Enantioselective arylative dearomatization of indoles via pd-catalyzed intramolecular reductive heck reactions

Article abstract of DOI:10.1021/jacs.5b01705

A highly enantioselective intramolecular arylative dearomatization of indoles via palladium-catalyzed reductive Heck reactions was developed. The new strategy led to a series of optically active indolines bearing C2-quaternary stereocenters in modest to good yields with excellent enantioselectivities (up to 99% ee).

Full text of DOI:10.1021/jacs.5b01705

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Communication
Enantioselective Arylative Dearomatization of Indoles via
Pd-catalyzed Intramolecular Reductive Heck Reactions
Chong Shen, Ren-Rong Liu, Ren-Jie Fan, Ying-Long Li, Teng-Fei Xu, Jian-Rong Gao, and Yi-Xia Jia
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b01705 • Publication Date (Web): 07 Apr 2015
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Enantioselective Arylative Dearomatization of Indoles via Pd-
catalyzed Intramolecular Reductive Heck Reactions
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Chong Shen, Ren-Rong Liu, Ren-Jie Fan, Ying-Long Li, Teng-Fei Xu, Jian-Rong Gao, and Yi-Xia
Jia*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
Supporting Information Placeholder
biaryl compounds,5 where Heck-type arylation has been pro-
ABSTRACT: A highly enantioselective intramolecular aryla-
tive dearomatization of indoles was developed via palladium-
posed as a possible mechanism.6 We envisaged that new ary-
lative dearomatization reaction might be realized through an
catalyzed reductive Heck reactions. The new strategy led to a
intramolecular reductive Heck reaction,7 if suitable substitu-
series of optically active indolines bearing C2-quaternary
ent was introduced onto the reactive site to prevent biaryl
stereocenters in modest to good yields and excellent enanti-
compound formation, and meanwhile the generated alkyl-
oselectivities (up to 99% ee).
palladium intermediate was trapped by proper hydride
sources. Following this hypothesis, we investigated the in-
tramolecular asymmetric arylative dearomatization of N-
substituted indoles via palladium-catalyzed reductive Heck
reactions (Figure 1).8,9 The new dearomatization strategy
provides a facile approach to chiral indolines bearing C2-
quaternary stereocenters,10 which are frequently occurring
core structures of bioactive natural products, such as trigo-
noliimine C,11 (-)-isatisine A,12 and hinckdentine A.13 Herein,
we wish to present our findings of highly enantioselective
Pd-catalyzed arylative dearomatization of a variety of indole
derivatives.
Enantioselective dearomatization of arenes has emerged as
an important transformation approaching a variety of opti-
cally active alicyclic systems, which constitute key moieties
of bioactive natural products and pharmaceuticals.1 Thanks
to the effort devoted to this field, many elegant catalytic
asymmetric dearomatization (CADA) reactions have been
developed, such as the asymmetric hydrogenation of het-
eroarenes,2 oxidative dearomatizations and alkylative
dearomatizations.1d,e In contrast, asymmetric arylative
dearomatization has met with less success and still remained
a challenging task. Among the few known methods, palladi-
um-catalyzed cross-coupling of two aryl moieties that pio-
neered by the groups of Buchwald, Bedford, and You has
been demonstrated as a reliable approach toward this chal-
lenge.3,4 A few examples have appeared in their enantioselec-
tive versions. In 2009, Buchwald and co-workers developed
an elegant Pd-catalyzed intramolecular enantioselective
dearomatization reaction of anilines, delivering chiral 3,3-
disubstituted-3aH-indoles in excellent enantioselectivities.3a
Soon after, Buchwald and You independently reported aryla-
tive dearomatizations of phenols and indoles, while quite a
few examples were tested in the enantioselective fashion.3d,e
Notably, very recently, success has been achieved for the
asymmetric arylative dearomatization of phenols by Tang
and co-workers, accessing chiral phenanthrenone derivatives
in high enantioselectivities.3h Obviously, all the aforemen-
tioned examples covering the racemic versions are only lim-
ited to aromatic substrates bearing free N-H or O-H bonds,
such as aniline, indole, pyrrole, and phenol. Indeed, keto-
enol tautomerism of such aromatic compounds under basic
condition facilitates the dearomatization and subsequent
carbon-carbon cross-coupling under Pd(0) catalyst. Un-
doubtedly, novel asymmetric dearomative arylation process
based on the development of new strategies is highly attrac-
tive.
Asymmtric arylative dearomatization of aniline (ref 3a)
Br
R
R
Pd(0)/L*
N
N
H
Asymmtric arylative dearomatization of phenol (ref 3d, 3h)
Br
R
R
Pd(0)/L*
OH
O
This work: Arylative dearomatization of N-protected indole
PdX
X R
R
R
Pd(0)
L*
R2
R2
[H]
R2
N
N
R1
N
R1
R1
O
O
O
O
H
N
O
N
NH
Br
Br
O
N
N
N
N
H
H
OH
Br
OH
O
OH
NHCOH
Trigonoliimine C
N
(-)-Isatisine A
Hinckdentine A
Figure 1. Methods for palladium-catalyzed asymmetric aryla-
tive dearomatizations and selected natural products contain-
ing C2-quaternary substituted indoline framework
At the outset, the asymmetric reductive Heck reaction of
N-(2-bromobenzoyl)-2-methylindole 1a was studied with
HCO2H/NEt3 as a hydride source, Pd(OAc)2 as a catalyst, and
In recent years, transition-metal-catalyzed direct arylation
of CAr-H bonds of (hetero)arenes offers an efficient access to
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16d
17d,e
L4
L1
HCO2Na
HCO2Na
MeOH
MeOH
81
98
96
(R)-BINAP as a ligand. As shown in Table 1, the reaction in
THF or Toluene at 100 oC did not afford any arylative product
(Table 1, entries 1-2). To our delight, the desired product 2a
was isolated in lower yields but with excellent enantioselec-
tivities when the reactions were performed in CH3CN or DCE
(1,2-dichloroethane) (Table 1, entries 3-4). Gratifyingly, the
yield was remarkably improved to 79% in methanol and the
excellent enantioselectivity was retained (Table 1, entry 5).
Comparable results were observed for reactions in EtOH and
iPrOH (Table 1, entries 6-7). Other amines (TMEDA, DIPA,
DABCO, and DBU) combined with HCO2H were then exam-
ined as hydride sources in MeOH, which gave similar results
as that with NEt3 (Table 1, entries 8-11). However, the results
were significantly improved when HCO2Na was used as a
hydride source, leading to product 2a in 85% yield and 97%
ee value (Table 1, entry 13). Subsequent ligand screening indi-
cated that generally bidentate phosphines were efficient chi-
ral ligands. The reactions with (R)-Tol-BINAP or (R)-
SYNPHOS as ligands also provided indoline 2a in good yields
and excellent enantioselectivities, whereas relatively lower ee
value was observed for (R)-SEGPHOS (Table 1, entries 14-16).
Finally, lowering the temperature to 80 oC afforded 2a in
comparable results albeit with a longer reaction time (Table 1,
entry 17). Therefore, the best results were obtained under the
conditions: 5 mol% Pd(OAc)2, 6 mol% (R)-BINAP, and 2.0
equiv. HCO2Na in 2.0 mL methanol at 100 oC for 10 h.14
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2
3
4
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6
7
8
82
aReaction conditions: 1a (0.2 mmol), Pd(OAc)2 (5 mol%), L*
(6 mol%), base (0.4 mmol), and the solvent (2.0 mL) indicat-
ed in a sealed Schlenk tube at 100 C (oil bath) for 10 h. I-
solated yiled. cDetermined by chiral HPLC. dIn the absence of
HCO2H. eAt 80 oC (oil bath) for 36 h.
o
b
Under the optimal reaction conditions, we then studied
the scope of the reaction.15 Substituent effect of indoles was
examined and the results were shown in Table 2. Excellent
enantioselectivities (92-99%) were exclusively observed for
the new quaternary stereogenic centers generated from all
the reactions. A range of C2-substituted indoles were well
tolerated, showing a broad scope of the reaction. Modest to
good yields and excellent enantioselectivities (over 97%)
were obtained for the substrates bearing alkyl groups (me-
thyl, benzyl, and cyclopropyl) (Table 2, entries 1, 2 and 16) or
an ester group (Table 2, entry 3). The C2-substituted aro-
matic groups were also investigated (Table 2, entries 4-15),
while the yields were influenced unfavorably by the steric
effect. In comparison to the reactions of the substrates bear-
ing para-substituted aryl groups, slightly lower yields were
obtained for those containing meta-substituents on the ben-
zene ring (Table 2, entries 10 and 11); and in particular, very
poor yield (15%) was observed for the substrate 1l with an
ortho-methyl group (Table 2, entry 12). Likewise, yields were
found to be a little lower for the substrates bearing electron-
withdrawing substituents at the para-position on benzene
ring (Table 2, entries 7-9). Notably, 2-naphthyl and heteroar-
omatic (2-furyl and 2-thienyl) groups were also tested in the
reaction, affording the desired products in modest yields and
excellent enantioselectivities (Table 2, entries 13-15). In addi-
tion, the influence of the substituted groups at C5 and C6
position of the indole ring was examined. Electron-donating
groups furnished the arylation with good results in terms of
yield and enantioselectivity (Table 2, entries 17 and 19-21).
However, electron-withdrawing group was unfavorable for
the reaction and the desired product were afforded in a rela-
tively low yield but with excellent ee value (Table 2, entry 18).
In addition, a novel pentacyclic chiral indoline 2v was afford-
ed in 55% yield and with 89% ee (Table 2, entry 22). It is
worth noting that a gram-scale reaction of 1a→2a was carried
out to give the product in 81% yield and with 97% ee, show-
ing the practice of this reaction (Eq. 1).
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Table 1. Optimization of the reaction conditionsa
Entry L*
Base
Solvent
THF
Yield(%)b Ee(%)c
1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
NEt3
<5
--
2
NEt3
Toluene <5
--
3
NEt3
CH3CN
DCE
36
35
79
75
70
77
80
78
69
80
85
82
82
96
96
97
97
96
98
97
97
97
93
97
97
82
Table 2. Substituent effect of substrate 1a
4
NEt3
5
NEt3
MeOH
EtOH
6
NEt3
7
NEt3
iPrOH
MeOH
MeOH
MeOH
MeOH
8
TMEDA
DIPA
DABCO
DBU
Entry R, R1
Yield(%)b Ee(%)c
9
1
Me, H (1a)
2a
2b
2c
2d
2e
2f
85
78
71
97
97
99
97
92
97
96
10
11
12d
13d
14d
15d
2
3
4
5
6
7
Bn, H (1b)
CO2Me, H (1c)
Ph, H (1d)
HCO2NH4 MeOH
81
HCO2Na
HCO2Na
HCO2Na
MeOH
MeOH
MeOH
4-MeO-C6H4, H (1e)
4-Me-C6H4, H (1f)
4-Cl-C6H4, H (1g)
88
75
68
2g
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4-F-C6H4, H (1h)
4-CF3-C6H4, H (1i)
3-Me-C6H4, H (1j)
3-Cl-C6H4, H (1k)
2-Me-C6H4, H (1l)
2-Naphthyl, H (1m)
2-Furyl, H (1n)
2h
2i
72
64
62
60
15
96
98
97
98
94
97
98
99
97
98
98
98
96
98
89
7
8
9
5-F (3g)
4g
4h
4i
67
64
76
97
94
99
1
2
3
4
5
6
7
8
9
4,5-F2 (3h)
10
11
2j
4,5-(MeO)2 (3i)
2k
2l
aReactions conditions: 3 (0.2 mmol), Pd(OAc)2 (5 mol%),
ligand L1 (6 mol%), HCO2Na (0.4 mmol) in MeOH (2.0 mL)
at 100 C (oil bath) for 10-16 h. Isolated yield. Determined
by chiral HPLC. dAt 120 oC (oil bath) for 20 h.
12
13
14
15
16
17
18
19
20
21
22
o
b
c
2m 68
2n
2o
67
62
89
76
46
80
87
75
55
As shown in Scheme 1, the asymmetric induction model
was proposed. The intramolecular aryl attack to indole was
favored from Si face, leading to product 2a in R configuration.
This was consistent to the observed configuration of com-
pound 5, derived from the bromination of 2a, based on the
X-ray structural analysis of its single crystal. Subsequently,
synthetic transformations of product 2a were conducted
(Scheme 2). A facile reduction of 2a with LiAlH4 in refluxing
THF led to a tetracyclic indoline 6 in 96% yield and with 95%
ee. However, the reduction occurred at room temperature
furnished the corresponding hemiaminal, which was readily
converted to adduct 7 as a single isomer in 83% yield and
with complete preservation of enantiopurity by an acid-
catalyzed addition of indole to the in situ formed iminium.
9
2-Thienyl, H (1o)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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c-Propyl, 5-MeO (1p) 2p
Ph, 5-Me (1q)
Ph, 5-Cl (1r)
2q
2r
2s
2t
Ph, 5-MeO (1s)
Ph, 5-iPr (1t)
Ph, 6-MeO (1u)
Ph, 6,7-(CH)4 (1v)
2u
2v
aReactions conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol%),
ligand L1 (6 mol%), HCO2Na (0.4 mmol) in MeOH (2.0 mL)
at 100 C (oil bath) for 16-36 h. Isolated yield. Determined
by chiral HPLC.
o
b
c
The effect of substituents on the benzene ring of 2-
bromobenzoyl was then investigated under the optimized
reaction conditions. As shown in Table 3, desired products
4b-i were obtained in modest to good yields and with excel-
lent enantioselectivities for the reactions with substrates
bearing either electron-donating or electron-withdrawing
groups at the C4, C5, and C6 position (Table 3, entries 2-9).
In contrast, substituent on C3 position of the bromobenzoyl
moiety disfavored the reaction, owing to large steric hin-
drance. For example, the reaction of substrate 3a containing
Scheme 1. Determination of the absolute configuration
and the asymmetric induction model
O
5.0 eq. LiAlH4
N
N
THF, 90 oC, 6 h
o
a 3-methyl group occurred at 120 C to afford the product 4a
in poor yield and with low ee value (Table 3, entry 1).
Table 3. Substituent effect of substrate 3a
6, 96% yield, 95% ee
2a
, 97% ee
H
N
5.0 eq. LiAlH4
THF, r.t., 6 h
OH
1.0 eq. indole
10 mol% TFA
N
N
CH2Cl2, r.t., 6 h
7
, 83% yield, 97% ee
Entry R3
Product Yield
(%)b
Ee (%)c
Scheme 2. Synthetic transformations of product 2a
In conclusion, we have developed a new strategy for the
asymmetric arylative dearomatization of indoles via palladi-
um-catalyzed reductive Heck reaction. A series of optically
active tetracyclic indolines bearing C2-quaternary stereogen-
ic centers were obtained in modest to good yields and with
excellent enantioselectivities. The new methodology present-
ed here offers new opportunities for the development of ary-
lative dearomatization reactions. Investigations on further
applications of this methodology in organic synthesis are
currently underway in the laboratory.
1d
2
3
3-Me (3a)
4a
4b
4c
4d
4e
4f
22
85
73
75
76
73
29
98
97
96
97
99
4-Me (3b)
4-F (3c)
4
5
5-MeO (3d)
5-Me (3e)
5-Cl (3f)
6
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Org. Lett. 2012, 14, 4525. (e) Liu, C.; Zhang, W.; Dai, L.-X.; You, S.-L.
Chem. Asian J. 2014, 9, 2113.
ASSOCIATED CONTENT
Supporting Information
1
2
3
4
5
6
7
8
(5) For recent reviews, see: (a) Campeau, L. C.; Fagnou, F. Chem.
Commun. 2006, 1253. (b) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174. (c) Chen, X.; Engle, K. M.; Wang, D.; Yu, J.
Angew. Chem., Int. Ed. 2009, 48, 5094. (d) Ackemann, L.; Vicente, R.;
Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792. (e) Rossi, R.;
Bellina, F.; Lessi, M.; Manzini, C. Adv. Synth. Catal. 2014, 356, 17.
(6) (a) Maeda, K.; Farrington, E. J.; Galardon, E.; John, B. D.;
Brown, J. M. Adv. Synth. Catal. 2002, 344, 104. (b) Glover, B.; Harvey,
A. K.; Liu, B.; Sharp, J. M.; Tymoschenko, M. F. Org. Lett. 2003, 5, 301.
(c) Lautens, M.; Fang, Y. Q. Org. Lett. 2003, 5, 3679. (d) Wang, J.-X.;
McCubbin, J. A.; Jin, M.; Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill,
M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923. (e) Ueda, K.; Yanagisawa,
S.; Yamaguchi, J.; Itami, K. Angew. Chem., Int. Ed. 2010, 49, 8946.
(f)Tang, S.-Y.; Guo, Q.-X.; Fu, Y. Chem. Eur. J. 2011, 17, 13866.
(7) Reviews for reductive Heck reaction, see: (a) Oestreich, M., Ed.
The Mizoroki-Heck Reaction; Wiley: Chichester, 2009. (b) Limk, J. T.;
Overman, L. E. Metal-catalyzed Cross Coupling reaction; Diederick,
F., Stang, P. J., Eds.; Wiely-VCH: Weinheim, 1998. (c) Brase, S.; de
Meijere, A. Cross-Coupling of Organyl Halides with Alkenes-The Heck
Reaction. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (d)
Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. Se-
lected examples for asymmetric reductive Heck reaction: (e) Namys-
lo, J. C.; Kaufmann, D. E. Chem. Ber. 1997, 130, 1327. (f) Wu, X.-Y.; Wu,
H.-D.; Zhou, Q.-L.; Chan, A. S. C. Tetrahedron: Asymmetry 2000, 11,
1255. (g) Minatti, A.; Zheng, X.; Buchwald, S. L. J. Org. Chem. 2007, 72,
9253.
(8) Zhao, L.; Li, Z.-Y.; Chang, L.; Xu, J.-Y.; Yao, H.-Q.; Wu X.-M.
Org. Lett. 2012, 14, 2066.
(9) Brown, D.; Grigg, R.; Sridharan, V.; Tambyrajah, V.
Tetrahedron Lett. 1995, 36, 8137.
(10) For recent reviews on quaternary stereocenters: (a) Christof-
fers, J.; Mann, A. Angew. Chem., Int. Ed. 2001, 40, 4591. (b) Denissova,
I.; Barriault, L. Tetrahedron 2003, 10105. (c) Christoffers, J.; Baro, A.
Adv. Synth. Catal. 2005, 347, 1473. (d) Bella, M.; Gasperi, T. Synthesis
2009, 1583. (e) Quasdorf, K. W.; Overman, L. E. Nature 2014, 516,
7530.
(11) Tan, C.-J.; Di, Y.-T.; Wang, Y.-H.; Zhang, Y.; Si, Y.-K.; Zhang,
Q.; Gao, S.; Hu, X.-J.; Fang, X.; Li, S.-F.; Hao, X.-J. Org. Lett. 2010, 12,
2370.
1
Full experimental and characterization data, including H
and 13C NMR for all the new compounds, chiral HPLC spectra
for the products, and crystal data are available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
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yxjia@zjut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for the financial support from the National
Natural Science Foundation of P. R. China (21372202), the
New Century Excellent Talents in University (NCET-12-1086),
and the Zhejiang Natural Science Fund for Distinguished
Young Scholars (R14B020005).
REFERENCES
(1) For selected reviews, see: (a) Pape, A. R.; Kaliappan, K. P.; Kün-
dig, E. P. Chem. Rev. 2000, 100, 2917. (b) Harman, W. D. Top. Organ-
omet. Chem. 2004, 7, 95. (c) Lopez Ortiz, F.; Iglesias, M. J.; Fernan-
dez, I.; Andujar Sanchez, C. M.; Gomez, G. R. Chem. Rev. 2007, 107,
1580. (d) Pouysegu, L.; Deffieux, D.; Quideau, S. Tetrahedron 2010,
66, 2235. (e) Roche, S. P.; Porco, Jr., J. A. Angew. Chem., Int. Ed. 2011,
50, 4068. (f) Zhuo, C.-X.; Zhang, W.; You, S.-L. Angew. Chem., Int. Ed.
2012, 51, 12662. (g) Ding, Q.; Ye, Y.; Fan, R. Synthesis. 2013, 1. (h)
Roche, S. P.; Tendoung, J. Y.; Treguier, B. Tetrahedron 2014, DOI:
10.1016/j.tet.2014.06.054.
(2) For a review, see: Wang, D. S.; Chen, Q.-A.; Lu, S.-M.; Zhou,
Y.-G. Chem. Rev. 2012, 112, 2557.
(3) For Pd-catalyzed arylative dearomatization reactions: (a) Gar-
cía-Fortanet, J.; Kessler, F.; Buchwald, S. L. J. Am. Chem. Soc. 2009,
131, 6676. (b) Bedford, R. B.; Butts, C. P.; Haddow, M. F.; Osborne, R.;
Sankey, R. F. Chem. Commun. 2009, 45, 4832. (c) Bedford, R. B.; Fey,
N.; Haddow, M. F.; Sankey, R. F. Chem. Commun. 2011, 47, 3649. (d)
Rousseaux, S.; García-Fortanet, J.; Del Aguila Sanchez, M. A.; Buch-
wald, S. L. J. Am. Chem. Soc. 2011, 133, 9282. (e) Wu, K.-J.; Dai, L.-X.;
You, S,-L. Org. Lett. 2012, 14, 3772. (f) Wu, K.-J.; Dai, L.-X.; You, S.-L.
Chem. Commun. 2013, 49, 8620. (g) Xu, R.-Q.; Gu, Q.; Wu, W.-T.;
Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc. 2014, 136, 15469. (h) Du, K.;
Guo, P.; Chen, Y.; Cao, Z.; Wang, Z.; Tang, W.-J. Angew. Chem., Int.
Ed. 2015, 54, 3033.
(4) For Cu-catalyzed arylative dearomatization of indoles with ar-
yliodoniums: (a) Zhu, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012,
134, 10815. (b) Guo, F.; Wang, L.; Wang, P.; Yu, J.; Han, J. Asian J. Org.
Chem. 2012, 1, 218. (c) Kieffer, M. E.; Chuang, K. V.; Reisman, S. E.
Chem. Sci. 2012, 3, 3170. d) Liu, C.; Zhang, W.; Dai, L.-X.; You, S.-L.
(12) Liu, J.-F.; Jiang, Z.-Y.; Wang, R.-R.; Zheng, Y.-T.; Chen, J.-J.;
Zhang, X.-M.; Ma, Y.-B. Org. Lett. 2007, 9, 4127.
(13) Blackman, A. J.; Hambley, T. W.; Picker, K.; Taylor, W. C.;
Thirasasana, N. Tetrahedron Lett. 1987, 28, 5561.
(14) No C7-arylation product was detected during optimization of
the reaction conditions.
(15) The following substrates were failed to give the desired prod-
ucts under the optimal reaction conditions. 2,3-Diphenylindole-1H-
indole was observed as the major byproduct for the former, while
hydrodebromination reaction occurred for the latter.
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Enantioselective Arylative Dearomatization of Indoles via Pd-catalyzed Intramolecular Reductive Heck Reactions
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