Enantioselective synthesis of N–C axially chiral indoles through chiral palladium-catalyzed 5-endo-hydroaminocyclization

Article abstract of DOI:10.1016/j.tet.2015.05.001

In the presence of (R)-SEGPHOS-PdCl₂catalyst, 5-endo-hydroaminocyclization of various 2-(tert-butyl)-N-(2-ethynylphenyl)anilines proceeds enantioselectively to afford optically active N–C axially chiral N-(2-tert-butylphenyl)indole derivatives

Full text of DOI:10.1016/j.tet.2015.05.001

Tetrahedron xxx (2015) 1e9
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Tetrahedron
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Enantioselective synthesis of NeC axially chiral indoles through
chiral palladium-catalyzed 5-endo-hydroaminocyclization
Yudai Morimoto a, Satoshi Shimizu a, Ayano Mokuya a, Nobutaka Ototake a, Akio Saito b,
,
Osamu Kitagawa a
*
a Department of Applied Chemistry, Shibaura Institute of Technology, 3-7-5 Toyosu, Kohto-ku, Tokyo 135-8548, Japan
b Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei,
Tokyo 184-8588, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of (R)-SEGPHOS-PdCl2 catalyst, 5-endo-hydroaminocyclization of various 2-(tert-butyl)-
N-(2-ethynylphenyl)anilines proceeds enantioselectively to afford optically active NeC axially chiral N-
(2-tert-butylphenyl)indole derivatives in good yields. The enantioselectivity depends strongly on the
bulkiness of ortho-substituents and the electron density on the arylethynyl group, and it is explained by
the dynamic axial chirality generated by the twisting of the aryl substituent.
Received 20 February 2015
Received in revised form 17 April 2015
Accepted 2 May 2015
Available online xxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Axial chirarity
Palladium
Chiral phosphines
Hydroaminocyclization
1. Introduction
Atropisomeric compounds with an NeC chiral axis have re-
ceived much attention as novel chiral molecules.1 Recent note-
worthy topics in this field include catalytic enantioselective
syntheses of NeC axially chiral compounds.2,3 In 2005, we suc-
ceeded in the highly enantioselective synthesis of N-arylated ortho-
tert-butylanilides
I
and
N-(ortho-tert-butylphenyl)-3,4-
dihydroquinolin-2-ones VII through chiral palladium-catalyzed
Buchwald-Hartwig amination (Fig. 1).2c,d This reaction was the
first practical catalytic asymmetric synthesis of NeC axially chiral
compounds. After our publication, highly enantioselective synthe-
ses of various NeC axially chiral compounds IeIX through catalytic
asymmetric reactions have been reported by many other groups.2,3
These compounds have amide skeletons, and include anilides I, II,
ureas III, carbamates IV, V, imides VI and lactams VIIeIX. However,
although a considerable number of NeC axially chiral compounds
with non-amide structure have also been found,1a,1q,1s,1t there has
been no report on their catalytic enantioselective synthesis.4
Fig. 1. Various NeC axially chiral compounds prepared with catalytic enantioselective
reactions.
* Corresponding author. Tel.: þ81 3 5859 8161; fax: þ81 3 5859 8101; e-mail
address: kitagawa@shibaura-it.ac.jp (O. Kitagawa).
http://dx.doi.org/10.1016/j.tet.2015.05.001
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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Y. Morimoto et al. / Tetrahedron xxx (2015) 1e9
In 2010, we succeeded in the enantioselective synthesis of var-
ious NeC axially chiral indoles via (R)-SEGPHOS-PdCl2-catalyzed 5-
endo-hydroaminocyclization of 2-(tert-butyl)-N-(2-ethynylphenyl)
anilines (Scheme 1, R2¼t-Bu).5 The present reaction is the first
catalytic asymmetric synthesis of non-amide type NeC axially
chiral compounds. We report here a full article of this reaction. In
addition to detailing the scope and limitations of the reaction and
the stereochemical assignment of the chiral axis, this paper de-
scribes new insights such as the additive effects of protic acid and
the relationship between the enantioselectivity and the electron
density on arylalkynyl group.
Scheme 2. Synthesis of racemic-indole 2a through 5-endo-hydroaminocyclization.
Subsequently, under the optimized conditions, a screening of
various chiral ligands was performed (Table 1). When (R)-C3-
Tunephos or (R)-SEGPHOS8 were used as the chiral ligand, rela-
tively good results were obtained (entries 12 and 13). In these cases,
indole product 2a was obtained in excellent yields (99%, 93%) and
moderate ee (58%ee, 60% ee). In general, the reaction in the pres-
ence of a chiral ligand required a longer reaction time than that of
ligand-free reactions (in the presence of only PdCl2).
Table 1
Screening of chiral ligands for the catalytic enantioselective 5-exo-aminocyclization
of 1a
Scheme 1. NeC axially chiral indoles and their catalytic asymmetric synthesis.
Entry
Chiral ligand
Yield (%)a
ee (%)b
1
(R,R)-Ph-box
85
4
2
3
4
5
6
7
8
(S,S)-t-Bu-box
(S)eP,N-Ligand
(S,S)-Trost ligand
(R)-(S)-BPPFA
(R,R)-Me-DUPHOS
(R)-DTBM-SEGPHOS
(R)-BINAP
85
11
d
d
3
4
1
2. Results and discussion
Trace
Trace
14
45
8
In 2006, Kamikawa and Uemura reported that 2-substituted
indole derivatives possessing an ortho-mono-substituted or ortho-
di-substituted phenyl group on the nitrogen atom have a high ro-
tational barrier around the NeAr bond.6 In these indole substrates,
it is significant that even the N-(2-methylphenyl)indole derivatives
display stable atropisomerism (Scheme 1, X: R2¼Me). They also
succeeded in the highly enantioselective synthesis of these indole
derivatives, although a stoichiometric chiral source was required in
their method.6
82
0
9
(R)-MOP
(R)-DIFLUOROPHOS
(R)-SYNPHOS
(R)-C3-Tunephos
(R)-SEGPHOS
69
89
99
99
2
10
11
12
13
26
55
58
60
93
a
Isolated yield.
b
The ee was determined by HPLC analysis using a chiral column.
We expected that N-(2-tert-butylphenyl)indoles (X: R2¼t-Bu)
would have an extremely high rotational barrier, and that their
catalytic asymmetric synthesis might be achievable through the
chiral transition metal-catalyzed 5-endo-hydroaminocyclization of
2-(tert-butyl)-N-(2-ethynylphenyl)anilines shown in Scheme 1.
Although 5-endo-hydroaminocyclization of ortho-ethynyl anilines,
which provides efficient synthesis of indole derivatives, has been
broadly investigated by many groups,7 its application to an asym-
metric reaction has not been reported to date.
Before investigating enantioselective reactions, we explored the
optimization of the reaction conditions by using 2-(tert-butyl)-N-
(2-(phenylethynyl)phenyl)anilines 1a as a substrate. After a survey
of various transition metal catalysts coordinating rac-BINAP, sol-
vents and reaction temperatures (room temperature to 80 ꢀC), it
was found that when the reaction of 1a was performed in the
presence of PdCl2 (5 mol %) and rac-BINAP (7 mol %) in EtOH for 6 h
at 80 ꢀC, indole product 2a was obtained in excellent yield (93%,
Scheme 2). The use of other transition metal catalysts (AuCl, AuCl3,
PtCl2, NiCl2, AgOTf) instead of PdCl2 gave the significantly lower
chemical yields (trace-59%). In the present reaction with rac-BINAP-
PdCl2 catalyst, the use of protic solvents was required. That is,
similar to the reaction in EtOH, those in MeOH, CF3CH2OH and
(CF3)2CHOH gave 2a in excellent yields (91%e93%), while reaction
in aprotic solvent such as THF, toluene, DMF, CH3CN, gave re-
markably lower chemical yields (trace-19%).
To evaluate the effect of an ortho-substituent on enantiose-
lectivity, the reaction of 2-(phenylethynyl)aniline 3aed with vari-
ous ortho-substituted phenyl groups on the nitrogen atom was
examined in the presence of (R)-SEGPHOS-PdCl2 catalyst in EtOH
(Table 2). The enantioselectivity decreased with decreasing bulki-
ness of the ortho-substituent, and the reaction with ortho-methoxy
derivative 3d gave the racemic product 4d. The indole products 2a
and 4aec were confirmed to have a high rotational barrier. That is,
when isolated 2a and 4aec were heated in EtOH for 15 h at 80 ꢀC,
no appreciable change in the ee was detected, providing evidence
that the partial racemization of indole products 2a and 4aec does
not occur under the present reaction conditions.
The enantioselectivity and the rate in the present reaction were
also significantly influenced by the substituents on the alkyne
(Table 3). Unlike phenylethynyl derivative 1a, the reaction of
ethynyl aniline 1b,c possessing an aliphatic substituent such as n-
butyl or cyclohexyl groups was negligible under the same condi-
tions. In the reaction of such less reactive substrates as 1b,c, the
addition of AgOTf (5 mol %), which leads to the generation of
a more reactive cationic Pd species, was effective. In these cases,
indole products 2b,c were obtained in good yields (84%, 72%),
while a decrease in the enantioselectivity was observed in com-
parison with that of 2a (29%ee, Entries 2 and 3). On the other hand,
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Y. Morimoto et al. / Tetrahedron xxx (2015) 1e9
3
Table 2
The ortho-substituent’s effect on enantioselectivity
Entry
1 or 3
R
2 or 4
Time (h)
Yield (%)a
ee (%)b
1
2
3
4
5
1a
3a
3b
3c
3d
t-Bu
CF3
i-Pr
Ph
2a
4a
4b
4c
4d
4
4
2
12
4
94
99
97
87
90
60
56
45
29
0
OMe
a
Fig. 2. The origin of increased enantioselectivity due to an ortho-substituent.
Isolated yield.
b
The ee was determined by HPLC analysis using a chiral column.
along the electron-withdrawing character of para-substituent. In
contrast, the reaction rate decreased as the electron-withdrawing
character of para-substituent increased (the reaction of 1j pos-
sessing a para-nitro group was negligible in the absence of AgOTf).
Table 3
Catalytic enantioselective 5-exo-aminocyclization with various aniline substrates
Table 4
The effect of para-substituents X on enantioselectivity
Entry
1
R
2
Time (h)
Yield (%)a
ee (%)b
1
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
n-C4H9
2a
2b
2c
2d
2e
2f
2g
2h
2i
4
24
38
9
93
84
72
95
71
90
67
85
90
60
29
29
67
77
80
82
83
83
2c
3c
4
Cyclohexyl
2-MeC6H4
2-MMOCH2C6H4
2-i-PrC6H4
2-NO2C6H4
2-ClC6H4
d
5
7
6
12
24
13
23
Entry
1
X
2
Time (h)
Yield (%)a
ee (%)b
7c
8
1c
2
3
4
5
1j
NO2
Cl
H
Me
OMe
2j
17
8
4
4
3
83
97
93
89
89
79
70
60
49
18
9
2-BrC6H4
1k
1a
1l
2k
2a
2l
a
Isolated yield.
b
c
The ee was determined by HPLC analysis using a chiral column.
5 mol % of AgOTf was added.
MMO¼methoxymethoxy.
1m
2m
d
a
Isolated yield.
b
c
The ee was determined by HPLC analysis using a chiral column.
5 mol % of AgOTf was added.
the reactions of alkynyl anilines 1dei with ortho-substituted
phenyl groups increased in enantioselectivity (67%ee to 83% ee,
Entries 4e9). In particular, the reactions of 1fei possessing bulkier
ortho-substituents such as iso-propyl, NO2, Cl and Br groups gave
the indole products 2fei with relatively good enantioselectivity
(80% ee to 83% ee, Entries 6e9). For the less reactive ortho-nitro
derivative 1g, the addition of AgOTf was required to get product 2g
(Entry 7).
The increased enantioselectivity with an ortho-substituent may
be due to chiral relay through the dynamic axial chirality formed
around the CalkynyleCphenyl bond (Fig. 2).9 That is, in the present
reaction, the construction of NeC axial chirality should occur in the
NeC bond forming step. In this step, direct enantiocontrol by the
chiral ligand on the Pd atom should be difficult because the chiral
ligand is relatively far way from the newly formed NeC axially
chiral structure. In the reaction of substrates having a bulky ortho-
substituent, chiral information of (R)-SEGPHOS may be effectively
transferred to the NeC chiral bond via the dynamic axial chirality
generated by twisting around the CalkynyleCphenyl bond.
To evaluate the effect of the para-substituents in Table 4, an
analysis was performed using a Hammett plot.10 As shown in Fig. 3,
relatively good linear relationships were observed between Ham-
mett s-values and enantioselectivities [log(major enantiomer/mi-
nor enantiomer)] for substrates 1a, 1jel except for para-methoxy
derivative 1m (R2¼0.95). In addition, the obtained positive reaction
constant (
r
-value¼þ0.48) may suggest that the enantioselectivity-
determining step involves the nucleophilic attack of an aniline ni-
trogen on an electrophilic Pd-alkyne complex.10 Only para-
methoxy derivative 1m departed significantly from the Hammett
straight line, and this may be due to the positive resonance effect of
the para-methoxy group.
In substrates 1a, 1jel, the incomplete twisting of the aryl group
on the alkyne may lead to dynamic axial chirality such as that of the
ortho-substituted phenyl derivatives shown in Fig. 2 (1J in Fig. 4).
Thus chiral information of (R)-SEGPHOS is effectively transferred to
the NeC chiral bond via chiral relay of this dynamic axial chirality.
As a result, in several substrates possessing a para-substituted
phenyl group, relatively good enantioselectivity was observed.
However, with para-methoxy derivative 1m, dynamic axial chiral-
ity could not be generated because of the formation of allenyl in-
termediate 1M due to the positive resonance effect of the para-
The enantioselectivity was also remarkably dependent on the
electron density on the arylethynyl group (Table 4). When reactions
of alkynylanilines 1jem possessing several para-substituted phenyl
groups (X¼NO2, Cl, Me, OMe) were performed under the same
conditions, the ee varied significantly (18%ee to 79% ee) increasing
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Y. Morimoto et al. / Tetrahedron xxx (2015) 1e9
propose the reaction mechanism in Fig. 5. That is, Pd-aniline
complex 1-A is formed initially, and then 1-A is converted to
alkyne-Pd complex 1-B to give indole intermediate 1-C through
subsequent 5-exo-cyclization. The conversion to 1-B from 1-A
proceeds slowly in comparison with 5-exo-cyclization, and
a strong protic acid such as p-TsOH may promote the conversion to
1-B through the protonation of an aniline nitrogen to accelerate the
reaction (Fig. 6).
Fig. 3. Hammett plot of enantioselectivity in 1j, k, a, l, m.
Fig. 5. A possible mechanism for enantioselective 5-exo-aminocyclization.
Fig. 4. A possible structure for the enantioselectivity determining step.
methoxy group (Fig. 4). Such an allene-like intermediate that al-
lows complete twisting structure may result in a significant de-
crease in enantioselectivity.
In the present reaction, we found that the addition of a protic
acid increased the reaction rate. When the reaction of 1a with (R)-
SEGPHOS-PdCl2 catalyst was performed for 4 h at 40 ꢀC, the
chemical yield (34%) of 2a decreased significantly in comparison
with that (93%) at 80 ꢀC, allowing recovery of 60% of starting ma-
terial 1a (Table 5, entry 1). However, under the same conditions, the
addition of 1 equiv of p-toluene sulfonic acid (p-TsOH) led to a re-
markable increase in the yield (95%, entry 2). In the presence of
0.3 equiv of p-TsOH, the product 2a was also obtained in good yield
(86%, entry 3), while neither trifluoroacetic acid nor acetic acid
accelerated the reaction (entries 4 and 5).
The acceleration of the reaction rate by p-TsOH indicates that
the nucleophilic 5-exo-cyclization step, which determines the
enantioselectivity, is not the rate-limiting step. On this basis, we
Fig. 6. A possible mechanism for the additive effect of p-TsOH.
Table 5
Effect of protic acid on the reaction of 1a
Another possibility is that the generation of an indole product 2
from an indole-Pd intermediate 1-C may be the rate-limiting step,
in which case p-TsOH would lead to an increase in the reaction rate
by promoting the protonation of 1-C (Fig. 5).11,12
As mentioned above, the present reaction did not efficiently
proceed in an aprotic solvent. For example, the reaction of 1a in THF
gave 2a in a poor yield (12%, Scheme 3). On the other hand, when the
reaction in THF was performed in the presence of 1 equiv of p-TsOH,
the indole product 2a was obtained in a quantitative yield (99%).12
Furthermore, in comparison with the reaction in EtOH (Table 3,
Entry 1, 60% ee), slight increase in the enantioselectivity was ob-
served (73% ee). In the reaction with 1i bearing ortho-bromophenyl
Entry
Protic acid
Yield (%)a
ee (%)b
1
2
3
4
5
None
34
95
86
34
16
56
60
59
58
55
p-TsOH (1 equiv)
p-TsOH (0.3 equiv)
CF3COOH (1 equiv)
CH3COOH (1 equiv)
a
Isolated yield.
b
The ee was determined by HPLC analysis using a chiral column.
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Y. Morimoto et al. / Tetrahedron xxx (2015) 1e9
5
Scheme 3. The effect of p-TsOH and solvent on the reaction of 1.
Fig. 7. X-ray crystal structure of 5g0.
group, the enantioselectivity (86% ee) also slightly increased in
comparison with that in EtOH (Table 3, Entry 9, 83% ee).
3. Conclusion
The absolute stereochemistries of major enantiomers in several
indole products 2a, 2g, 2i, 2j were determined in accordance with
Scheme 4. The reduction of the nitro group in 2g (82%ee) and
subsequent condensation with (S)-acetoxypropionyl chloride gave
diasteromeric amides 5g and 5g0. By MPLC separation of 5g and 5g0
followed by X-ray crystal analysis of the minor diastereomer 5g0
(Fig. 7),13 the major enantiomer in 2g obtained by the use of (R)-
We performed the enantioselective synthesis of NeC axially
chiral indole derivatives through (R)-SEGPHOS-PdCl2-catalyzed 5-
endo-hydroaminocyclization of achiral ortho-alkynyl anilines pos-
sessing an N-(ortho-tert-butyl)phenyl group (up to 83% ee). The
enantioselectivity depended remarkably on the bulkiness of ortho-
substituents and the electron density on an arylethynyl group,
which can be explained as chiral relay due to the dynamic axial
chirality generated by the twisting of an aryl substituent. The
present reaction is the first asymmetric application in indole syn-
thesis of the 5-endo-hydroaminocyclization of ortho-alkynylaniline
as well as the first example of a catalytic enantioselective synthesis
of non-amide NeC axially chiral compounds.
SEGPHOS was determined to be (S)-configuration bearing a b-facial
t-Bu group. The major enantiomers in three other indole products
2a, 2i, 2j were also confirmed to have the same configurations
through the conversion shown in Scheme 4.
4. Experimental section
4.1. General techniques
Melting points were uncorrected. 1H and 13C NMR spectra were
recorded on a 300 MHz spectrometer. In 1H and 13C NMR spectra,
chemical shifts were expressed in
d (ppm) downfield from CHCl3
(7.26 ppm) and CDCl3 (77.0 ppm), respectively. Mass spectra were
recorded by electrospray ionization (TOF). Column chromatography
was performed on silica gel (75e150 mm). Medium-pressure liquid
chromatography (MPLC) was performed on a 25ꢁ4 cm i.d. pre-
packed column (silica gel, 10
mm) with a UV detector. High-
performance liquid chromatography (HPLC) was performed on
a 25ꢁ0.4 cm i.d. chiral column with a UV detector.
4.2. Synthesis of hydroaminocyclization precursors
Precursors 1a, 1b, 1d, 1e, 1f, 1g, 1h, 1i, 1l were prepared in ac-
cordance with the procedure described in preliminary communi-
cation.5 Other precursors 1c, 1j, 1k, 1m, 3ae3d were prepared as
follows.
4.2.1. 2-tert-Butyl-N-(2-(cyclohexylethynyl)phenyl)aniline (1c). To
a solution of (Ph3P)2PdCl2 (42 mg, 0.06 mmol) and CuI (24 mg,
0.1 mmol) in Et3N (4 mL) were added 2-bromo-iodobenzene
(0.38 mL, 3.0 mmol) and ethynylcyclohexane (0.39 mL, 3.0 mmol)
at rt. After being stirred for 23 h at rt, the mixture was poured into
saturated NH4Cl aq and extracted with AcOEt. The AcOEt extracts
were washed with brine, dried over MgSO4, and evaporated to
dryness. Purification of the residue by column chromatography
(hexane only) gave 1-bromo-2-(cyclohexylethynyl)benzene
(777 mg, 98%). To a solution of Pd(OAc)2 (27 mg, 0.12 mmol) and (o-
tol)3P (71 mg, 0.23 mmol), t-BuONa (421 mg, 4.4 mmol) in toluene
(10 mL) were added 1-bromo-2-(cyclohexylethynyl)benzene
Scheme 4. Stereochemical assignment of several indole products 2a, 2g, 2i, 2j.
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6
Y. Morimoto et al. / Tetrahedron xxx (2015) 1e9
(769 mg, 2.9 mmol) and 2-tert-butylaniline (0.46 mL, 2.9 mmol) at
rt. After being stirred for 13 h at 100 ꢀC, the mixture was poured
into saturated NaHCO3 aq and extracted with AcOEt. The AcOEt
extracts were washed with brine, dried over Na2SO4, and evapo-
rated to dryness. Purification of the residue by column chroma-
tography (hexane only) gave 1c (534 mg, 55%). 1c: yellow oil; IR
(0.65 mL, 5.0 mmol) in accordance with the procedure for the
synthesis of 1c (296 mg, 17%). 1m: colorless oil; IR (neat) 3421,
2361 cmꢂ1 1H NMR (CDCl3)
; d: 7.42e7.47 (4H, m), 7.37 (1H, dd,
J¼1.4, 7.8 Hz), 7.22 (1H, dt, J¼1.4, 7.3 Hz), 7.09e7.14 (2H, m), 6.87
(2H, d, J¼8.7 Hz), 6.83 (1H, d, J¼8.2 Hz), 6.72 (1H, dt, J¼0.9, 7.3 Hz),
6.51 (1H, br s), 3.83 (3H, s), 1.45 (9H, s); 13C NMR (CDCl3)
d: 159.6,
(neat) 3420 cmꢂ1; 1H NMR (CDCl3)
d
: 7.45 (1H, dd, J¼1.4 and 7.8 Hz),
146.8,144.3,139.8,132.8,132.1,129.3,127.2,126.8,124.6,117.7,115.2,
114.1, 111.9, 109.0, 95.2, 84.8, 55.3, 34.9, 30.6; MS (m/z) 355 (Mþ);
Anal. Calcd for C25H25NO: C, 84.47; H, 7.09; N, 3.94. Found: C, 84.61;
H, 6.99; N, 3.91.
7.32e7.36 (2H, m), 7.20 (1H, dt, J¼1.4, 7.3 Hz), 7.11 (1H, dt, J¼1.4,
7.3 Hz), 7.05 (1H, dt, J¼1.4, 8.2 Hz), 6.75 (1H, d, J¼8.2 Hz), 6.66 (1H,
dt, J¼0.9, 7.3 Hz), 6.36 (1H, br s), 2.64 (1H, m), 1.89e1.92 (2H, m),
1.72e1.79 (2H, m), 1.26e1.59 (6H, m), 1.43 (9H, s); 13C NMR (CDCl3)
d
: 146.8, 144.5, 140.0, 132.1, 128.7, 127.14, 127.11, 126.8, 124.6, 117.5,
4.2.5. 2-Trifluoromethyl-N-(2-(phenylethynyl)phenyl)aniline
(3a). To a solution of Pd(OAc)2 (11 mg, 0.05 mmol) and rac-BINAP
(50 mg, 0.08 mmol), Cs2CO3 (456 mg, 1.4 mmol) in toluene (6 mL)
were added 1-bromo-2-(phenylethynyl)benzene5 (257 mg,
1.0 mmol) and 2-trifluoromethylaniline (193 mg, 1.2 mmol) at rt.
After being stirred for 2 h at 100 ꢀC, the mixture was poured into
saturated NaHCO3 aq and extracted with AcOEt. The AcOEt extracts
were washed with brine, dried over Na2SO4, and evaporated to
dryness. Purification of the residue by column chromatography
(hexane only) gave 3a (297 mg, 88%). 3a: colorless oil; IR (ATR)
111.7, 109.5, 100.3, 77.1, 34.9, 33.0, 30.7, 30.0, 25.9, 25.0; MS (m/z)
331 (Mþ); Anal. Calcd for C24H29N: C, 86.96; H, 8.82; N, 4.23. Found:
C, 86.83; H, 8.60; N, 4.19.
4.2.2. 2-tert-Butyl-N-(2-(4-chlorophenyl)ethynyl)phenyl)aniline
(1k). To a solution of Pd(OAc)2 (26.9 mg, 0.12 mmol) and (o-tol)3P
(73.0 mg, 0.24 mmol), t-BuONa (0.43 g, 4.50 mmol) in toluene
(10 mL) were added 1-bromo-2-trimethylsilylethynylbenzene5
(0.76 g, 3.0 mmol) and 2-tert-butylaniline (0.47 mL, 3.0 mmol) at
rt. After being stirred for 4 h at 100 ꢀC, the mixture was poured into
saturated NaHCO3 aq and extracted with AcOEt. The AcOEt extracts
were washed with brine, dried over Na2SO4, and evaporated to
dryness. Purification of the residue by column chromatography
(hexane only) gave 2-tert-butyl-N-(2-(trimethylsilylethynyl)phe-
nyl)aniline (510 mg, 53%). To a solution of 2-tert-butyl-N-(2-(tri-
methylsilylethynyl)phenyl)aniline (940 mg, 2.92 mmol) in CH2Cl2
(1 mL) and CH3OH (2 mL) was added K2CO3 (525 mg, 3.80 mmol).
After being stirred for 3 h at rt, the mixture was poured into water
and extracted with haxane. The hexane extracts were washed with
brine, dried over Na2SO4, and evaporated to dryness. Purification of
the residue by column chromatography (hexane only) gave 2-tert-
butyl-N-(2-(ethynyl)phenyl)aniline (649 mg, 89%). To a solution of
(Ph3P)2PdCl2 (32 mg, 0.04 mmol) and CuI (17 mg, 0.09 mmol) in
Et3N (2.0 mL) were added 1-chloro-4-iodobenzene (542 mg,
2.27 mmol) and 2-tert-butyl-N-(2-(ethynyl)phenyl)aniline (567 mg,
2.27 mmol) in Et3N (2.0 mL) at rt. After being stirred for 6 h at rt, the
mixture was poured into saturated NH4Cl aq and extracted with
AcOEt. The AcOEt extracts were washed with brine, dried over
Na2SO4, and evaporated to dryness. Purification of the residue by
column chromatography (hexane only) gave 1k (761 mg, 93%). 1k:
3410, 2210 cmꢂ1
;
1H NMR (CDCl3)
d
: 7.67 (1H, d, J¼7.8 Hz),
7.56e7.61 (4H, m), 7.48 (1H, t, J¼7.8 Hz), 7.34e7.41 (4H, m), 7.29
(1H, dt, J¼2.3, 6.9 Hz), 7.06e7.10 (2H, m), 6.97 (1H, t, J¼7.8 Hz); 13
C
NMR (CDCl3) d: 143.2, 140.4, 132.63, 132.59, 131.4, 129.3, 128.5,
128.4, 127.0 (q, JCeF¼5.8 Hz), 124.6, (q, JCeF¼273.2 Hz), 122.7, 121.2,
120.7, 119.4, 119.3 (q, JCeF¼28.8 Hz), 115.1, 112.2, 96.2, 84.9; 19F NMR
(CDCl3)
d
: ꢂ62.1; MS (m/z) 360 (MNaþ); Anal. Calcd for C21H14F3N:
C, 74.77; H, 4.18; N, 4.15. Found: C, 74.84; H, 4.40; N, 4.34.
4.2.6. 2-iso-Propyl-N-(2-(phenylethynyl)phenyl)aniline (3b). 3b was
prepared from 1-bromo-2-(phenylethynyl)benzene5 (722 mg,
2.8 mmol) and 2-iso-propylaniline (380 mg, 2.8 mmol) in accor-
dance with the procedure for the synthesis of 1c (529 mg, 61%). 3b:
white solid; mp 70e72 ꢀC, IR (ATR) 3398, 2208 cmꢂ1 1H NMR
;
(CDCl3)
d
: 7.58e7.61 (2H, m), 7.55 (1H, dd, J¼1.4, 7.3 Hz), 7.39e7.46
(5H, m), 7.27 (1H, dt, J¼1.8, 7.3 Hz), 7.22 (2H, dt, J¼1.4, 7.3 Hz), 6.98
(1H, d, J¼8.2 Hz), 6.84 (1H, dt, J¼0.9, 7.3 Hz), 6.47 (1H, br s), 3.32
(1H, sep, J¼6.9 Hz), 1.33 (6H, d, J¼6.9 Hz); 13C NMR (CDCl3)
d: 146.5,
142.1, 138.3, 132.3, 131.4, 129.6, 128.4, 128.3, 126.4, 126.3, 124.6,
123.6, 123.0, 118.2, 112.4, 108.9, 95.4, 85.8, 27.9, 23.1; MS (m/z) 334
(MNaþ); Anal. Calcd for C23H21N: C, 88.71; H, 6.80; N, 4.50. Found:
C, 88.45; H, 6.73; N, 4.53.
yellow oil; IR (neat) 3425, 2206 cmꢂ1; 1H NMR (CDCl3)
d: 7.40e7.47
(4H, m), 7.36 (1H, dd, J¼1.4, 7.8 Hz), 7.30e7.33 (2H, m), 7.22 (1H, dt,
J¼1.4, 7.3 Hz), 7.11e7.16 (2H, m), 6.82 (1H, d, J¼8.7 Hz), 6.73 (1H, dt,
4.2.7. 2-Phenyl-N-(2-(phenylethynyl)phenyl)aniline (3c). 3c was
prepared from 1-bromo-2-(phenylethynyl)benzene5 (257 mg,
1.0 mmol) and 2-phenylaniline (169 mg, 1.0 mmol) in accordance
with the procedure for the synthesis of 1c (264 mg, 76%). 3c: white
J¼0.9, 7.6 Hz), 6.45 (1H, br s), 1.44 (9H, s); 13C NMR (CDCl3)
d: 147.1,
144.4, 139.6, 134.3, 132.5, 132.3, 129.9, 128.8, 127.2, 126.93, 126.88,
124.9, 121.6, 117.8, 112.1, 108.2, 94.0, 87.3, 34.9, 30.6; MS (m/z) 359
(Mþ, 35Cl); Anal. Calcd for C24H22ClN: C, 80.10; H, 6.16; N, 3.89.
Found: C, 80.24; H, 6.26; N, 3.86.
solid; mp 113e115 ꢀC, IR (ATR) 3379, 2203 cmꢂ1; 1H NMR (CDCl3)
d:
7.58 (1H, dd, J¼0.9, 8.7 Hz), 7.43e7.50 (4H, m), 7.23e7.38 (9H, m),
7.13 (2H, dd, J¼1.4, 7.8 Hz), 7.09 (1H, dt, J¼0.9, 7.3 Hz), 6.84 (1H, dt,
4.2.3. 2-tert-Butyl-N-(2-(4-nitrophenyl)ethynyl)phenyl)aniline
(1j). 1j was prepared from 1-iodo-4-nitrobenzene (499 mg,
2.0 mmol) and 2-tert-butyl-N-(2-(ethynyl)phenyl)aniline (500 mg,
2.0 mmol) in accordance with the procedure for the synthesis of 1k
(622 mg, 84%). 1j: yellow solid; mp 143e144 ꢀC; IR (neat) 3377,
J¼1.4, 7.3 Hz), 6.69 (1H, s); 13C NMR (CDCl3)
d: 144.3, 138.7, 138.6,
132.6, 132.3, 131.3, 131.0, 129.35, 129.32, 128.8, 128.2, 128.1, 127.5,
122.8, 122.0, 119.3, 118.4, 113.5, 110.7, 95.7, 85.3; MS (m/z) 368
(MNaþ); Anal. Calcd for C26H19N: C, 90.40; H, 5.54; N, 4.05. Found:
C, 90.32; H, 5.61; N, 4.10.
2177 cmꢂ1
;
1H NMR (CDCl3)
d
: 8.21 (2H, d, J¼8.7 Hz), 7.61 (2H, d,
J¼8.7 Hz), 7.46e7.49 (2H, m), 7.35 (1H, dd, J¼0.9, 7.8 Hz), 7.14e7.26
4.2.8. 2-Methoxy-N-(2-(phenylethynyl)phenyl)aniline (3d). 3d was
prepared from 1-bromo-2-(phenylethynyl)benzene5 (771 mg,
3.0 mmol) and 2-methoxyaniline (369 mg, 3.0 mmol) in accordance
with the procedure for the synthesis of 3a (165 mg, 28%). 3d: yellow
(3H, m), 6.82 (1H, d, J¼8.2 Hz), 6.75 (1H, dt, J¼0.9, 7.3 Hz), 6.42 (1H,
br s), 1.45 (9H, s); 13C NMR (CDCl3)
d: 147.5, 146.9, 144.5, 139.3, 132.7,
131.8, 130.8, 130.1, 127.3, 127.1, 127.0, 125.2, 123.8, 118.0, 112.3, 107.2,
93.5, 92.0, 34.9, 30.6; MS (m/z) 370 (Mþ); Anal. Calcd for C24H22N2O2:
C, 77.81; H, 5.99; N, 7.56. Found: C, 77.53; H, 5.98; N, 7.53.
oil; IR (ATR) 3386, 2204 cmꢂ1 1H NMR (CDCl3)
; d: 7.53e7.58 (2H,
m), 7.49 (1H, dd, J¼1.8, 7.8 Hz), 7.44e7.47 (1H, m), 7.41 (1H, d,
J¼7.3 Hz), 7.34e7.40 (3H, m), 7.25 (1H, dt, J¼1.4, 8.2 Hz), 7.08 (1H, br
s), 6.92e6.96 (3H, m), 6.85 (1H, dt, J¼0.9, 7.3 Hz), 3.91 (3H, s); 13C
4.2.4. 2-tert-Butyl-N-(2-(4-methoxyphenyl)ethynyl)phenyl)aniline
(1m). 1m was prepared from 1-ethynyl-4-methoxybenzene
NMR (CDCl3) d: 149.2, 144.1, 132.4, 131.5, 131.4, 129.4, 128.4, 128.2,
Please cite this article in press as: Morimoto, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.001

Y. Morimoto et al. / Tetrahedron xxx (2015) 1e9
7
123.3, 121.1, 120.7, 119.3, 116.3, 114.0, 111.1, 110.8, 95.7, 85.9, 55.7; MS
(m/z) 322 (MNaþ); HRMS. Calcd for C21H17NONa (MNaþ) 322.1208.
Found: 322.1214.
7.3 Hz), 7.13e7.23 (7H, m), 6.83e6.87 (1H, m), 6.85 (1H, s), 0.92
(9H, s); 13C NMR (CDCl3)
: 148.6, 141.1, 140.1, 135.5, 133.2, 132.5,
d
131.6, 130.1, 129.3, 129.1, 128.5, 127.5, 126.9, 122.3, 120.34, 120.28,
111.6, 102.7, 36.0, 31.4; MS (m/z) 359 (Mþ, 35Cl); Anal. Calcd for
4.3. Synthesis of axially chiral indoles
C24H22ClN: C, 80.10; H, 6.16; N, 3.89. Found: C, 80.00; H, 6.17; N,
3.88.
Indoles 2a, 2b, 2d, 2e, 2f, 2g, 2h, 2i, 2l were prepared in accor-
dance with the procedure described in preliminary communica-
tion.5 Other indoles 2c, 2j, 2k, 2m, 4ae4d were prepared as follows.
4.3.4. 1-(2-tert-Butylphenyl)-2-(4-methoxyphenyl)-1H-indole
(2m). 2m was prepared from 1j (118 mg, 0.3 mmol) in accordance
with the procedure for the synthesis of 2k (80 ꢀC, 3 h). Purification
of the residue by column chromatography (hexane only) gave 2m
(106 mg, 89%). The ee (18%ee) of 2j was determined by HPLC
analysis using a CHIRALCEL OD-H column [25 cmꢁ0.46 cm i.d.; 7.0%
i-PrOH in hexane; flow rate, 0.8 mL/min; (ꢂ)-2m (major);
tR¼10.9 min, (þ)-2m (minor); tR¼11.9 min]. 2m (18%ee): pale yel-
4.3.1. 1-(2-tert-Butylphenyl)-2-cyclohexyl-1H-indole (2c). A solu-
tion of PdCl2 (2.6 mg, 0.015 mmol) and (R)-SEGPHOS (12.4 mg,
0.020 mmol) in EtOH (1 mL) was stirred for 10 min at rt, and then
AgOTf (3.7 mg, 0.014 mmol) was added to the reaction mixture.
After being stirred for 20 min at 80 ꢀC, 1c (96.2 mg, 0.29 mmol) in
EtOH (2 mL) was added, and the mixture was stirred for 38 h at
80 ꢀC. EtOH solvent was evaporated to dryness. Purification of the
residue by column chromatography (hexane only) and sub-
sequently MPLC (hexane only) gave 2c (70.4 mg, 73%). The ee (29%
ee) of 2c was determined by HPLC analysis using a CHIRALCEL OD-3
column [25 cmꢁ0.46 cm i.d.; 1.0% i-PrOH in hexane; flow rate,
0.4 mL/min; (þ)-2c (major); tR¼8.9 min, (ꢂ)-2c (minor);
low solid; mp 114e115 ꢀC, [
2966 cmꢂ1; H NMR (CDCl3)
a
]
D
ꢂ12.4 (c 0.52, CHCl3); IR (KBr)
d
: 7.61e7.66 (2H, m), 7.45 (1H, dt, J¼0.9,
7.3 Hz), 7.30 (1H, dt, J¼0.9, 7.6 Hz), 7.22 (2H, d, J¼8.5 Hz), 7.19 (1H,
dd, J¼1.4, 7.8 Hz), 7.10e7.15 (2H, m), 6.76e6.85 (2H, m), 6.75 (2H, d,
J¼8.5 Hz), 3.76 (3H, s), 0.94 (9H, s); 13C NMR (CDCl3)
d: 158.9, 148.6,
141.4,140.8,135.8, 132.7,130.0,129.5,128.9,127.8,126.7,125.7,121.7,
120.01,119.97,113.7,111.4,101.4, 55.2, 36.0, 31.4; MS (m/z) 355 (Mþ);
Anal. Calcd for C25H25NO: C, 84.47; H, 7.09; N, 3.94. Found: C, 84.73;
H, 6.95; N, 3.93.
tR¼9.8 min]. 2c (29%ee): pale yellow solid; mp 113e114 ꢀC, [
a]
D
þ2.7 (c 0.51, CHCl3); IR (KBr) 2930 cmꢂ1
; d: 7.68
1H NMR (CDCl3)
(1H, dd, J¼1.4, 8.2 Hz), 7.57 (1H, dd, J¼1.4, 6.8 Hz), 7.45 (1H, dt,
J¼1.4, 7.6 Hz), 7.27 (1H, dt, J¼1.4, 7.8 Hz), 6.99e7.08 (3H, m), 6.74
(1H, dd, J¼1.4, 8.0 Hz), 6.39 (1H, s), 2.24 (1H, tt, J¼3.2, 11.9 Hz), 1.99
(1H, d, J¼13.3 Hz), 1.83 (2H, dd, J¼1.4, 11.0 Hz), 1.61e1.73 (3H, m),
1.15e1.29 (3H, m), 1.08 (9H, s), 0.97e1.05 (1H, m); 13C NMR (CDCl3)
4.3.5. 1-(2-Trifluoromethylphenyl)-2-phenyl-1H-indole (4a). 4a was
prepared from 3a (97 mg, 0.29 mmol) in accordance with the
procedure for the synthesis of 2k (80 ꢀC, 4 h, heating). Purification
of the residue by column chromatography (hexane only) gave 4a
(96 mg, 99%). The ee (56% ee) of 4a was determined by HPLC
analysis using a CHIRALCEL OD-3 column [25 cmꢁ0.46 cm i.d.; 0.5%
i-PrOH in hexane; flow rate, 1.0 mL/min; (ꢂ)-4a (major);
tR¼8.9 min, (þ)-4a (minor); tR¼13.1 min]. 4a (56% ee): white solid;
d: 149.0, 148.8, 139.1, 135.0, 132.5, 129.3, 128.9, 128.1, 126.7, 120.7,
119.6, 119.4, 111.2, 97.6, 36.4, 36.1, 35.8, 32.0, 31.6, 26.7, 26.4, 26.0;
MS (m/z) 331 (Mþ); Anal. Calcd for C24H29N: C, 86.96; H, 8.82; N,
4.23. Found: C, 86.66; H, 8.62; N, 4.18.
mp 111e113 ꢀC, [
NMR (CDCl3)
a
]
D ꢂ32.6 (c 0.40, CHCl3); IR (ATR) 3059 cmꢂ1; 1H
4.3.2. 1-(2-tert-Butylphenyl)-2-(4-nitrophenyl)-1H-indole
(2j). 2j
d
: 7.83 (1H, dd, J¼1.4, 7.8 Hz), 7.69 (1H, dd, J¼1.4,
was prepared from 1j (110 mg, 0.3 mmol) in accordance with the
procedure for the synthesis of 2c (80 ꢀC, 4 h, heating). Purification
of the residue by column chromatography (hexane/AcOEt¼50) and
subsequently MPLC (hexane/AcOEt¼150) gave 2j (91 mg, 83%). The
ee (79% ee) of 2j was determined by HPLC analysis using a CHIR-
ALCEL OD-3 column [25 cmꢁ0.46 cm i.d.; 1.0% i-PrOH in hexane;
flow rate, 1.0 mL/min; (ꢂ)-2j (major); tR¼7.8 min, (þ)-2j (minor);
6.8 Hz), 7.65 (1H, dt, J¼1.4, 7.3 Hz), 7.59 (1H, t, J¼7.3 Hz), 7.37 (1H, d,
J¼7.8 Hz), 7.27e7.30 (2H, m), 7.20e7.25 (3H, m), 7.13e7.19 (2H, m),
6.89 (1H, d, J¼7.8 Hz), 6.87 (1H, s); 13C NMR (CDCl3)
d: 141.8, 140.6,
136.8,132.9,132.5,132.3,129.5 (q, JCeF¼30.7 Hz),129.0,128.4,128.2,
128.1, 127.7 (q, JCeF¼5.8 Hz), 127.4, 122.9 (q, JCeF¼274.1 Hz), 122.3,
120.7, 120.4, 110.9, 103.7; 19F NMR (CDCl3)
d: ꢂ61.1; MS (m/z) 360
(MNaþ); Anal. Calcd for C21H14F3N: C, 74.77; H, 4.18; N, 4.15. Found:
C, 74.69; H, 4.45; N, 4.20.
tR¼15.8 min]. 2j (79% ee): yellow solid; mp 97e98 ꢀC, [
a
]
D ꢂ130.3 (c
0.59, CHCl3); IR (KBr) 2966 cmꢂ1 1H NMR (CDCl3)
; d: 8.05 (2H, d,
J¼9.2 Hz), 7.70 (1H, dd, J¼1.4, 8.0 Hz), 7.67 (1H, dd, J¼1.4, 8.2 Hz),
7.50 (1H, dt, J¼1.4, 7.3 Hz), 7.42 (2H, d, J¼9.2 Hz), 7.34 (1H, dt, J¼1.4,
7.3 Hz), 7.15e7.22 (3H, m), 7.06 (1H, d, J¼0.9 Hz), 6.88 (1H, dd, J¼1.4,
4.3.6. 1-(2-iso-Propylphenyl)-2-phenyl-1H-indole (4b). 4b was pre-
pared from 3b (93 mg, 0.3 mmol) in accordance with the pro-
cedure for the synthesis of 2k (80 ꢀC, 2 h, heating). Purification of
the residue by column chromatography (hexane only) gave 4b
(91 mg, 97%). The ee (45% ee) of 4b was determined by HPLC
analysis using a CHIRALCEL OD-3 column [25 cmꢁ0.46 cm i.d.;
hexane only; flow rate, 2.0 mL/min; (þ)-4b (minor); tR¼10.2 min,
7.3 Hz), 0.93 (9H, s); 13C NMR (CDCl3)
d: 148.5, 146.2, 141.7, 139.4,
138.5, 135.2, 132.3, 130.3, 129.5, 127.9, 127.3, 123.7, 123.5, 120.9,
120.8, 111.8, 105.1, 36.0, 31.4; MS (m/z) 370 (Mþ); Anal. Calcd for
C
24H22N2O2: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.68; H, 6.05; N,
7.31.
(ꢂ)-4b (major); tR¼12.0 min]. 4b (45% ee): yellow oil; [
a
]
D ꢂ29.7 (c
1.46, CHCl3); IR (ATR) 3058 cmꢂ1; 1H NMR (CDCl3)
d
: 7.73 (1H, dd,
4.3.3. 1-(2-tert-Butylphenyl)-2-(4-chlorophenyl)-1H-indole (2k). A
solution of PdCl2 (2.6 mg, 0.015 mmol) and (R)-SEGPHOS (12.4 mg,
0.020 mmol) in EtOH (1 mL) was stirred for 10 min at rt. 1k
(104 mg, 0.29 mmol) in EtOH (2 mL) was added to the mixture, and
the mixture was stirred for 8 h at 80 ꢀC. EtOH solvent was evap-
orated to dryness. Purification of the residue by column chroma-
tography (hexane/AcOEt¼100) gave 2k (102 mg, 97%). The ee (70%
ee) of 2k was determined by HPLC analysis using a CHIRALCEL OD-
3 column [25 cmꢁ0.46 cm i.d.; hexane only; flow rate, 1.0 mL/min;
(ꢂ)-2k (major); tR¼13.3 min, (þ)-2k (minor); tR¼16.3 min]. 2k
J¼1.8, 7.3 Hz), 7.46 (1H, dt, J¼1.4, 7.8 Hz), 7.39 (2H, dt, J¼1.4, 7.3 Hz),
7.31e7.36 (3H, m), 7.21e7.25 (3H, m), 7.15e7.20 (2H, m), 6.99 (1H,
dd, J¼1.8, 6.9 Hz), 6.88 (1H, s), 2.41 (1H, sep, J¼6.9 Hz), 0.92 (3H, d,
J¼6.9 Hz), 0.69 (3H, d, J¼6.9 Hz); 13C NMR (CDCl3)
d: 147.5, 141.4,
139.8, 135.8, 132.5, 129.8, 129.0, 128.5, 128.1, 127.9, 127.3, 127.0,
126.5, 122.1, 120.31, 120.25, 110.8, 102.2, 27.6, 24.8, 22.4; MS (m/z)
334 (MNaþ); HRMS. Calcd for C23H21NNa (MNaþ) 334.1572. Found:
334.1574.
4.3.7. 1-(2-Phenylphenyl)-2-phenyl-1H-indole (4c). 4c was pre-
pared from 3c (104 mg, 0.3 mmol) in accordance with the pro-
cedure for the synthesis of 2k (80 ꢀC, 13 h, heating). Purification of
the residue by column chromatography (hexane only) gave 4c
(70%ee): yellow solid; mp 36e37 ꢀC, [
(KBr) 2970 cmꢂ1 1H NMR (CDCl3)
dd, J¼1.4, 8.2 Hz), 7.46 (1H, dt, J¼0.9, 7.1 Hz), 7.30 (1H, dt, J¼1.4,
a
]
D ꢂ53.9 (c 0.54, CHCl3); IR
;
d: 7.65e7.68 (1H, m), 7.63 (1H,
Please cite this article in press as: Morimoto, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.001

8
Y. Morimoto et al. / Tetrahedron xxx (2015) 1e9
(89 mg, 86%). The ee (29% ee) of 4c was determined by HPLC
analysis using a CHIRALCEL OD-3 column [25 cmꢁ0.46 cm i.d.; 0.5%
i-PrOH in hexane; flow rate, 1.0 mL/min; (ꢂ)-4c (major);
tR¼6.6 min, (þ)-4c (minor); tR¼8.3 min]. 4c (29% ee): yellow solid;
PrOH in hexane; flow rate, 0.5 mL/min; (ꢂ)-1a (major); tR¼9.2 min,
(þ)-1a (minor); tR¼10.2 min].5
Acknowledgements
mp 106e108 ꢀC; [
NMR (CDCl3)
a
]
D ꢂ44.4 (c 0.40, CHCl3); IR (ATR) 3059 cmꢂ1; 1H
d
: 7.70e7.74 (2H, m), 7.59 (1H, dt, J¼1.8, 7.8 Hz), 7.52
This work was partly supported by a Grant-in-Aid for Scientific
Research (C26460014).
(1H, dt, J¼1.4, 7.3 Hz), 7.42 (1H, dd, J¼1.8, 7.8 Hz), 7.38 (1H, m),
7.23e7.28 (2H, m), 7.06e7.18 (4H, m), 6.97 (2H, t, J¼7.8 Hz), 6.81
(2H, d, J¼6.9 Hz), 6.60 (1H, s), 6.42 (2H, d, J¼7.3 Hz); 13C NMR
Supplementary data
(CDCl3) d: 141.1, 140.5, 139.1, 138.2, 135.8, 132.4, 131.3, 129.5, 128.3,
128.20, 128.17, 128.0, 127.8, 127.7, 127.6, 126.8, 122.1, 120.43, 120.39,
110.7, 102.6; MS (m/z) 368 (MNaþ); HRMS. Calcd for C26H19NNa
(MNaþ): 368.1415. Found: 368.1407.
Supplementary data (Copies of 1H NMR and 13C NMR spectra of
all compounds and crystallographic data for compounds 5g0.) re-
lated to this article can be found at http://dx.doi.org/10.1016/
j.tet.2015.05.001.
4.3.8. 1-(2-Mehtoxyphenyl)-2-phenyl-1H-indole (4d). 4d was pre-
pared from 3d (90 mg, 0.3 mmol) in accordance with the pro-
cedure for the synthesis of 2k (80 ꢀC, 3 h, heating). Purification of
the residue by column chromatography (hexane/AcOEt¼300)
gave 4d (89 mg, 99%). The ee (0% ee) of 4d was determined by
HPLC analysis using a CHIRALPAK AD-H column [25 cmꢁ0.46 cm
i.d.; 1.0% i-PrOH in hexane; flow rate, 1.0 mL/min; 4d; tR¼9.2 min,
References and notes
1. Typical examples of NeC axially chiral compounds: (a) Bock, L. H.; Adams, R. J.
Am. Chem. Soc. 1931, 53, 374; (b) Kashima, C.; Katoh, A. J. Chem. Soc. Perkin Trans.
€
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Eur. J. Med. Chem. Chim. Ther. 1984, 19, 381; (d) Roussel, C.; Adjimi, M.; Chemlal,
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H.; Schuster, D.; Mannschreck, A. J. Chem. Perkin Trans. 2 1990, 619; (f) Kawa-
moto, T.; Tomishima, M.; Yoneda, F.; Hayami, J. Tetrahedron Lett. 1992, 33, 3169;
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3131; (h) Dai, X.; Wong, A.; Virgil, S. C. J. Org. Chem. 1998, 63, 2597; (i) Kitagawa,
O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.; Shiro, M. J. Org. Chem. 1998, 63,
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1999, 1295; (k) Hata, T.; Koide, H.; Taniguchi, N.; Uemura, M. Org. Lett. 2000, 2,
1907; (l) Kondo, K.; Iida, T.; Fujita, H.; Suzuki, T.; Yamaguchi, K.; Murakami, Y.
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Mino, T.; Fujita, T.; Katoh, A.; Nishino, T.; Kashima, C. Angew. Chem., Int. Ed. 2003,
42, 4360; (n) Tetrahedron Symposium-in-print on Axially Chiral Amides (Atropi-
somerism); Clayden, J., Ed.Tetrahedron; 2004; 60, p 4325; (o) Tokitoh, T.; Ko-
bayashi, T.; Nakada, E.; Inoue, T.; Yokoshima, S.; Takahashi, H.; Natsugari, H.
Heterocycles 2006, 70, 93; (p) Yilmaz, E. M.; Dogan, I. Tetrahedron: Asymmetry
2008, 19, 2184; (q) Kawabata, T.; Jiang, C.; Hayashi, K.; Tsubaki, K.; Yoshimura, T.;
Majumdar, S.; Sasamori, T.; Tokitoh, N. J. Am. Chem. Soc. 2009, 131, 54; (r) Ayitou,
A. J.; Jesuraj, J. L.; Barooah, N.; Ugrinov, A.; Sivaguru, J. J. Am. Chem. Soc. 2009,
131, 11314; (s) Mino, T.; Komatsu, S.; Wakui, K.; Yamada, H.; Saotome, H.; Sa-
kamoto, M.; Fujita, T. Tetrahedron: Asymmetry 2010, 21, 711; (t) Alkorta, I.; El-
guero, J.; Roussel, C.; Vanthuyne, N.; Piras, P. Adv. Heterocycl. Chem. 2012, 105, 1.
2. Typical examples for catalytic enantioselective synthesis of NeC axially chiral
compounds: (a) Kitagawa, O.; Kohriyama, M.; Taguchi, T. J. Org. Chem. 2002, 67,
8682; (b) Terauchi, J.; Curran, D. P. Tetrahedron: Asymmetry 2003, 14, 587; (c)
Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T. J. Am. Chem. Soc. 2005,
127, 3676; (d) Kitagawa, O.; Yoshikawa, M.; Tanabe, H.; Morita, T.; Takahashi,
M.; Dobashi, Y.; Taguchi, T. J. Am. Chem. Soc. 2006, 128, 12923; (e) Brandes, S.;
Bella, M.; Kjoersgaard, A.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2006, 45, 1147;
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Duan, W.; Imazaki, Y.; Shintani, R.; Hayashi, T. Tetrahedron 2007, 63, 8529; (h)
Oppenheimer, J.; Hsung, R. P.; Figueroa, R.; Johnson, W. L. Org. Lett. 2007, 9,
3969; (i) Tanaka, K.; Takahashi, Y.; Suda, T.; Hirano, M. Synlett 2008, 1724; (j)
Clayden, J.; Turner, H. Tetrahedron Lett. 2009, 50, 3216; (k) Takahashi, M.; Ta-
nabe, H.; Nakamura, T.; Kuribara, D.; Yamazaki, T.; Kitagawa, O. Tetrahedron
2010, 66, 288; (l) Liu, H.; Feng, W.; Kee, C. W.; Leow, D.; Loh, W.-T.; Tan, C.-H.
Adv. Synth. Catal. 2010, 352, 3373; (m) Onodera, G.; Suto, M.; Takeuchi, R. J. Org.
Chem. 2012, 77, 908; (n) Shirakawa, S.; Liu, K.; Maruoka, K. J. Am. Chem. Soc.
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Commun. 2014, 5451; (p) Iorio, N. D.; Righi, P.; Mazzanti, A.; Mancinelli, M.;
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Du, H. Org. Biomol. Chem. 2015, 13, 125; (r) Kamikawa, K.; Arae, S.; Wu, W.-Y.;
Nakamura, C.; Takahashi, T.; Ogasawara, M. Chem.dEur. J. 2015, 21, 4954.
3. For reviews: (a) Takahashi, M.; Kitagawa, O. Yuki Gosei Kagaku Kyokaishi 2011, 69,
985; (b) Takahashi, I.; Suzuki, Y.; Kitagawa, O. Org. Prep. Proced. Int. 2014, 46, 1.
4. Recently we succeeded in catalytic enantioselective synthesis of NeC axially
chiral N-(2-tert-butylphenyl)quinolin-4-ones with non-amide structure Taka-
hashi, I.; Morita, F.; Kusagaya, S.; Fukaya, H.; Kitagawa, O. Tetrahedron: Asym-
metry 2012, 23, 1657 Quick recently Kamikawa, et al. also reported highly
enantioselective catalytic synthesis of axially chiral indoles (see ref. 2r).
5. Preliminary communication Ototake, N.; Morimoto, Y.; Mokuya, A.; Fukaya, H.;
Shida, Y.; Kitagawa, O. Chem.dEur. J. 2010, 16, 6752.
ent-4d; tR¼11.4 min]. 4d: orange oil; IR (ATR) 3060 cmꢂ1
;
1H
NMR (CDCl3)
d
: 7.75 (1H, m), 7.40 (1H, dt, J¼1.4, 8.2 Hz),
7.20e7.37 (8H, m), 7.15 (1H, m), 7.06 (1H, dt, J¼1.4, 7.8 Hz), 7.00
(1H, dd, J¼0.9, 8.2 Hz), 6.87 (1H, s), 3.55 (3H, s); 13C NMR (CDCl3)
d
: 155.4, 141.6, 138.9, 133.1, 130.0, 129.2, 128.2, 128.1, 127.9, 127.2,
127.1, 122.0, 120.8, 120.4, 120.3, 112.3, 110.7, 102.5, 55.3; MS (m/z)
322 (MNaþ); HRMS. Calcd for C21H17NONa (MNaþ) 322.1208.
Found: 322.1207.
4.4. Stereochemical assignment of indole products
2a, 2g, 2i, 2j. 2g and 2i were converted to 5g and 5g0 or 6 in
accordance with the procedure described in preliminary commu-
nication.5 The conversion of 2i and 2j to 2a is as follows.
4.4.1. Conversion of 2i to 2a. To a solution of 2i (105 mg, 0.26 mmol,
84% ee) in THF (2 mL) was added 1.6 M hexane solution of n-BuLi
(0.20 mL) at ꢂ20 ꢀC. After being stirred for 10 minmin at ꢂ20 ꢀC, the
mixture was poured into 2N HCl aq and extracted with AcOEt. The
AcOEt extracts were washed with brine, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt¼100) gave 2a (71 mg, 83%). The 1H
NMR of 2a coincided with that described in preliminary commu-
nication.5 The reaction proceeded without any decrease in the ee.
The ee (84% ee) of 2a was determined by HPLC analysis using
a CHIRALPACK IA column [25 cmꢁ0.46 cm i.d.; 0.5% i-PrOH in
hexane; flow rate, 0.5 mL/min; (ꢂ)-1a (major); tR¼9.2 min, (þ)-1a
(minor); tR¼10.2 min].5
4.4.2. Conversion of 2j to 2a. To a solution of 2j (91 mg, 0.28 mmol,
79% ee) in MeOH and THF (2.5 and 1.5 mL) was added 5% PdeC. The
reaction mixture was stirred for 20 h under H2 atmosphere. After
removal of PdeC by filtration, evaporation of solvent gave amine
(77 mg, 96%). To a solution of amine (77 mg, 0.23 mmol) in THF
(2 mL) were added 0.7 M NaNO2 aq (0.79 mL), H3PO2 (0.12 mL, 2.3
mmo) and Cu2O (2.6 mg, 0.018 mmol) at 0 ꢀC. After being stirred for
23 h at rt, the mixture was poured into Na2CO3 aq and extracted
with AcOEt. The AcOEt extracts were washed with brine, dried over
MgSO4, and evaporated to dryness. Purification of the residue by
column chromatography (hexane/AcOEt¼100) gave 2a (17 mg,
22%). The 1H NMR of 2a coincided with that described in pre-
liminary communication.5 The reaction proceeded without any
decrease in the ee. The ee (79% ee) of 2a was determined by HPLC
analysis using a CHIRALPACK IA column [25 cmꢁ0.46 cm i.d.; 0.5% i-
6. (a) Kamikawa, K.; Kinoshita, S.; Furusyo, M.; Takemoto, S.; Matsuzaka, H.; Ue-
mura, M. J. Org. Chem. 2007, 72, 3394; (b) Mori, A.; Kinoshita, S.; Furusho, M.;
Kamikawa, K. Chem. Commun. 2010, 6846 See also ref.1s.
7. (a) Taylor, E. C.; Katz, A. H.; Salgado-Zamora, H.; McKillop, A. Tetarahedron Lett.
1985, 26, 5963; (b) Sakai, N.; Annaka, K.; Fujita, A.; Sato, A.; Konakahara, T. J.
Org. Chem. 2008, 73, 4160 and references cited therein. For Reviews; (c) Cacchi,
S.; Fabrizi, G. Chem. Rev. 2005, 105, 2873; (d) Humphrey, G. R.; Kuethe, J. T.
Chem. Rev. 2006, 106, 2875.
Please cite this article in press as: Morimoto, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.001

Y. Morimoto et al. / Tetrahedron xxx (2015) 1e9
9
8. (a) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura, T.; Kumo-
bayashi, H. Adv. Synth. Catal. 2001, 343, 264; (b) Sumi, K.; Kumobayashi, K. Top.
Organomet. Chem. 2004, 6, 63.
11. Cacchi et al found that, under acidic CH2Cl2-3N HCl two-phase conditions, the
PdCl2-n-Bu4NCl combination can successfully promote the indole forming re-
action through 5-endo-aminocyclization of ortho-alkynyl anilines. They men-
tioned that the acceleration of the reaction may be due to protolytic cleavage of
the carbon-palladium in the s-palladium-indole intermediate by HCl Cacchi, S.;
Carnicelli, V.; Marinelli, F. J. Organomet. Chem. 1994, 475, 289.
12. The reaction of nitrophenyl derivatives 1g and 1j was not promoted by the
addition of p-TsOH. As mentioned above, in the reactions with 1g and 1j
bearing a strong electron-withdrawing group, the use of cationic palladium
species generated by the addition of AgOTf was required. This result may in-
dicate that the rate limiting step in the present reaction is the formation of
9. Typical examples on chiral relay: (a) Sugg, E. E.; Griffin, J. F.; Portoghese, P. S. J.
Org. Chem. 1985, 50, 5032; (b) Bull, S. D.; Davis, S. G.; Fox, J. D.; Garner, A. C.;
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Lectka, T.; Matt, P. V. J. Am. Chem. Soc. 1999, 121, 7559; (d) Aggarwal, V. K.; Jones,
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hedron: Asymmetry 2001, 12, 695; (g) Quaranta, L.; Corminboeuf, O.; Renaud, P.
Org. Lett. 2002, 4, 39; (h) Corminboeuf, O.; Quaranta, L.; Renaud, P.; Liu, M.;
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10393.
palladium-alkyne complex 1-B rather than protolysis of
intermediate 1-C.
s-palladium-indole
13. The crystal structure of 5g0 was deposited at the Cambridge Crystallographic
Data Center (the deposition number: CCDC 763524). See also Supplementary
data.
Please cite this article in press as: Morimoto, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.05.001