Enantioselective synthesis of 2-amino-3-nitrile-chromenes catalyzed by cinchona alkaloids: A remarkable additive effect

Article abstract of DOI:10.1016/j.cclet.2015.08.013

2-Amino-3-nitrile-chromenes with potential antitumor activity were constructed by a novel catalytic system. In combination with α-naphthol, quinine could effectively promote the Michael-cyclization process of malononitrile with functionalized chalcones in high yields and moderate to good enantioselectivity (up to 84% ee). It is notable that the enantioselectivity could be greatly improved when α-naphthol was employed as additive.

Full text of DOI:10.1016/j.cclet.2015.08.013

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Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Enantioselective synthesis of 2-amino-3-nitrile-chromenes catalyzed
by cinchona alkaloids: A remarkable additive effect
Yuan-Qin Zheng, Chun-Feng Luan, Zhi-Jing Wang, Yong-Qi Yao, Zhi-Chuan Shi,
*
*
Xue-Feng Li , Zhi-Gang Zhao , Feng Chen
College of Chemistry and Environment Protection Engineering, Southwest University for Nationalities, Chengdu 610041, China
A R T I C L E I N F O
A B S T R A C T
Article history:
2-Amino-3-nitrile-chromenes with potential antitumor activity were constructed by a novel catalytic
Received 20 June 2015
Received in revised form 27 July 2015
Accepted 11 August 2015
Available online xxx
system. In combination with
a-naphthol, quinine could effectively promote the Michael-cyclization
process of malononitrile with functionalized chalcones in high yields and moderate to good
enantioselectivity (up to 84% ee). It is notable that the enantioselectivity could be greatly improved
when
a-naphthol was employed as additive.
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Keywords:
Published by Elsevier B.V. All rights reserved.
Additive effect
2-Amino-3-nitrile-chromene
Functionalized chalcones
Enantioselective
1. Introduction
fins [6]. Later Xie et al. [7] and other groups [8] synthesized these
heterocycles through the nucleophilic addition of malononitrile to a
2-Amino-3-nitrile-chromene is an important medicinal scaffold
and displays a wide range of biological properties. In addition to in
vitro antibacterial activity [1], its derivatives might be employed to
treat drug-resistant cancer. For example, compound MX58151
(Fig. 1) retained activity in tumor cells resistant towards current
antimitotic agents, taxanes (including Taxol and Taxotere), and
Vinca alkaloids [2]. Furthermore, these heterocycles were identi-
fied as vascular-disrupting agents (VDA), and one of the leading
compounds, Crolibulin (EPC2407) (Fig. 1) [3], is currently in phase
II clinical trials.
Considering its attractive biological activities, the development
of efficient synthetic approaches for this structure is of significant
interest. Although there are numerous reports on the construction
of its racemic form [4], examples of the catalytic asymmetric
syntheses of these scaffolds were relatively less explored. Notably,
the R-isomer of Crolibulin exhibited stronger antitumor activity
(50–100 times more active) than the corresponding S-isomer
[5]. Yang and Zhao successfully obtained 2-amino-3-nitrile-
chromene derivatives possessing a naphthene group via an
functional acceptor, followed by an intramolecular cyclization.
Recently Yang and other groups developed a valuable catalytic
process to synthesize enantiomerically pure 2-amino-4H-chromenes
utilizing a Michael addition of 2-iminochromenes [9]. Although high
yields and excellent enantioselectivity have been achieved in these
published examples, it was the modified organocatalysts rather than
the natural products that exhibited optimal catalytic reactivity and
stereoselectivity almost in all cases [10].
The synthesis of a suitable organocatalyst requires many
redesigning sessions and long or expensive synthetic procedures.
On the other hand, many enzymes, which are highly efficient
biological catalysts, only displayed high activity and enantios-
electivity when coenzymes were involved [11]. Motivated by the
enzymatic systems, many readily available achiral additives were
involved in the catalytic asymmetric transformations and an
impressive improvement, in terms of reactivity and stereoselec-
tivity was observed when compared with the use of organocata-
lysts alone [12]. This approach was beneficial in avoiding tedious
chemical syntheses and would ultimately allow the highly efficient
construction of libraries of catalyst systems by simply changing the
additives. Based on our continuous efforts on asymmetric Michael
reaction [13], herein we describe a domino process to construct 2-
amino-3-nitrile-chromenes via a Michael-cyclization sequence of
functionalized chalcones and malononitriles promoted by naturally
occurring cinchona alkaloids. Notably, a remarkable enantioselectivity
addition–cyclization reaction of 2-naphthol with a,a-dicyanoole-
*
Corresponding authors.
E-mail addresses: lixuefeng@swun.edu.cn (X.-F. Li), zzg63129@163.com
(Z.-G. Zhao).
http://dx.doi.org/10.1016/j.cclet.2015.08.013
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Y.-Q. Zheng, et al., Enantioselective synthesis of 2-amino-3-nitrile-chromenes catalyzed by cinchona
alkaloids: A remarkable additive effect, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.013

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poorer enantioselectivity (entry 2). Quinidine 4c and cinchonine
4d (Fig. 2) delivered adducts with an opposite configuration and
inferior optical purity than those delivered by quinine 4a (entries
3 and 4). We next studied the effect of the modified cinchona
alkaloids. As we could see, the dihydroquinine 4e (Fig. 2) exhibited
slightly higher enantioselectivity and poorer reactivity than
quinine (entry 5). The C60-OH cinchona alkaloids 4f and 4g
(Fig. 2) were examined and unsatisfactory stereoselectivity was
detected in both cases (entries 6 and 7). A range of biscinchona
alkaloids 4h–4k (Fig. 2) failed to complete the domino reaction
even after one week, and less than 50% ee values were observed
(entries 8–11). Furthermore, the 9-epi-amino cinchona alkaloid 4l
and the corresponding thiourea 4m (Fig. 2) were investigated, and
the desired products were obtained with marginal optical purity
(entries 12 and 13). Moreover, when the Takemoto catalyst 4n
(Fig. 2) was employed, only 36% ee was achieved (entry 14). The
Fig. 1. Structures of corresponding biologically active molecules.
improvement was observed once additives were introduced to the
catalyst system.
2. Experimental
subsequent solvent screening revealed that polarity has
a
1H NMR and 13C NMR spectra were recorded on Varian 400 MHz
spectrometers. ESI-HRMS spectra were recorded on a BioTOF
instrument (Bruker Daltonics). Enantiomeric excess (ee) was
determined by HPLC analysis on Chiralpak AS-H, AD-H, and OD-
H columns. Optical rotation data were recorded on an SGW-1
automatic polarimeter. The spectral data and spectra of all the
compounds are presented in the Supporting information.
The functionalized chalcones 1a–q were prepared according to
the procedures reported in literature [14]. Commercial grade
solvents were dried and redistilled before use. All other reagents
were purchased from commercial sources and used without
further purification.
remarkable impact on the enantioselectivity (entries 15–20). Only
marginal stereoselectivity was obtained when the more polar
solvents, THF and MeOH, were used (entries 19 and 20).
Unfortunately, no enantioselective improvement was observed
when this transformation was performed at 0 8C (entry 21).
Using the identified quinine 4a as the optimal catalyst and
toluene as the solvent of choice, we next focused on effects of the
additives on the enantioselectivity and catalytic activity. The
˚
addition of molecular sieves (M.S., 4 A) led to an impairment of the
reaction rate but negligible improvement of ee values (Table 2,
entries 1 and 2). It has been documented that the structural
modifications of cinchona alkaloids exerted a direct impact on
their asymmetric induction [16]. As previously reported, acids
might protonate the N-quinuclidine moiety and induce conforma-
tional changes of cinchona alkaloids, resulting in different catalytic
behaviors [17]. Inspired by Baiker’s observations on the heteroge-
neous hydrogenation of ethyl pyruvate [17b,c], we attempted to
introduce readily available acidic additives to the catalytic system.
As summarized in Table 2, when 5 mol% of aromatic carboxylic
acid was added, a slight enantioselectivity increase was attained at
the cost of a decrease in reactivity (entries 3–6). Aliphatic
3. Results and discussion
Initially, we examined the catalytic effect of a series of natural
cinchona alkaloids. The designed cascade reaction of functional
chalcone 1a and malononitrile proceeded smoothly in toluene and
afforded the desired 2-amino-3-nitrile-chromene 3a, with quinine
4a (Fig. 2) giving an almost quantitative yield [15] (Table 1, entry
1). Cinchonidine 4b (Fig. 2) displayed lower catalytic activity and
Et
Et
R1
R
R
1 = vinyl, R2 = H R3 = OMe, Q 4a
1 = vinyl, R2 = H R3 = H, CND 4b
N
N
N
N
OH
R3
N
O
O
H
N
H
N
H
N
R1 = Et, R2 = H R3 = OMe, DHQN 4e
R1 = vinyl, R2 = H R3 = OH, 4f
R1 = vinyl, R2 = Bn R3 = OH, 4g
OMe
MeO
R = OMe, QD, 4c
R = H, CN, 4d
N
H
OR2
N
R
4h [DHQD]2PHAL
Et
N
O
Et
O
Et
N
O
Et
N
N
O
H
O
H
H
N
H
OMe
MeO
O
N
N
OMe
MeO
N
N
N
4i [DHQD]2AQN
4j [DHQD]2PYR
Et
R1
Et
CF3
N
N
R3
N
4l
R = NH2,
O
CF3
O
S
H
H
H
N
N
N
OMe
S
N
N
H
CF3
MeO
Me
N
Me
H
4m
R
R =
N
N
H
CF3
4n
N
H
N
4k [DHQ]2PYR
Fig. 2. Structures of corresponding organocatalysts.
Please cite this article in press as: Y.-Q. Zheng, et al., Enantioselective synthesis of 2-amino-3-nitrile-chromenes catalyzed by cinchona
alkaloids: A remarkable additive effect, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.013

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3
Table 1
Table 2
Screening reaction conditions for the domino reaction of 1a with 2.a
Additives screening for the domino reaction of 1a with 2.a
O
Yield (%)i
ee (%)j
O
Entry
Additive
Time (h)
Ph
Ph
1
M. S. (20 mg)
M. S. (40 mg)
PhCO2H
48
96
99
75
68
70
72
76
67
71
76
71
69
73
75
71
73
78
81
74
72
78
79
81
76
73
69
71
73
cat. (20 mol %)
CN
2
.
NC
CN
+
toluene, 23 oC
3b
75
97
4b
2,4-(NO2)2PhCO2H
p-MeOPhCO2H
o-OHPhCO2H
HOAc
114
66
>99
>99
>99
>99
>99
>99
67
OH
O
NH2
5b
1a
2
3a
6b
114
120
120
72
7b
Entry
Catalyst
Solvent
Time (h)
Yield (%)b
ee (%)c
8b
TFA
1
4a
4b
4c
4d
4e
4f
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
24
49
>99
>99
>99
94
68
34
9b
TsOH
2
10c
11c
12c
13c
14c
15c
16c
17d
18e
19f
20g
21g,h
22g
23g
24c
25c
PhOH
37
3
28
ꢀ46
ꢀ21
67
p-MePhOH
p-MeOPhOH
p-NO2PhOH
2,4,6-(NO2)3PhOH
144
144
144
168
144
144
48
85
4
144
36
96
5
99
32
6
72
87
0
99
7
4g
4h
4i
72
39
ꢀ11
32
a
b
a
a
a
a
a
-Naphthol
-Naphthol
-Naphthol
-Naphthol
-Naphthol
-Naphthol
-Naphthol
43
8
168
168
168
168
168
80
49
81
9
76
ꢀ13
49
>99
93
10
11
12
13
14
15
16
17
18
19
20
21d
4j
66
72
4k
4l
43
ꢀ15
ꢀ22
13
168
168
168
168
120
37
99
46
>99
>99
>99
>99
96
4m
4n
4a
4a
4a
4a
4a
4a
4a
89
80
88
36
R-BINOL
S-BINOL
tBuOH
28
>99
98
48
CHCl3
21
56
Ether
30
77
58
CF3CH2OH
78
>99
PhCF3
24
>99
73
49
a
Unless otherwise noted, all the reactions were performed with 0.1 mmol of 1a,
0.12 mmol of malononitrile 2, 20 mol% of quinine 4a, and the corresponding
additive in 1 mL of solvent at 23 8C. HOAc = CH3CO2H, TFA = Trifluoroacetic acid,
TsOH = p-Toluenesulfonic acid.
THF
30
6
MeOH
28
96
<5
68
Toluene
48
94
a
Unless otherwise noted, all of the reactions were performed with 0.1 mmol of
3a, 0.12 mmol of malononitrile 2, and 20 mol% of catalyst in 1 mL of solvent at 23 8C.
DCM = dichloromethane, THF =Tetrahydrofuran.
b
5 mol% of additive.
c
One equivalent of additive.
d
20 mol% of additive.
b
Isolated yield after flash chromatography on silica gel.
e
30 mol% of additive.
c
Determined by HPLC on a chiral AS-H column.
f
40 mol% of additive.
d
The reaction was performed at 0 8C.
g
50 mol% of additive.
h
20 mg of M.S. was added.
i
Isolated yield after flash chromatography on silica gel.
j
carboxylic acids and sulfonic acids were also examined (entries
7–9) and acetic acid enhanced the ee value from an original value
of 68–76% (entry 7). Considering the strong acidity of carboxylic
acids, in the following study we performed the tandem reaction of
1a with malononitrile in the presence of less acidic phenolic
compounds (entries 10–23) [12e,h]. When one equivalent of
phenol and its analogues were added in the cascade reaction, a
significant decrease in reactivity was observed and prolonged
reaction time was required in almost all cases. The use of phenolic
compounds improved the enantioselectivity to a greater extent
when compared to carboxylic and sulfonic acids (entries 10–23 vs.
3–9). The electronic effect on the aromatic ring of phenol was not
apparent (entries 11–14 vs. 10). The electron-rich para-methyl
substituted phenol afforded 75% ee (entry 11) while the electron-
poor 2,4,6-trinitrophenol delivered 78% ee (entry 14). Further
Determined by HPLC on a chiral AS-H column.
It further confirmed that it’s the quinine rather than the additives
that played a crucial role during the course of asymmetric
induction. Finally, alcohols were found to slightly enhance the
enantioselectivity (entries 24 and 25).
Having established the optimal reaction conditions, we
subsequently examined the substrate scope of the domino reaction
of functionalized chalcone 1 and malononitrile 2. As summarized
in Table 3, all the reaction proceeded smoothly in the presence of
20 mol% quinine and 50 mol%
a-naphthol in toluene and the
desired chromenes were generated in high yields (75%–99%) and
moderate to good enantioselectivity (49%–84% ee). The substrate
scope study revealed that electron-donating and electron-with-
drawing groups, locating at the phenyl group adjacent to the
carbonyl group, were all well tolerated. All the substrates 1b–g
underwent efficient cascade reactions with malononitrile, afford-
ing the desired heterocycles in high yields (entries 2–7). Generally
speaking, the substrates containing electron-withdrawing groups
afforded comparable ee values with the substrates containing
electron-donating groups (entries 5–7 vs. 3–4). An ortho-substi-
tuted chalcone 1b produced the corresponding product with
poorer enantioselectivity (49% ee), probably caused by the steric
effect of the methyl group (entry 2). Moreover, reactions with
heteroaryl-containing substrates 1h–i proceeded well and the
desired products were obtained with moderate stereoselectivity
(entries 8 and 9). Notably, a pronounced positive additive effect
studies indicated that
electivity and 81% ee was detected (entry 15). However,
only generated the desired compound with 74% ee (entry 16).
Considering the poor conversion of -naphthol, the subsequent
a
-naphthol greatly improved the enantios-
b
-naphthol
a
investigation focused on the loading of additive. A decrease in
loading led to a significant conversion enhancement (entries
17–20). The transformation completed within 72 h in the presence
of 20 or 30 mol%
reduced (entries 17 and 18). Fortunately, the enantioselectivity
remained in the presence of 50 mol% -naphthol and almost
quantitative yield was obtained after one week (entry 20). Next, we
added -naphthol together with the molecular sieves to the
a-naphthol, however, the enantioselectivity also
a
a
reaction. This resulted in an inferior enantioselectivity (76% ee)
(entry 21). The chiral additive 1,10-bi-2-naphthol (BINOL) was also
evaluated [12g] (entries 22 and 23) and poorer stereo control was
observed for both additives. Both (R)-BINOL and (S)-BINOL
afforded the desired heterocycles with the same configuration.
was observed again in 1b–i when the
a-naphthol was involved
under otherwise identical conditions (entries 2–9, data outside
brackets vs. data in brackets). Up to 37% enantioselectivity
improvement was observed in the case of 1i with a thienyl group
(entry 9). We next investigated the effect of another phenyl group
Please cite this article in press as: Y.-Q. Zheng, et al., Enantioselective synthesis of 2-amino-3-nitrile-chromenes catalyzed by cinchona
alkaloids: A remarkable additive effect, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.013

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Table 3
Substrate spectrum investigation of the domino reaction of 1 and 2.a
O
O
R1
R1
4a (20 mol%)
6
3
CN
α-Naphthol (50 mol %)
5
.
NC
CN
+
R2
1
OH
R2
Toluene
4
O
NH2
2
3
2
1
Entry
R1
H
R2
Temp. (8C)
Time (h)
Yield (%)b
ee (%)c
1
H (1a)
H (1b)
H (1c)
H (1d)
H (1e)
H (1f)
H (1g)
H (1h)
H (1i)
23
23
23
23
23
23
23
23
23
10
10
10
10
10
10
10
10
168
120
120
120
120
120
120
120
120
168
168
168
120
168
120
168
120
>99
81 (R)d
49 (37)e
68 (43)e
72 (68)e
72 (63)e
67 (45)e
70 (53)e
57 (39)e
49 (12)e
74
2
o-CH3C6H4
p-CH3C6H4
p-CH3OC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
2-Furyl
99 (85)e
99 (99)e
98 (95)e
93 (98)e
99 (99)e
91 (99)e
94 (96)e
93 (99)e
99
3
4
5
6
7
8
9
2-Thienyl
C6H5
10
11
12
13
14
15
16
17
3-CH3O (1j)
5-Cl (1k)
C6H5
99
71
C6H5
3,5-Br2 (1l)
3,5-Br2 (1m)
3,5-Br2 (1n)
3,5-Br2 (1o)
3,5-Br2 (1p)
3,5-Br2 (1q)
99
84
p-CH3C6H4
p-CH3OC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
82
80
75
83
99
82
93
81
99
81
a
Unless otherwise noted, all of the reactions were performed with 0.1 mmol of 1, 0.12 mmol of malononitrile 2, 20 mol% of quinine 4a, and 50 mol% of
toluene at 23 8C.
a-naphthol in 1 mL of
b
Isolated yield after flash chromatography on silica gel.
c
Determined by HPLC on a chiral column.
d
The configuration of the product.
e
The data in parentheses is for the transformations conducted without
a-naphthol under otherwise identical conditions.
on the terminal double bond in the functionalized chalcones
(entries 10–12). Compounds 1j–l successfully converted into the
desired chromenes. Almost quantitative yields and better enan-
tioselectivity could be achieved at 10 8C when compared to
reactions conducted at 23 8C. Gratifyingly, up to 84% ee was
achieved for substrate 1l with two bromine atoms on the phenyl
group (entry 12). Further studies indicated that good enantios-
electivity remained for dibromo-substituted chalcones 1m–q
when electron-donating and electron-withdrawing groups were
introduced to the phenyl group adjacent to the carbonyl group
(entries 13–17). The configuration of the products was determined
to be R on the basis of the reported optical rotation. [7]
addition of the nitrile group led to intermediate B. Finally,
intermediate C underwent tautomerization to give the desired
compound 3a. The preferential attack of malononitrile towards the
re-face of the enone might likely be assisted by a favorable
p–p
stacking interaction between the quinoline residue of the catalyst
and the aromatic moiety linked to the carbonyl group. This resulted
in an R-configured product.
To further investigate the role of additive, the Michael addition
of an ortho-methoxy substituted chalcone 5 with malononitrile
was conducted under the identical conditions mentioned above
(Scheme 2). Notably, the beneficial effect was observed again. The
process generated the desired adduct with 79% ee in the absence of
The postulated reaction pathway is summarized in Scheme 1. Our
domino process might share a similar transition state as Lattanzi’s
enantioselective Michael reaction [15] due to the similar configura-
tion of the product. In the initial step, malononitrile was
deprotonated by the tertiary amine moiety of quinine and orientated
via a hydrogen bond. Meanwhile, the hydroxy group was involved in
a hydrogen-bonding interaction with the oxygen in the carbonyl
moietyinchalcone1a. The formationof a ternarycomplex of quinine,
chalcone 1a, and malononitrile would stereoselectively afford
intermediate A. Subsequently, the intermolecular oxo-nucleophilic
a
-naphthol; however, up to 82% ee was obtained once 50 mol%
naphthol was introduced. This confirmed that the additive effect
was general. The participation of -naphthol resulted in a decrease
a-
a
in the reaction rate and an improvement in enantioselectivity
(Table 1, entry 1 vs. Table 2, entry 20; Table 3, entries 2–9). We
postulated that the acidic
the protonation of the tertiary amine moiety of quinine. This would
disturb the deprotonation of malononitrile and slow down the
reaction rate. At the same time, the resulting complex of quinine
a-naphthol could attach to quinine via
and
a-naphthol might possess catalytic activity and afforded
Scheme 1. Proposed mechanism for the domino reaction.
Please cite this article in press as: Y.-Q. Zheng, et al., Enantioselective synthesis of 2-amino-3-nitrile-chromenes catalyzed by cinchona
alkaloids: A remarkable additive effect, Chin. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.08.013

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5
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better enantioselectivity when compared to the process solely
catalyzed by quinine [16]. As a result, a significant enhancement of
enantioselectivity was observed. Nevertheless, the real catalytic
mechanism still needs further investigation.
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4. Conclusion
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We have developed an efficient strategy to construct 2-amino-
3-nitrile-chromenes, with potential antitumor activity, from
readily accessible functionalized chalcones and malononitrile.
The natural cinchona alkaloids such as quinine could efficiently
promote the tandem conversion to produce the desired hetero-
cycles in high yields (75%–99%) and moderate to good enantios-
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electivity (49%–84% ee). In particular, achiral a-naphthol exerted a
positive impact to the stereoselectivity and a significant improve-
ment in enantioselectivity. The beneficial additive effect was
frequently observed in the case of primary and secondary amine-
promoted transformations; however, it was seldom found in the
process catalyzed by tertiary amines. Although an enhancement of
reactivity and enantioselectivity was observed in the case of the
heterogeneous catalytic enantioselective hydrogenation of ethyl
pyruvate after achiral tertiary amines were utilized, the cinchona
alkaloids were employed in the reaction as the ligand and not the
organocatalyst [18]. Further research actively performed in our lab
(b) K. Hu, A. Lu, Y. Wang, et al., Chiral bifunctional squaramide catalyzed
asymmetric tandem Michael-cyclization reaction: efficient synthesis of optically
active 2-amino-4H-chromene-3-carbonitrile derivatives, Tetrahedron: Asymme-
try 24 (2013) 953–957;
(c) Q. Ren, W.Y. Siau, Z. Du, et al., Expeditious assembly of a 2-amino-4H-
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7781–7785.
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concentrates on clarifying the definite role of
synthetic utilizations of the attained product.
a-naphthol and the
(c) W. Li, H. Liu, X. Jiang, et al., Enantioselective organocatalytic conjugate
addition of nitroalkanes to electrophilic 2-iminochromenes, ACS Catal.
(2012) 1535–1538;
2
Acknowledgments
(d) Y. Gao, D.M. Du, Facile synthesis of chiral 2-amino-4-(indol-3-yl)-4H-chro-
mene derivatives using thiourea as the catalyst, Tetrahedron: Asymmetry 24
(2013) 1312–1317;
(e) W. Chen, Y. Cai, X. Fu, et al., Enantioselective one-pot synthesis of 2-amino-4-
(indol-3-yl)-4H-chromenes, Org. Lett. 13 (2011) 4910–4913.
This work was financially supported by the National Natural
Science Foundation of China (No. 21402163) and the Science and
Technology Department of Sichuan Province (No. 2013JY0135).
Zheng Yuanqin gratefully acknowledges the Graduate Innovation
Project of Southwest University for Nationalities (No.
CX2015SZ064).
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Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2015.08.013.
(c) A. Martinez-Castaneda, K. Kedziora, I. Lavandera, et al., Highly enantioselec-
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