Highly efficient enantioselective three-component synthesis of 2-amino-4H-chromenes catalysed by chiral tertiary amine-thioureas

Article abstract of DOI:10.1039/c2cc30731f

A three-component cascade reaction of salicylaldehyde, malononitrile/ cyanoacetate and nitromethane catalysed by chiral tertiary amino-thioureas was developed, which leads to the production of highly functionalized 2-amino-4H-chromenes in good yields with good to excellent enantioselectivities.

Full text of DOI:10.1039/c2cc30731f

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COMMUNICATION
Highly efficient enantioselective three-component synthesis of
2-amino-4H-chromenes catalysed by chiral tertiary amine-thioureasw
Gaosheng Yang,* Chongrong Luo, Xiaolong Mu, Tingting Wang and Xin-Yuan Liu*
Received 2nd February 2012, Accepted 17th April 2012
DOI: 10.1039/c2cc30731f
A three-component cascade reaction of salicylaldehyde, malononitrile/
cyanoacetate and nitromethane catalysed by chiral tertiary
amino-thioureas was developed, which leads to the production
of highly functionalized 2-amino-4H-chromenes in good yields
with good to excellent enantioselectivities.
preparation, external additives (such as inorganic bases or other
cooperative catalysts) or a specialized product scope with the
substituent on the 3-position strictly restricted to the nitrile group.
Organocatalytic asymmetric multi-component cascade reactions
are powerful tools for the fast construction of optically active
molecules from simple starting materials with excellent selectivity
and high atom- and step-economy.5 In this regard, compared to
other common organocatalysts like chiral secondary or primary
amines and phosphoric acids,5 examples of such reactions catalysed
by chiral tertiary amine-thioureas are sparse.6 As part of our
continuing efforts toward the synthesis of chiral heterocyclic
compounds using chiral tertiary amine-thiourea organocatalysts,6b
we described herein an application of this type of catalysts to
the asymmetric one-pot three-component cascade reaction of
salicylaldehyde and malononitrile/cyanoacetate with nitro-
methane. A variety of chiral 2-amino-4H-chromenes were
obtained in good to excellent yields (up to 92%) with excellent
enantioselectivities (up to 96% ee). Noteworthy is that this is a
general and efficient protocol for the rapid synthesis of chiral
2-amino-4H-chromenes from readily accessible starting materials
utilizing only tertiary amine-thiourea organocatalysts with no
need for any additional additives.7 Furthermore, an exceptional
and very intriguing inversion of the absolute configuration of the
major products was also revealed when changing the substrate
from malononitrile to cyanoacetate.
2-Amino-4H-chromenes are common structural motifs in a
number of both biologically active and natural compounds.1
In particular, 4-aryl/alkyl-2-amino-4H-chromene derivatives
bearing a nitrile or ester group at the 3-position show
pro-apoptotic activity against a range of cancer cells as a
single agent or in combination with chemo radiotherapy.2
Given the fact that within a chiral surrounding two enantiomers
often show distinct biological activity, the development of effective
protocols to access optically pure 2-amino-4H-chromenes would
be extremely desirable to further study the correlation between the
chirality of these compounds and their propensities for biological
activities to search for more potent and/or appropriate
pharmaceutical candidates. In contrast to the numerous
reports on the synthesis of racemic 2-amino-4H-chromenes,3
examples on the construction of these structures in catalytic
asymmetric ways are rather limited, while asymmetric organo-
catalysis has proved to be an efficient way for this purpose.4
For examples, by using the cooperative catalysis composed of
9-amino-9-deoxyepiquinine and (R)-1,10-binaphth-2,20-diyl
hydrogen phosphate, Xie and co-workers have shown asymmetric
reactions of a,b-unsaturated ketones with malononitrile to give
chiral 2-amino-4H-chromenes with high enantioselectivities;4a
Wang and co-workers have utilized indane-amine-thiourea
organocatalysts to promote the asymmetric reaction of tert-
We first examined the solvent effect in the three-component
reaction of salicylaldehyde (1a), malononitrile (2a) and nitro-
methane (3a) with catalyst C1 (Fig. 1). The reaction proceeded
smoothly in CH2Cl2 in the presence of 4 A MS at rt to form the
desired product 4a in 78% yield and 68% ee (Table 1, entry 1).
However, the use of other solvents such as toluene, n-hexane, THF,
DCE, and isopropanol did not give better results (entries 2–6).
A panel of catalysts (Fig. 1) were also screened in this reaction
(entries 8–10). To our delight, the use of Takemoto catalyst
butyl(2-hydroxyphenyl)(phenylsulfonyl)
methylcarbamate
with malononitrile to afford 2-amino-4H-chromenes with good
enantioselectivities in the presence of Li2CO3.4b However, these
current asymmetric processes often suffer from several drawbacks
such as rather complex starting materials requiring tedious prior
Anhui Key Laboratory of Functional Molecular Solids, College of
Chemistry and Materials Science, Anhui Normal University,
Wuhu 241000, China. E-mail: gshyang@mail.ahnu.edu.cn,
xyliu79@gmail.com; Fax: +86-553-3883517; Tel: +86-553-3869310
w Electronic supplementary information (ESI) available: Experimental
procedures, product characterizations for new compounds, Scheme S1,
and Fig. S1. CCDC 860045 (4b), 860044 (5b), and 860046 (Ia). For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc30731f
Fig. 1 Chiral tertiary amine-thiourea catalysts used in this study.
c
5880 Chem. Commun., 2012, 48, 5880–5882
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Table 1 Optimization of reaction conditionsa
Table 2 Scope studya
Molar ratio
of 1a/2a/3a Yieldb (%) eec (%)
Entry Catalyst
Solvent
Entry 1 (R1, R2, R3, R4) 3 (R5) Product Yieldb (%) eec (%)
1
2
3
4
5
6
C1
C1
C1
C1
C1
C1
CH2Cl2
Toluene
n-Hexane
THF
1.0/1.0/1.0 78
1.0/1.0/1.0 76
1.0/1.0/1.0 82
1.0/1.0/1.0 49
1.0/1.0/1.0 84
68
14
21
36
53
26
1
2
3
4
5
6
7
8
1a (H, H, H, H)
1b (H, H, Br, H)
1c (H, H, Cl, H)
3a (H) 4a
3a (H) 4b
3a (H) 4c
88
92
85
80
78
75
64
88d
76
83
76
78
81
86
76
41
84
87
82
81
96
80
83
58, 75
1d (H, H, NO2, H) 3a (H) 4d
DCE
1e (Br, H, Br, H)
1f (Cl, H, Cl, H)
1g (H, H, H, MeO) 3a (H) 4g
1a (H, H, H, H)
1a (H, H, H, H)
1b (H, H, Br, H)
1c (H, H, Cl, H)
1e (Br, H, Br, H)
1f (Cl, H, Cl, H)
3a (H) 4e
3a (H) 4f
Isopropanol 1.0/1.0/1.0 74
7
No catalyst CH2Cl2
1.0/1.0/1.0 NR
1.0/1.0/1.0 61
1.0/1.0/1.0 84
1.0/1.0/1.0 95
1.0/1.0/1.0 67
1.0/1.0/1.0 74
1.0/1.2/1.5 88
1.0/1.5/1.2 85
1.0/1.5/1.5 93
1.0/1.5/2.0 94
1.0/2.0/1.5 90
1.0/1.2/1.5 60
—
69
82
8
9
C2
C3
C4
C3
C3
C3
C3
C3
C3
C3
C3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3b (Me) 4h
3a (H) 5a
3a (H) 5b
3a (H) 5c
3a (H) 5d
3a (H) 5e
9
87
91
84
10
11d
12e
13
14
15
16
17
18f
ꢀ34
10
11
12
13
14
15
16
78
71
89
84
76
79
80
74
71
77 (>99)e
77 (97)e
87
1h (H, H, MeO, H) 3a (H) 5f
1i (H, Cl, H, Cl) 3a (H) 5g
1g (H, H, H, MeO) 3a (H) 5h
61
a
Unless otherwise noted, the reaction was conducted with 0.3 mmol
of salicylaldehyde (1), 0.36 mmol of malononitrile (2a)/ethyl cyano-
acetate 2b, 0.45 mmol of nitroalkane (3), 50 mg of 4 A MS and catalyst
C3 (10 mol%) in 1.5 mL CH2Cl2 at room temperature for 30 h/48 h.
a
Unless otherwise noted, the reaction was conducted with 0.3 mmol
of salicylaldehyde (1a), 50 mg of 4 A MS and catalyst (10 mol%)
b
in 1.5 mL of solvent at room temperature for 30 h. Isolated yield.
c
b
c
d
Determined by chiral HPLC analysis on a chiral OJ-H column.
e
The loading of catalyst was 5 mol%. 4 A MS was not added.
Isolated yield. Determined by chiral HPLC analysis. Ratio of
d
f
e
diastereomers is 43 : 57. After recrystallization from dichloro-
methane/n-hexane.
The reaction was conducted at 0 1C for 48 h.
C38 resulted in a significantly improved enantioselectivity
(82%) (entry 9). Notably, no reaction took place in the
absence of the catalyst (entry 7). Next, the molar ratio of the
reactants was screened. We found the presence of an optimum
ratio of 2a to 3a in this system (entry 13), whereas decreasing
or increasing this ratio all led to inferior results (entries 14–17).
Both the yield and ee values were decreased by lowering
the catalytic loading from 10 mol% to 5 mol%, with no use
of 4 A MS or by lowering the reaction temperature to 0 1C
(entries 11, 12, 18). Therefore, the three-component reaction of
1a, 2a and 3a with the molar ratio of 1 : 1.2 : 1.5 was best
carried out using 10 mol% of catalyst C3 in the presence of
4 A MS in CH2Cl2 at room temperature (entry 13).
Fig. 2 X-Ray crystal structure of 4b and 5b.
To further investigate the scope of this reaction, we then
tested the use of cyanoacetate (2b) as substrate instead of
malononitrile (2a). In general, cyanoacetate demonstrated
reactivity similar to that of malononitrile (Table 2). Under
similar reaction conditions, besides salicylaldehyde (1a), other
differently substituted salicylaldehydes with electron-withdrawing
or electron-donating substituents on the phenyl ring were also
well tolerated in the reaction to afford the corresponding products
5 in good yields and with good to excellent enantioselectivities
(entries 9–16). An electron-donating MeO group on the meta
position of aldehyde could still give comparably good results,
while its presence on the ortho position gave considerably
diminished yield and ee value (entries 14 and 16). Notably, the
ee value of these products could be improved upon simple
recrystallization (entries 13 and 14). The absolute configuration
of (S)-5b was also established by X-ray crystallographic analysis
(Fig. 2, Flack w = 0.016(17)) and the stereochemistry of other
products 5a and 5c–5h were assigned correspondingly. It should
Under the optimized reaction conditions, we examined the
substrate scope of this three-component reaction. A variety of
salicylaldehydes were similarly treated with malononitrile (2a)
and nitromethane (3a). As depicted in Table 2, salicylaldehydes
having one or two electron-withdrawing or electron-donating
substituent(s) on different positions of the phenyl ring could be
successfully employed to afford the corresponding chiral 2-amino-
4H-chromenes in good yields and high ee (Table 2, entries 2–7).
Functional groups, such as chloride, bromide, methoxy, and even
nitro groups were well tolerated. When nitroethane (3b) was used
as the substrate, high yield could still be obtained albeit with
diminished ee value and poor diastereoselectivity (entry 8). The
absolute configuration of product 4b was determined to be (R)
by X-ray crystallographic analysis (Fig. 2, Flack w = 0.03(3)).
The absolute configuration of products 4a and 4c–4g were
assigned in reference to 4b.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5880–5882 5881

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be noted that the absolute configuration of the major products
obtained here is inversed compared to those derived from
malononitrile (2a) while in the presence of the same chiral
tertiary amine-thiourea catalyst C3 under otherwise same
conditions.
In summary, a general and efficient three-component cascade
asymmetric reaction of salicylaldehyde, malononitrile/cyanoacetate
and nitromethane has been developed using a simple chiral
tertiary amino-thiourea as catalyst without the need for
additional additives. This protocol provides an atom-economic
and straightforward method for the synthesis of chiral highly
functionalized 2-amino-4H-chromenes in good yields with high
enantioselectivities from simple starting materials. Furthermore,
the absolute configuration of the major products was found to be
switchable via a simple change in one of the reactants while still
using the same catalyst system. Further studies to expand the
substrate scope and to probe the origin of stereocontrol are
currently in progress.
Several control experiments were conducted to gain some
insight into the mechanism of this three-component cascade
reaction (Scheme S1 in the ESIw). In the presence of the racemic
catalyst (ꢁ)-C1, no reaction occurred between salicylaldehyde (1a)
and nitromethane (3a) (Scheme S1 (ESIw), eqn (1)). In contrast,
the reaction of 1a with malononitrile (2a) took place smoothly
under the same reaction conditions to give 6a and Ia, respectively,
clearly indicating that the reaction of 1a with 2a should be
involved as the first step in this three-component cascade sequence
(Scheme S1 (ESIw), eqn (2)). The reaction of Ia with 3a catalysed
by C3 afforded chiral product 4a in 72% yield with 73% ee
(eqn (1)). Under the same conditions, the reaction of racemic 6a
with 3a also resulted in comparable result (eqn (2)).9 These results
suggested that 6a might be in equilibrium with Ia in the reaction
system, and a nucleophilic attack by 3a would pull the equilibrium
to generate the final product 4a, which is also consistent with
previous findings.3b,c
We thank Prof. Hongtao Zhang, Yun Wei and Shuangliu
Zhou for their help with X-ray crystallographic analyses. This
work was supported by the National Natural Science Foundation
of China (20972001, 21172002) and Anhui Provincial Natural
Science Foundation (090416236).
Notes and references
1 (a) M. Kidwai, S. Saxena, M. K. R. Khan and S. S. Thukral, Bioorg.
Med. Chem. Lett., 2005, 15, 4295; (b) N. J. Thumar and M. P. Patel,
ARKIVOC, 2009, 13, 363; (c) N. M. Sabry, H. M. Mohamed,
E. S. A. E. H. Khattab, S. S. Motlaq and A. M. El-Agrody, Eur.
J. Med. Chem., 2011, 46, 765.
2 For selected examples, see: (a) J. M. Doshi, D. Tian and C. Xing,
J. Med. Chem., 2006, 49, 7731; (b) W. Kemnitzer, S. Jiang, Y. Wang,
S. Kasibhatla, C. Crogan-Grundy, M. Bubenik, D. Labrecque,
R. Denis, S. Lamothe, G. Attardo, H. Gourdeau, B. Tseng,
J. Drewea and S. X. Cai, Bioorg. Med. Chem. Lett., 2008, 18, 603;
(c) S. G. Das, J. M. Doshi, D. Tian, S. N. Addo, B. Srinivasan,
D. L. Hermanson and C. Xing, J. Med. Chem., 2009, 52, 5937.
3 For selected examples, see: (a) D. Gree, S. Vorin, V. L. Manthati,
F. Caijo, G. Viault, F. Manero, P. Juin and R. Gree, Tetrahedron
Lett., 2008, 49, 3276; (b) M. N. Elinson, A. S. Dorofeev,
F. M. Miloserdov, A. I. Ilovaisky, S. K. Feducovich,
P. A. Belyakov and G. I. Nikishina, Adv. Synth. Catal., 2008,
350, 591; (c) M. N. Elinson, A. I. Ilovaisky, V. M. Merkulova,
P. A. Belyakov, A. O. Chizhov and G. I. Nikishin, Tetrahedron,
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ð1Þ
ð2Þ
On the basis of the above observations and previous studies,3 a
possible mechanism for the present tertiary amino-thiourea-
catalysed three-component cascade reaction was proposed
(Scheme 1). First, a tandem Knoevenagel condensation–cyclization
reaction of 1 with 2 would generate an intermediate I, which might
be in fast equilibrium with 6. Then the addition of 3 to I giving the
desired final product 4 or 5 should be the main stereodifferentiating
step. However, the exact mechanism for the stereoselective control
process, especially the unexpected reversal of the product absolute
configuration resulting from the use of 2a and 2b, remains unclear
at present and deserves further detailed study.
4 (a) J. W. Xie, X. Huang, L. P. Fan, D. C. Xu, X. S. Li, H. Su and
Y. H. Wen, Adv. Synth. Catal., 2009, 351, 3077; (b) Q. Ren,
W. Y. Siau, Z. Du, K. Zhang and J. Wang, Chem.–Eur. J., 2011,
17, 7781.
5 For selected recent reviews, see: (a) D. J. Ramon and M. Yus,
Angew. Chem., Int. Ed., 2005, 44, 1602; (b) C. F. Barbas III, Angew.
Chem., Int. Ed., 2008, 47, 42; (c) Ł. Albrecht, H. Jiang and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 8492;
(d) A. Moyano and R. Rios, Chem. Rev., 2011, 111, 4703.
6 (a) Y. Yamaoka, H. Miyabe and Y. Takemoto, J. Am. Chem. Soc.,
2007, 129, 6686; (b) X. S. Wang, G. S. Yang and G. Zhao,
Tetrahedron: Asymmetry, 2008, 19, 709; (c) S. Bai, X. Liang,
B. Song, P. S. Bhadury, D. Hu and S. Yang, Tetrahedron: Asymmetry,
2011, 22, 518.
7 During the preparation of this manuscript, a paper describing chiral
thiourea-catalysed asymmetric three-component reactions among
aromatic aldehyde, malononitrile, and coumarin/cyclohexane-1,3-
dione to give pyranocoumarins and 2-amino-4H-pyran appeared:
G. Zhang, Y. Zhang, J. Yan, R. Chen, S. Wang, Y. Ma and
R. Wang, J. Org. Chem., 2012, 77, 878.
8 T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003,
125, 12672.
9 The good chemical yield obtained here makes less probable a
process involving a direct SN2 substitution of 6a with 3a to give
the chiral product 4a.
Scheme 1 Proposed mechanism of the three-component reaction.
5882 Chem. Commun., 2012, 48, 5880–5882
c
This journal is The Royal Society of Chemistry 2012