C7-Functionalization of Indoles via Organocatalytic Enantioselective Friedel-Crafts Alkylation of 4-Amino- indoles with 2-Butene-1,4-diones and 3-Aroylacrylates

Article abstract of DOI:10.1002/adsc.201900377

An efficient protocol for the enantioselective C7 Friedel-Crafts alkylation between 4-aminoindoles and 2-butene-1,4-diones or 3-aroylacrylates was reported. This process was catalyzed by a chiral phosphoric acid, affording the corresponding 1,4-disubstituted indoles in moderate to high yields with good to high enantioselectivities. This reaction could be performed on a gram scale without loss of efficiency, and a representative derivatization of the products was also investigated to prepare the corresponding C3 formylation compound. (Figure presented.).

Full text of DOI:10.1002/adsc.201900377

Title: C7-Functionalization of Indoles via Organocatalytic Enantio-
selective Friedel-Crafts Alkylation of 4-Aminoindoles with 2-
Butene-1,4-diones and 3-Aroylacrylates
Authors: Tongkun Huang, Yunlong Zhao, Shanshui Meng, Albert S. C.
Chan, and Junling Zhao
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900377
Link to VoR: http://dx.doi.org/10.1002/adsc.201900377

10.1002/adsc.201900377
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
C7-Functionalization of Indoles via Organocatalytic
Enantioselective Friedel-Crafts Alkylation of 4-Aminoindoles
with 2-Butene-1,4-diones and 3-Aroylacrylates
Tongkun Huang,+ Yunlong Zhao,+ Shanshui Meng,* Albert S. C. Chan,* Junling
Zhao*
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China.
E-mail: mengshsh@mail.sysu.edu.cn; chenxz3@mail.sysu.edu.cn; zhaojling3@mail.sysu.edu.cn.
+Those authors contribute equally to this work
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
chemical syntheses of this structure motif have mainly
relied on de novo ring syntheses,[6] directing group
facilitated C-H functionalization,[7] or cross-couplings of
the corresponding indole C7 halogenated parent
compounds.[8] Taking advantage of the nucleophilic
similarity of naphthols and hydroxyindoles in
organocatalysis, the use of hydroxyindoles in Friedel-
Crafts alkylation provided a new solution for this tricky
problem, and electrophilic substitutions could occur at the
C7 position when 6-hydroxyindoles were used.[9] However,
C3 substitutions were still the preferred processes for many
electrophiles in this strategy,[10] and the catalytic regio and
enantioselective Friedel-Crafts alkylation at the C7
position of indole ring remains a challenge.
Abstract. An efficient protocol for the enantioselective
C7 Friedel-Crafts alkylation between 4-aminoindoles and
2-butene-1,4-diones or 3-aroylacrylates was reported. This
process was catalyzed by a chiral phosphoric acid,
affording the corresponding 1,4-disubstituted indoles in
moderate to high yields with good to high
enantioselectivities. This reaction could be performed on a
gram scale without loss of efficiency, and a representative
derivatization of the products was also investigated to
prepare the corresponding C3 formylation compound.
Keywords: C7-Friedel-Crafts reaction; Organocatalysis;
Indole; Enantioselectivity; Regioselectivity.
Inspired by the total syntheses of the C7-substituted
indolactam alkaloids,[8] we recently reported the C7
Friedel-Crafts alkylation of β,γ-unsaturated α-ketimino
esters with 4-aminoindoles, affording the 4,7-disubstituted
indole derivatives in high yields with excellent regio and
stereoselectivity.[11] In this process, the introduction of an
amino group at the indole C4 position changed the
nucleophilic activity of indole nucleus, where the C7
position is becoming more nucleophilic than the C3
position. As part of our ongoing research program on
asymmetric transformations of indoles,[4c,9d,11-12] we were
determined to further expand the substrate scope of our
strategy to obtain structurally diverse, optically enriched
4,7-disubstituted indoles for biological applications. 2-
Butene-1,4-diones and 3-aroylacrylates are popular
electrophiles,[13] and have been used in many asymmetric
transformations including the C3 Friedel-Crafts reaction of
indoles.[13a-b] We present herein our most recent research
progress on the chiral phosphoric acid catalyzed regio and
enantioselective C7 Friedel-Crafts alkylation of 4-
aminoindoles with these two kinds of acceptors.
The indole scaffold is one of the most important
nitrogen-containing heteroaromatic nuclei. It is widely
distributed in nature and has a broad spectrum of
applications in numerous research fields, such as:
pharmaceuticals, fragrances, agrochemicals, pigments, and
materials science.[1] As
a result, the synthesis of
functionalized indoles, especially optically active indole
derivatives, has garnered significant attention in organic
synthesis. The catalytic asymmetric Friedel-Crafts
alkylation is the most direct and thoroughly investigated
methodology for the regioselective functionalization of
indoles, and great achievements have been made during the
last two decades.[2] However, these alkylations
preferentially occur at the more nucleophilic C3 position of
indoles due to the inherent reactivity of the indole ring. In
some specific cases, dearomatization reactions[3] or C2
alkylations[4] would occur when C3 substituted indoles
were used. Nucleophilic substitutions at the less reactive
benzene ring of indoles continue to be scarce, exemplified
by the functionalization of indoles at the C7 position. C7
functionalized indoles are found in many biologically
active, naturally occurring indole alkaloids,[5] and the
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900377
Advanced Synthesis & Catalysis
Table 1. Optimization of the reaction conditions[a]
entry
1
2
3
4
5
6
7
8
catalyst
C1
C2
C3
C4
C5
C6
C7
C5
C5
C5
C5
C5
C5
C5
C5
C5
C6
solvent
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CH3Cl
EtOAc
1,4-dioxane
THF
yield[%][b]
60
ee[%][c]
22
46
2
14
85
85
62[d]
75
87
87
91
85
79
86
52
91[e]
87
66
97
57
98
96
70
80
93
30
74
83
90
98
87
50
31
9
10
11
12
13
14
15
16
17
Et2O
toluene
C6H5Cl
CH3CN
THF
THF
[a]
Reaction was carried out with (1a, 0.11 mmol), (2a, 0.10 mmol), and C (5 mol%) in 1 mL of solvent for 16 h at room
temperature under N2.
[b] Isolated yields are given.
[c] Enantiomeric excess was determined by HPLC (Daicel Chiralpak AD-H, hexane/i-PrOH =75:25 (v/v), λ = 254 nm, flow rate =
1.0 mL/min, 25 oC).
[d] Opposite configuration.
[e] With addition of 4 Ǻ molecular sieves (MS, 50 mg).
Our investigation started with a model reaction between
(E)-1,4-diphenyl-2-butene-1,4-dione (1a) and 4-
substituents on the aromatic ring of 1 have limited effect
on the reaction, both electron-donating and electron-
withdrawing groups were tolerated to give the
corresponding products in moderate to high yields (43-
98%) with good to high enantioselectivities (73-96% ee).
Then, the substrate scope with respect to 4-aminoindoles
was examined. In general, the substituents variation on the
4-aminoindoles substantially affects the efficiency of the
reaction. The use of N-(2-chlorobenzyl)-1H-indol-4-amine
(2b) gave 3p in lower yield (30%) with comparably high
ee value (90% ee), while N-isobutyl-1H-indol-4-amine
(2c) produced 3q in 75% yield with 78% ee. However, the
presence of a substituent on the pyrrole ring of 2 resulted
in a decrease of the reaction rate and stereoselectivity. For
example, when 2-methyl substrate 2d was examined, the
corresponding product 3r was obtained in only 34% yield
and 56% ee. It is noteworthy that some of the substrates,
such as 1b, 1g-l and so on, showed low activities in THF
due to the poor solubility, and dichloromethane was used
as solvent in those reactions. The absolute configuration of
the C7 Friedel-Crafts alkylation products was determined
to be S by the X-ray structure analysis of 3d.[15]
benzylaminoindole (2a) mediate by 5 mol% of chiral
phosphoric acid catalysts[14] in dichloromethane at rt
(Table 1). The results indicated that this reaction has an
excellent regioselectivity under these conditions, and C7
alkylation product 3a was formed as the only adduct in
this transformation. (R)-BINOL-derived catalyst C5 and
(R)-H8-BINOL-derived C6 gave the best outcomes,
affording the corresponding 3a both in 85% ee with
almost quantitative yields (Table 1, entries 5 and 6). In
order to further improve the stereoselectivity, the reaction
solvents were screened using C5 as the catalyst. Higher ee
values were obtained in solvents like chlorobenzene, ethyl
acetate, THF or dioxane, among which THF proved to be
the best (91% ee, Table 1, entry 11).
With the optimal reaction condition determined, we
then studied the scope of the reaction (Table 2). First,
various substituted diaryl 2-butene-1,4-diones (1a-o) were
subjected to the C7 Friedel-Crafts alkylation with 4-
benzylaminoindole (2a) to test the generality of the
electrophiles. It was found that the electronic nature of the
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900377
Advanced Synthesis & Catalysis
Table 2. Scope of the reaction between 4-aminoindoles and 2-alkene-1,4-diones[a]
[a] Reaction conditions: (1, 0.11 mmol), (2, 0.10 mmol), C5 (5 mol%), THF (1 mL), room temperature, N2, 16-30 h, unless
otherwise noted. Isolated yields are given. Enantiomeric excess was determined by HPLC on a chiral stationary phase.
[b] Used DCM as solvent.
[c] Used chlorobenzene as solvent.
Table 3. Optimization of the reaction conditions for the reaction of 2a to 3-aroylacrylates[a]
entry
1[d]
2[d]
3
4
5
6
7
8
9
10
11
12
13
14
15
16
solvent
THF
THF
CHCl3
CCl4
DCE
additives
--
yield[%][b]
20
ee[%][c]
59
60
80
62
81
56
79
64
76
82
78
81
81
83
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
4 Å MS
--
20
85
70
85
50
81
51
87
88
80
84
83
85
87
62
EA
DCM
CH3CN
Toluene
C6H5F
C6H5Cl
C6H5Br
C6H5F
C6H5F
C6H5F
C6H5F
3 Å MS
5 Å MS
5 Å MS
84
84[e]
[a] Unless noted otherwise, the reaction was carried out with 0.1 mmol scale in 1 mL solvent at room temperature, and the ratio of
2 : 4 was 1 : 1.5.
[b] Isolated yields are given.
[c] Enantiomeric excess was determined by HPLC on a chiral stationary phase.
[d] Reaction time is 72h.
[e] C6 was used as catalyst.
In addition to 2-butene-1,4-diones, 3-aroylacrylate 4a
was also applicable in the C7 Friedel-Crafts alkylation
with 4-aminoindoles, however, affording the product 5a in
low yield (20%) and moderate enantioselectivity (59% ee)
with a prolonged reaction time (Table 3, entry 1). The
addition of 4 Ǻ molecule sieves slightly improved the
stereoselectivity to 60% ee (Table 3, entry 2). We
subsequently optimized the reaction conditions by varying
the reaction solvent, and fluorobenzene showed the best
efficiency to give 5a in 88% yield and 82% ee (Table 3,
entry 10). The enantioselectivity was further improved to
84% ee with the addition of 5 Ǻ molecule sieves (Table 3,
entry 15).
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900377
Advanced Synthesis & Catalysis
Table 4. Scope of the reaction between 4-aminoindoles and 3-aroylacrylates[a]
[a] Reaction conditions: (2, 0.10 mmol), (4, 0.15 mmol), C5 (5 mol%), 5Å MS (50 mg), fluorobenzene (1 mL), room temperature,
24-96 h, unless otherwise noted. Isolated yields are given. Enantiomeric excess was determined by HPLC on a chiral stationary
phase.
Scheme 1. C4 Friedel-Crafts alkylation of 7-(benzylamino)indole (6)
Scheme 2. Possible transition state of this phosphoric acid catalyzed reaction.
Scheme 3. Gram-scale synthesis of 3d and transformation of 3a
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900377
Advanced Synthesis & Catalysis
We then investigated the substrate scope with respect to
3-aroylacrylates and 4-aminoindoles (Table 4). The results
revealed that the size of the ester group has little effect on
the reaction, high yields (86-98%) of corresponding
products (5a-d) with high ee values (84-87%) were
obtained. Substituents variations on the aromatic ring of 4
were well tolerated, affording 5e-j with 78-87% yields and
74-87% ee. 2-Thienyl substrate 4l was applicable but with
moderate enantioselectivity (62% ee). The effect of
substituents on the amino group of 2 was also studied, and
high yields of products 5n-r were obtained with 82-88%
ee. However, when 4-aminoindole was used, only trace
amounts of product 5m was observed on TLC.
General Procedure for the C7 alkylation of 4-
aminoindoles with 3-aroylacrylates
To a sample bottle equipped with a magnetic stirring
bar was added
2 (0.10 mmol), 4 (0.15 mmol),
fluorobenzene (1.0 mL), C5 (3.7 mg, 0.005 mmol), 5 Ǻ
molecular sieves (50 mg). The reaction was stirred at
room temperature under nitrogen atmosphere until TLC
analysis showed full consumption of 3-aroylacrylate 4.
The reaction mixture was directly purified by flash
column chromatography on silica gel (CH2Cl2/PE = 2:1
v/v) to give the corresponding product 5.
To further explore the scope of this transformation, 7-
(benzylamino)indole (6) was used as a nucleophile to react
with 4a and 1a respectively. Gratifyingly, the
corresponding C4 functionalized indole derivatives 7 and
8 were obtained in moderate yields but with low
enantioselectivities even with the use of 10 mol% C5
(Scheme 1).
Acknowledgements
We thank the National Natural Science Foundation of China
(Grant 21772199) and the Research Foundation for Advanced
Talents of Sun Yat-sen University (36000-18821101) for
financial support of this program.
The possible transition state of this reaction was
proposed to explain the absolute configuration of the C7
functionalized products. As shown in Scheme 2, both
substrates were activated by phosphoric acid catalyst
through hydrogen-bonding interactions, C7 nucleophilic
attack at the Re face of 1 or 4 is favored in this rigid chiral
environment to afford the corresponding product in S
configuration.
References
[1] a) R. J. Sundberg, in The Chemistry of Indoles,
Academic Press, New York, 1970; b) R. K. Brown, in
Indoles (Ed.: W. J. Houlihan), Wiley-Interscience, New
York, 1972; c) R. J. Sundberg, in Indoles, Academic
Press, Sunderland, 1996.
Finally, the scalability and utility of this method were
investigated. The reaction was scaled up to 2 mmol of 2-
[2] For reviews on asymmetric Friedel-Crafts reactions,
see: a) T. B. Poulsen, K. A. Jørgensen, Chem. Rev.
2008, 108, 2903-2915; b) K. A. Jørgensen, Synthesis
2003, 1117-1125; c) M. Bandini, A. Melloni, A.
Umani-Ronchi, Angew. Chem. 2004, 116, 560-566;
Angew. Chem. Int. Ed. 2004, 43, 550-556; d) M.
Bandini, A. Melloni, S. Tommasi, A. Umani-Ronchi,
Synlett 2005, 1199-1222; e) M. Bandini, A. Eichholzer,
Angew. Chem. 2009, 121, 9786-9824; Angew. Chem.
Int. Ed. 2009, 48, 9608-9644; f) S. L. You, Q. Cai, M.
Zeng, Chem. Soc. Rev. 2009, 38, 2190-2201; g) G.
Bartoli, G. Bencivenni, R. Dalpozzo, Chem. Soc. Rev.
2010, 39, 4449-4465; h) R. Dalpozzo, Chem. Soc. Rev.
2015, 44, 742-778.
[3] a) C. X. Zhuo, W. Zhang, S. L. You, Angew. Chem.
2012, 124, 12834-12858; Angew. Chem. Int. Ed. 2012,
51, 12662-12686; b) Q. F. Wu, C. Zheng, S. L. You,
Angew. Chem. 2012, 124, 1712-1715; Angew. Chem.
Int. Ed. 2012, 51, 1680-1683; c) J. E. Spangler, H. M.
L. Davies, J. Am. Chem. Soc. 2013, 135, 6802-6805.
[4] For recent examples on asymmetric C-2 Friedel-Crafts
alkylation, see: a) H. G. Cheng, L. Q. Lu, T. Wang, Q.
Q. Yang, X. P. Liu, Y. Li, Q. H. Deng, J. R. Chen, W. J.
Xiao, Angew. Chem. 2009, 121, 3332-3336; Angew.
Chem. Int. Ed. 2013, 52, 3250-3254; b) Y. L. Zhang, X.
H. Liu, X. H. Zhao, J. L. Zhang, L. Zhou, L. L. Lin, X.
M. Feng, Chem. Commun. 2013, 11311-11313; c) B. Bi,
Q. X. Lou, Y. Y. Ding, S. W. Chen, S. S. Zhang, W. H.
Hu, J. L. Zhao, Org. Lett. 2015, 17, 540-543; d) J. Q.
Weng, R. J. Fan, Q. M. Deng, R. R. Liu, J. R. Gao, Y.
X. Jia, J. Org. Chem. 2016, 81, 3023-3030; e) Z. Zhou,
Y. Li, L. Gong, E. Meggers, Org. Lett. 2017, 19, 222-
225; f) J. L. Wu, J. Y. Wang, P. Wu, G. J. Mei, F. Shi,
Org. Chem. Front. 2017, 4, 2465-2479; g) B. B. Huang,
butene-1,4-dione
benzylaminoindole
1d
2a,
and
2.2
mmol
of
4-
C7
the
corresponding
functionalized indole 3d was formed in 93% yield with the
high enantioselectivity retained (Scheme 3a). A indole C3
formylation process occurred when compound 3a was
treated with Vilsmeier-Haack reagent, producing 9 in 85%
yield with a slightly decreased enantioselectivity (Scheme
3b).
In conclusion, we have successfully applied our strategy
for the regio and enantioselective C7 Friedel-Crafts
alkylation of 4-aminoindoles with 2-butene-1,4-diones and
3-aroylacrylates as acceptors. Various substituted
substrates were examined to give the corresponding 1,4-
disubstituted indole derivatives in moderate to high yields
with good to high enantioselectivities. An representative
example for the formylation of the products at the indole
C3 position was also given.
Experimental Section
General Procedure for the C7 alkylation of 4-
aminoindoles with 2-butene-1,4-dones
To a sample bottle equipped with a magnetic stirring
bar was charged with 1 (0.11mmol), 2 (0.1mmol), THF
(1.0 mL), C5 (3.7 mg, 0.005 mmol). The reaction was
stirred at room temperature under nitrogen atmosphere
until 2 was consumed (determined by TLC). Then, the
reaction mixture was directly purified by silica gel column
chromatography (PE/EtOAc = 5:1 v/v) to give the
corresponding product 3.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900377
Advanced Synthesis & Catalysis
L. Wu, R. R. Liu, L. L. Xing, R. X. Liang, Y. X. Jia,
Org. Chem. Front. 2018, 5, 929-932.
Catal. 2016, 6, 2689-2693; c) M. Montesinos-
Magraner, C. Vila, G. Blay, I. Fernández, M. C. Muñoz,
J. R. Pedro, Org. Lett. 2017, 19, 1546-1549; d) M. J.
Xiao, D. F. Xu, W. H. Liang, W. Y. Wu, A. S. C. Chan,
J. L. Zhao, Adv. Synth. Catal. 2018, 360, 917-924; e) Z.
T. Yang, W. L. Yang, L. Chen, H. Sun, W. P. Deng,
Adv. Synth. Catal. 2018, 360, 2049-2054; f) J. Y. Liu,
X. C. Yang, H. Lu, Y. C. Gu, P. F. Xu, Org. Lett. 2018,
20, 2190-2194; g) C. Vila, J. Rostoll-Berenguer, R.
Sꢀnchez-García, G. Blay, I. Fernꢀndez, M. C. Muꢁoz, J.
R. Pedro, J. Org. Chem. 2018, 83, 6397-6407; h) C.
Vila, A. Tortosa, G. Blay, M. C. Muꢁoz, J. R. Pedro,
New J. Chem. 2019, 43, 130-134.
[10] a) Y. X. Jia, J. Zhong, S. F. Zhu, C. M. Zhang, Q. L.
Zhou, Angew. Chem. 2007, 119, 5661-5663; Angew.
Chem. Int. Ed. 2007, 46, 5565-5667; b) S. Saha, S. K.
Alamsetti, C. Schneider, Chem. Commun. 2015, 1461-
1464; c) X. Han, W. Ouyang, B. Liu, W. Wang, P. Tien,
S. Wu, H.-B. Zhou, Org. Biomol. Chem. 2013, 11,
8463-8475; d) C. Wolf, P. Zhang, Adv. Synth. Catal.
2011, 353, 760-766; d) F. A. Cruz, Y. Zhu, Q. D.
Tercenio, Z. Shen, Y. M. Dong, J. Am. Chem. Soc.
2017, 139, 10641-10644.
[11] W. Xun, B. Xu, B. Chen, S. S. Meng, A. S. C. Chan,
F. G. Qiu, J. L. Zhao, Org. Lett. 2018, 20, 590-593.
[12] a) Y. L. Zhao, L. S. Wang, J. L. Zhao, Tetrahedron
Lett. 2017, 58, 213-217; b) Y. Y. Ding, D. F. Xu, S. S.
Meng, Y. Li, J. L. Zhao, Adv. Synth. Catal. 2018, 360,
664-669.
[13] For selected examples on the asymmetric
transformation of 2-butene-1,4-diones and 3-
aroylacrylates, see: a) G. Blay, I. Fernández, A.
Monleón, M. C. Muñoz, J. R. Pedro, C. Vila, Adv. Synth.
Catal. 2009, 351, 2433-2440; b) S. Chatterjee, L.
Hintermann, M. Mandal, A. Achari, S. Gupta, P.
Jaisankar, Org. Lett. 2017, 19, 3426-3429; c) W. Zhou,
X. Su, M. Tao, C. Zhu, Q. Zhao, J. Zhang, Angew.
Chem. 2015, 127, 15066-15070; Angew. Chem. Int. Ed.
2015, 54, 14853-14857; d) C. Qin, Y. Liu, Y. Yu, Y.
Fu, H. Li, W. Wang, Org. Lett. 2018, 20, 1304-1307;
(e) X. Dong, L. Liang, E. Li, Y. Huang, Angew. Chem.
2015, 127, 1641-1644; Angew. Chem. Int. Ed. 2015, 54,
1621-1625.
[5] a) K. R. Schramma, L. B. Bushin, M. R.
Seyedsayamdost, Nat. Chem. 2015, 7, 431-437; b) M.
Varoglu, T. H. Corbett, F. A. Valeriote, P. Crews, J.
Org. Chem. 1997, 62, 7078-7079; c) J. H. Cardellina II,
F. J. Marner, R. E. Moore, Science, 1979, 204, 193-195;
d) N. Aimi, H. Odaka, S. Sakai, H. Fujiki, M.
Suganuma, R. E. Moore, G. M. Patterson, J. Nat. Prod.
1990, 53, 1593-1596; e) H. Kumagai, M. Iijima, K.
Dobashi, H. Naganawa, T. Sawa, M. Hamada, M.
Ishizuka, T. Takeuchi, J. Antibiot. 1991, 44, 1029-1032;
f) Y. Hitotsuyanagi, H. Fujiki, S. Suganuma, N. Aimi,
S. Sakai, Y. Endo, K. Shudo, T. Sugimura, Chem.
Pharm. Bull. 1984, 32, 4233-4236; g) M. Chen, L. Gan,
S. Lin, X. Wang, L. Li, Y. Li, C. Zhu, Y. Wang, B.
Jiang, J. Jiang, Y. Yang, J. Shi, J. Nat. Prod. 2012, 75,
1167-1176.
[6] R. K. Brown, Chemistry of Heterocyclic Compounds,
John Wiley & Sons, Inc., 2008, pp 227-558.
[7] a) M. Simonetti, D. M. Cannas, A. Panigrahi, S.
Kujawa, M. Kryjewski, P. Xie, I. Larrosa, Chem. Eur. J.
2017, 23, 549-553; b)Y. Q. Yang, X. D. Qiu, Y. Zhao,
Y. C. Mu, Z. Z. Shi, J. Am. Chem. Soc. 2016, 138, 495-
498; c) L. T. Xu, C. Zhao, Y. P. He, L. S. Tan, D. W.
Ma, Angew. Chem. 2016, 128, 329-333; Angew. Chem.
Int. Ed. 2016, 55, 321-325; d) Z. Q. Song, A. P.
Antonchick, Org. Biomol. Chem. 2016, 14, 4804-4808;
e) R. P. Loach, O. S.Fenton, K. Amaike, D. S. Siegel, E.
Ozkal, M. Movassaghi, J. Org. Chem. 2014, 79, 11254-
11263; f) D. W. Robbins, T. A. Boebel, J. F. Hartwig, J.
Am. Chem. Soc. 2010, 132, 4068-4069; g) S. Paul, G. A.
Chotana, D. Holmes, R. C. Reichle, R. E. Maleczka, M.
R. Smith, J. Am. Chem. Soc. 2006, 128, 15552-15553;
h) C. G. Hartung, A. Fecher, B. Chapell, V. Snieckus,
Org. Lett. 2003, 5, 1899-1902.
[8] a) B. Meseguer, D. Alonso-Diáz, N. Griebenow, T.
Herget, H. Waldmann, Chem. Eur. J. 2000, 6, 3943-
3957; b) R. H. Snell, R. L. Woodward, M. C. Willis,
Angew. Chem. 2011, 123, 9282-9285; Angew. Chem.
Int. Ed. 2011, 50, 9116-9119; c) B. Meseguer, D.
Alonso-Diáz, N. Griebenow, T. Herget, H. Waldmann,
Angew. Chem. 1999, 111, 3083-3087; Angew. Chem.
Int. Ed. 1999, 38, 2902-2905; d) N. F. Fine Nathel, T.
K. Shah, S. M. Bronner, N. K. Garg, Chem. Sci. 2014,
5, 2184-2190; e) S. P. Govek, L. E. Overman, J. Am.
Chem. Soc. 2001, 123, 9468-9469; f) C. R. Jamison, J.
J. Badillo, J. M. Lipshultz, R. J. Comito, D. W. C.
MacMillan, Nat. Chem. 2017, 9, 1165-1169.
[14] For reviews, see: a) M. Terada, Bull. Chem. Soc. Jpn.
2010, 83, 101-119; b) X. Yu, W. Wang, Chem. Asian J.
2008, 3, 516-532; c) T. Akiyama, Chem. Rev. 2007,
107, 5744-5758; d) A. G. Doyle, E. N. Jacobsen, Chem.
Rev. 2007, 107, 5713-5743; e) T. Akiyama, J. Itoh, K.
Fuchibe, Adv. Synth. Catal. 2006, 348, 999-1010.
[15] CCDC 1901198 (3d) contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge
Crystallographic Data Centre.
[9] a) P. H. Poulsen, K. S. Feu, B. M. Paz, F. Jensen, K. A.
Jørgensen, Angew. Chem. 2015, 127, 8321-8325;
Angew. Chem. Int. Ed. 2015, 54, 8203-8207; b) M.
Montesinos-Magraner, C. Vila, A. Rendón-Patiño, G.
Blay, I. Fernández, M. C. Muñoz, J. R. Pedro, ACS
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900377
Advanced Synthesis & Catalysis
UPDATE
C7-Functionalization of Indoles via
Organocatalytic Enantioselective Friedel-Crafts
Alkylation of 4-Aminoindoles with 2-Butene-1,4-
diones and 3-Aroylacrylates
Adv. Synth. Catal.Year, Volume, Page – Page
Tongkun Huang, Yunlong Zhao, Shanshui Meng,*
Albert S. C. Chan* and Junling Zhao*
7
This article is protected by copyright. All rights reserved.