
Figure 28 (-)-(4aS,9aS)-5-Fluoro-2,3,4,4a,9,9a-hexahydro-1H-carbazole
(2n)
Peak
Retention time/min
13.036
Area%
5.624
1
2
19.570
94.376
19

ACCEPTED MANUSCRIPT
(-)-(4aS,9aS)-5-Methyl-2,3,4,4a,9,9a-hexahydro-1H-carbazole (2o):
HPLC conditions: Chiralcel IC-3, Hexane / i-PrOH 90 : 10, UV 254 nm, 25 ℃, 1.0 mL / min, t1 =
4.6 min (minor), t2 = 8.3 min (major).
Figure 29 racemate of 5-Methyl-2,3,4,4a,9,9a-hexahydro-1H-carbazole
Peak
Retention time/min
4.608
Area%
49.808
50.192
1
2
8.260
Figure 30 (-)-(4aS,9aS)-5-Methyl-2,3,4,4a,9,9a-hexahydro-1H-carbazole (2o)
Peak
Retention time/min
4.644
Area%
6.115
1
2
8.468
93.885
20

ACCEPTED MANUSCRIPT
(-)-(4aS,9aS)-5-Methoxy-2,3,4,4a,9,9a-hexahydro-1H-carbazole (2p):
HPLC conditions: Chiralcel IC-3, Hexane / i-PrOH 90 : 10, UV 254 nm, 25 ℃, 1.0 mL / min, t1 =
9.3 min (minor), t2 = 12.9 min (major).
Figure 31 racemate of 5-Methoxy-2,3,4,4a,9,9a-hexahydro-1H-carbazole
Peak
Retention time/min
9.358
Area%
49.851
50.149
1
2
12.959
Figure 32 (-)-(4aS,9aS)-5-Methoxy-2,3,4,4a,9,9a-hexahydro-1H-carbazole (2p)
Peak
Retention time/min
9.765
Area%
8.064
1
2
13.222
91.936
21