Chiral bifunctional squaramide catalyzed asymmetric tandem Michael-cyclization reaction: Efficient synthesis of optically active 2-amino-4H-chromene-3-carbonitrile derivatives

Article abstract of DOI:10.1016/j.tetasy.2013.07.010

We have developed an efficient bifunctional squaramide catalyst for the asymmetric tandem Michael addition-cyclization of malononitrile to functionalized nitroolefins. This organocatalytic asymmetric reaction provides convenient and valuable access to hig

Full text of DOI:10.1016/j.tetasy.2013.07.010

Tetrahedron: Asymmetry 24 (2013) 953–957
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral bifunctional squaramide catalyzed asymmetric tandem
Michael-cyclization reaction: efficient synthesis of optically active
2-amino-4H-chromene-3-carbonitrile derivatives
a,
a
Keling Hu a, Aidang Lu b, Youming Wang a, , Zhenghong Zhou , Chuchi Tang
⇑
⇑
a Institute and State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, PR China
b Engineering Research Center of Seawater Utilization Technology, Ministry of Education, Hebei University of Technology, Tianjin 300130, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 June 2013
Accepted 4 July 2013
We have developed an efficient bifunctional squaramide catalyst for the asymmetric tandem Michael
addition–cyclization of malononitrile to functionalized nitroolefins. This organocatalytic asymmetric
reaction provides convenient and valuable access to highly functionalized 2-amino-4H-chromene deriv-
atives, which possess important biological activities, in good yields with moderate to high enantioselec-
tivities (up to 95% ee).
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
3-cyano-4H-chromene 2 bearing a 3-bromo-4,5-dimethoxyphenyl
at the 4-position (MX58151, Fig. 1) represents a promising class
The chromene moiety often appears as an important structural
component in both biologically active and natural compounds.1 In
recent years, functionalized chromenes have demonstrated a wide
range of biological properties, such as antimicrobial and anti-
fungal,2 antioxidant,3 antileishmanial,4 antitumor and anticancer,5
anti-HIV,6 antiproliferation,7 anti-inflammatory,8 antidyslipidem-
of proapoptotic small-molecule agents with multiple action modes
against the breast cancer cell line T47D, the lung cancer cell line
H1299, and the colorectal cancer cell line DLD-1.5f,14
For most chiral pharmaceuticals, usually only one enantiomeric
form provides the desired effect, while the other enantiomer is of-
ten inactive or less active. In some cases the other enantiomer
actually has severe side effects or toxicity. Therefore, the develop-
ment of effective protocols to access enantiomerically pure 2-ami-
no-4H-chromenes would be extremely desirable 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,15 examples of the construction of these structures
in organocatalytic asymmetric ways are relatively limited despite
the fact that asymmetric organocatalysis has evolved as a powerful
tool for the preparation of enantiomerically enriched com-
pounds.16 In 2008, Zhao reported the first asymmetric synthesis
of 2-amino-4H-chromene derivatives (naphthopyran derivatives)
with moderate enantioselectivities via a bifunctional thiourea cat-
alyzed tandem addition-cyclization reaction of 2-naphthol with
ic,9 TNF-
a
inhibitors,10 as well as in the treatment of Alzheimer’s
disease,11 and Schizophrenia disorder.12 Among the various chro-
mene family members, 2-amino-4H-chromenes are especially
important for medicinal applications. For example, ethyl 2-ami-
no-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-
carboxylate 1 (HA14-1, Fig. 1) and related compounds are early
Bcl-2 antagonists and have been shown to synergize with various
anticancer therapies of diverse mechanisms of action.13 2-Amino-
OMe
O
MeO
Br
N
O
O
a,a
-dicyanoolefins.17 Employing 9-amino-9-deoxyepiquinine in
Br
O
CN
combination with (R)-1,10-binaphth-2,20-diyl hydrogen phosphate
as the catalyst, Xie et al. accomplished the synthesis of functional-
ized 2-amino-2-chromenes with good to excellent enantioselectiv-
ities via one-pot tandem reactions of functionalized enones with
malononitrile.18 Wang et al. documented the assembly of the 2-
amino-4H-chromene skeleton with good to high enantioselectivi-
ties by using an enantioselective Mannich-cyclization cascade
sequence.19 Under the catalysis of a bifunctional thiourea catalyst,
Wang19a and Du20 realized the stererocontrolled construction of
O
NH2
Me2N
O
NH2
1
2
Figure 1. Bioactive 2-amino-4H-chromenes.
⇑
Corresponding authors. Tel.: +86 22 23503891; fax: +86 22 23503627.
E-mail addresses: youmingwang@eyou.com (Y. Wang), z.h.zhou@nankai.edu.cn
(Z. Zhou).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.010

954
K. Hu et al. / Tetrahedron: Asymmetry 24 (2013) 953–957
Table 1
the 2-amino-4H-chromene scaffold via the tandem Michael addi-
tion–cyclization of malononitrile to functionalized nitroolefins,
however, in most cases, unsatisfactory selectivities were obtained.
Recently, Yang et al. developed an efficient chiral bifunctional thio-
urea catalyzed three-component cascade reaction of salicylalde-
hyde, malononitrile/cyanoacetate, and nitromethane, generating
highly functionalized 2-amino-4H-chromenes with good to excel-
lent enantioselectivities.21 Wang accomplished the preparation of
2-amino-4H-chromenes with high levels of enantioselectivity via
organocatalytic conjugate addition of nitroalkanes to 2-imino-
chromenes.22 Despite these recent advances, there are still some
drawbacks associated with these previously reported procedures,
such as low catalytic efficacy and in some cases, unsatisfactory ste-
reoselectivity. Therefore, the development of alternative efficient
catalysts for the stereocontrolled construction of the 2-amino-
4H-chromene skeleton is highly desirable. As part of our continued
interest in the stereoselective synthesis of biologically relevant
heterocycles,23 we herein report our research on the stereocon-
trolled construction of the 2-amino-4H-chromene scaffold through
the bifunctional squaramide catalyzed tandem Michael-cyclization
reaction of functionalized nitroolefins and malononitrile.
Catalyst evaluationa
NO2
CN
NO2
CN
Cat. (10 mol%)
CH2Cl2, 20 °C
+
*
CN
OH
O
NH2
3a
4
5a
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
I
12
95
92
>99
98
85
83
9
ꢀ38
ꢀ26
ꢀ42
63
IIa
IIb
IIc
IIIa
IIIb
IIIc
1
5 min
5 min
1
1
2
52
65
98
a
All reactions were carried out with 2-(E)-2-nitrovinylphenol 3a (0.50 mmol),
malononitrile 4 (0.75 mmol), and squaramide catalyst (10 mol %) in methylene
chloride (2 mL) at 20 °C.
b
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC analysis.
c
2. Results and discussion
Table 2
Optimization of reaction conditionsa
Initially, we investigated the Michael-cyclization reaction of
malononitrile 4 to 2-(E)-2-nitrovinylphenol 3a in methylene chlo-
ride at 20 °C in the presence of 10 mol % of bifunctional squara-
mide catalysts24 I–III (Fig. 2). The results are summarized in
Table 1.
NO2
NO2
CN
IIIc (10 mol%)
solvent, 20 °C
CN
+
CN
OH
O
NH2
3a
4
5a
CF3
Entry
Solvent
Time (h)
Yieldb (%)
eec,d (%)
O
O
CF3
1
2
3
4
CH2Cl2
CHCl3
Et2O
PhCH3
CH3CN
CHCl3
CHCl3
CHCl3
2
2
72
2
3
3
98
97
75
95
92
82
98
95
65
87
70
67
5
58
74
77
O
O
Me2N
R
CF3
N
NH
H
N
N
N
CF3
H
H
5
IIa, R = Bn
6e
7f
8g
i
b
, R = Pr
I
2
2.5
c, R = t Bu
a
CF3
Unless otherwise noted, all reactions were carried out with 2-(E)-2-nitrovi-
O
O
nylphenol 3a (0.50 mmol), malononitrile 4 (0.75 mmol), and squaramide catalyst
IIIc (10 mol %) in solvent (2 mL) at 20 °C.
Ph
b
Ph
IIIa
, R = Me
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC analysis.
N
N
CF3
b
, R2 = (CH2)4
c
H
H
c
, R2 = (CH2)5
NR2
d
The absolute configuration was assigned by comparison of the specific rotation
value with the reported data in Ref. 19a.
Figure 2. Different pyrrolidine-based organocatalysts.
e
The reaction was performed at 0 °C.
The reaction was carried out at 30 °C.
f
g
With a 5 mol % catalyst loading.
As shown in Table 1, under the catalysis of chiral bifunctional
squaramide catalysts I–III, the model reaction ran smoothly to pro-
vide the corresponding 2-amino-4-nitromethyl-4H-chromene-3-
carbonitrile 5a in good to excellent yields. However, the chiral dia-
mine backbone of the squaramide catalyst was found to signifi-
cantly affect both the catalytic efficacy and enantioselectivity of
the reaction. For example, squaramide catalyst I bearing a structur-
ally rigid 9,10-ethylene-9,10-dihydroanthracene skeleton, which
had previously been successfully employed for the Michael addi-
piperidinyl group derived from (1R,2R)-1,2-diphenylethane-1,2-
diamine was the best catalyst for this enantioselective reaction
(entry 7, 65% ee).
With the promising catalyst IIIc in hand, for further optimiza-
tion, the solvent and reaction temperature as well as the catalyst
loading, were evaluated and the results are collected in Table 2.
In general, less polar solvents are crucial for obtaining good enanti-
oselectivities (entries 1–4, 65–87% ee). The poor result in the polar
solvent acetonitrile suggested the potential destruction of hydro-
gen bonding between the substrate and the catalyst. The best re-
sult was obtained by performing the model reaction in
chloroform at 20 °C in the presence of 10 mol % of catalyst IIIc (en-
try 2, 87% ee). No superior result was obtained by variation of the
reaction temperature (entries 6 and 7) or adjusting the catalyst
loading (entry 8).
tion of 4-hydrxoycoumarins to b,c-unsaturated a-ketophospho-
nates,23e demonstrated much lower catalytic activity, and gave
product 5a in 12 h with low enantioselectivity (entry 1, 9% ee).
An obvious improvement in catalytic activity and enantioselectiv-
ity was observed for squaramide catalysts IIa–c derived from
L
-amino acids and IIIa–c incorporated the (1R,2R)-1,2-diphenyleth-
ane-1,2-diamine scaffold (entries 2–7). With respect to the enanti-
oselectivity, squaramide-based catalyst IIIc23a containing
a

K. Hu et al. / Tetrahedron: Asymmetry 24 (2013) 953–957
955
Having established the optimal reaction conditions (with
10 mol % IIIc as the catalyst, in chloroform at 20 °C), the generality
of this cascade process was next examined by using various func-
tionalized nitroolefins derived from substituted salicylaldehydes.
The results are listed in Table 3.
good to excellent yields (up to >99%) with moderate to high enanti-
oselectivities (up to 95% ee).
4. Experimental
4.1. General procedure for the synthesis of squaramide catalyst
IIa–c
Table 3
The IIIc-catalyzed cascade Michael addition/cyclization reaction of malononitrile 4
and functionalized nitroolefins 3a
To a solution of the corresponding chiral diamine (3.0 mmol) in
methanol (15 mL) was added 3-(3,5-bis(trifluoromethyl)-phenyla-
mino)-4-methoxycyclo-but-3-ene-1,2-dione (2.5 mmol) in one
portion. The resulting mixture was stirred at room temperature
until completion of the reaction (monitored by TLC). The precipi-
tate was filtered, washed with methanol, and then dried in a vac-
uum to afford the product as a white solid.
NO2
NO2
CN
CN
5
8
4
IIIc (10 mol%)
CHCl3, 20 °C
3
CN
6
7
X
+
X
OH
2
O
NH2
1
3a−k
4
5a−k
4.1.1. 3-((S)-3-Phenyl-1-(piperidin-1-yl)propan-2-ylamino)-4-
(3,5-bis(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-
dione IIa
Entry
5 (X)
Time (h)
Yieldb (%)
eec,d (%)
1
2
3
4
5
6
7
8
5a (H)
5b (6-F)
5c (6-Cl)
5d (6-Br)
5e (6,8-Br2)
5f (6-NO2)
5g (6-MeO)
5h (6-Me)
5i (7-Me)
5j (8-Me)
2
0.5
1.5
4
3
4
1.5
2
2.5
24
12
97
>99
82
84
85
85
88
82
82
85
84
87
74
62
76
95
60
41
57
62
67
81
White solid, 78% yield, mp 243–244 °C, ½a D20
¼ ꢀ90:0 (c 1.0,
ꢁ
DMSO). 1H NMR (DMSO-d6, 400 MHz): d 1.32–1.42 (m, 6H) 2.18–
2.42 (m, 5H), 2.56–2.62 (m, 1H), 2.76–2.97 (m, 3H), 4.49 (br s,
1H), 7.19–7.27 (m, 5 Harom), 7.62 (s, 1 Harom), 8.02 (s, 2 Harom),
10.12 (br s, 1H). 13C NMR (DMSO-d6, 100.6 MHz): 2.38, 25.5, 49.6,
52.5, 53.6, 54.2, 61.8, 62.6, 114.5, 117.9, 123.1 (q, J = 272.8 Hz),
124.8, 125.3, 128.2, 129.1, 131.3 (q, J = 32.9 Hz), 137.7, 141.0,
161.7, 169.9, 180.1, 184.3. HRMS (ESI) m/z calcd for C26H24F6N3O2
[MꢀH]ꢀ: 524.1778, found 524.1779.
9
10
11
5k (5,6-(CH@CH)2)
a
All reactions were carried out with 2-(E)-2-nitrovinylphenol 3a (0.50 mmol),
malononitrile 4 (0.75 mmol), and squaramide catalyst IIIc (10 mol %) in chloroform
(2 mL) at 20 °C.
4.1.2. 3-((S)-3-Phenyl-1-(piperidin-1-yl)propan-2-ylamino)-4-
(3,5-bis(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-
dione IIb
b
Yield of the isolated product after chromatography on silica gel.
Determined by chiral HPLC analysis.
c
d
The absolute configurations of the known products were assigned by compar-
White solid, 86% yield, mp 211–212 °C, ½a D20
¼ ꢀ85:0 (c 1.0,
ꢁ
ison of the specific rotation values with the reported data,19a and the remaining
configurations are assumed by analogy.
DMSO). 1H NMR (DMSO-d6, 400 MHz): d 0.91 (s, 6 H), 1.33–1.41
(m, 5 H) 1.79–2.04 (m, 2 H), 2.00–2.46 (m, 6 H), 2.64–2.96 (m, 1
H), 4.13 (br s, 1 H), 7.64 (s, 1 Harom), 8.07 (s, 2 Harom), 10.15
(br s, 1H). 13C NMR (DMSO-d6, 100.6 MHz): 16.7, 19.2, 23.8, 25.5,
30.4, 49.5, 52.5, 54.2, 56.9, 60.1, 60.9, 114.5, 117.9, 123.1 (q,
J = 272.7 Hz), 124.8, 125.4, 131.3 (q, J = 32.9 Hz), 141.1, 161.8,
170.4, 180.1, 184.5. HRMS (ESI) m/z calcd for C22H24F6N3O2
[MꢀH]ꢀ: 476.1778, found 476.1786.
As shown in Table 3, functionalized nitroolefins bearing both
electron-withdrawing 3b–f and electron-donating substituents
3e–j could be applied to this transformation, generating the corre-
sponding 2-amino-4H-chromenes in good to excellent yield. Func-
tional groups, such as fluoro, chloro, bromo, methoxy, and even
nitro groups were well tolerated. With respect to the enantioselec-
tivity, nitroolefins containing electron-withdrawing groups on the
aromatic ring gave higher enantioselectivities than those with
electron-donating groups (entries 2–6 vs entries 6–8). 3,5-Dibro-
mosalicylaldehyde derived nitroolefin 3e appeared to be the best
substrate, providing product 5e with the highest ee value of 95%
(entry 5). 2-Hydroxynaphthalene-1-carbaldehyde derived nitro-
olefin 3k also worked well to give naphthopyran derivative 5k
with high enantioselectivity (entry 11, 81% ee). Moreover, the sub-
stitution pattern of the arene had some influence on the stereo-
chemical outcome of the reaction. In the case of a methyl
substituted nitroolefin, the enantioselectivity decreased gradually
when increasing the distance between the methyl and the
hydroxyl group.
4.1.3. 3-((S)-3,3-Dimethyl-1-(piperidin-1-yl)butan-2-ylamino)-
4-(3,5-bis(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-
dione IIc
White solid, 86% yield, mp 245–246 °C, ½a D20
¼ ꢀ75:0 (c 1.0,
ꢁ
DMSO). 1H NMR (DMSO-d6, 400 MHz): d 0.93 (s, 9H), 1.32–1.38
(m, 5H) 1.97–2.50 (m, 7H), 2.68–2.96 (m, 1H), 4.01 (br s, 1H),
7.62 (s, 1 Harom), 8.08 (s, 2 Harom), 10.10 (br s, 1H). 13C NMR
(DMSO-d6, 100.6 MHz): 23.8, 25.6, 25.9, 26.1, 33.7, 33.9, 49.2,
52.5, 54.1, 57.8, 58.8, 60.1, 60.4, 114.4, 117.8, 123.1 (q,
J = 272.7 Hz), 124.5, 124.8, 131.3 (q, J = 32.9 Hz), 141.1, 161.5,
170.6, 180.0, 184.5. HRMS (ESI) m/z calcd for
C27H26F6N3O2
[MꢀH]ꢀ: 490.1934, found 490.1929.
4.2. General procedure for bifunctional squaramide IIIc-
catalyzed asymmetric tandem Michael addition-cyclization
reaction of malononitrile and functionalized nitroolefins
3. Conclusion
In conclusion, the organocatalytic tandem Michael addition–
cyclization of malononitrile and functionalized nitroolefins for
the stereocontrolled construction of 2-amino-4H-chromene scaf-
fold has been investigated. Under the catalysis of a chiral bifunc-
tional squaramide derived from (1R,2R)-1,2-diphenylethane-1,2-
diamine, the reaction of a wide range of nitroolefins ran smoothly
to afford highly functionalized 2-amino-4H-chromene derivatives,
which have extensive biological and pharmacological activities, in
To a stirred mixture of catalyst IIIc (0.050 mmol), functionalized
nitroolefin 3 (0.50 mmol) in chloroform (2 mL) was added malon-
onitrile 4 (0.75 mmol) at 20 °C. After the reaction was complete
(monitored by TLC), the reaction mixture was concentrated under
reduced pressure and the crude product was purified by column
chromatography on silica gel (100–200 mesh, PE/EtOAc = 2/1) to

956
K. Hu et al. / Tetrahedron: Asymmetry 24 (2013) 953–957
afford the desired 2-amino-4H-chromenes 5. The title compounds
were fully characterized by 1H, 13C NMR, and specific rotation data.
Enantiomeric excesses of the products were determined by chiral
HPLC analysis.
4.2.6. (R)-2-Amino-6-nitro-4-nitromethyl-4H-chromene-3-
carbonitrile 5f
Yellow solid, 85% yield, mp 164–165 °C, ½a D25
¼ ꢀ60:0 (c 1.0,
ꢁ
CHCl3), 60% ee. 1H NMR (DMSO-d6, 400 MHz): d 4.48 (br s, 1H),
4.77 (dd, J = 4.0, 12.8 Hz, 1H), 4.99 (dd, J = 3.6, 12.8 Hz, 1H), 7.26
(d, J = 8.8 Hz, 1 Harom), 7.39 (br s, 2H), 8.17 (dd, J = 1.6, 8.8 Hz, 1
Harom), 8.41 (s, 1 Harom). 13C NMR (DMSO-d6, 100.6 MHz): d
34.0, 49.7, 80.2, 117.4, 119.0, 121.0, 124.6, 124.7, 143.7, 153.9,
161.2. HPLC analysis (Chiralpak AD-H column, hexane:2-propa-
nol = 70:30, flow rate = 1.0 mL/min, wavelength = 254 nm):
Rt = 10.07 (minor) and 19.74 min (major).
4.2.1. (R)-2-Amino-4-nitromethyl)-4H-chromene-3-carbonitrile
5a
Yellow solid, 97% yield, mp 142–143 °C, ½a D25
¼ ꢀ21:5 (c 1.5,
ꢁ
CHCl3), 87% ee. 1H NMR (DMSO-d6, 400 MHz): d 4.32 (br s, 1H),
4.68 (dd, J = 4.8, 12.0 Hz, 1H), 4.78 (dd, J = 4.4, 12.0 Hz, 1H), 7.03
(d, J = 7.6 Hz, 1 Harom), 7.17 (br s, 1 Harom + 2H), 7.30–7.34 (m,
2 Harom). 13C NMR (DMSO-d6, 100.6 MHz): d 34.6, 50.0, 80.7,
116.1, 119.3, 119.7, 124.7, 128.2, 129.0, 149.3, 162.1. HPLC analysis
(Chiralpak AD-H column, hexane:2-propanol = 80:20, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 10.10 (minor) and
11.82 min (major).
4.2.7. (R)-2-Amino-6-methoxy-4-(nitromethyl)-4H-chromene-
3-carbonitrile 5g
Yellow solid, 88% yield, mp 175–176 °C, ½a D25
¼ ꢀ35:0 (c 1.0,
ꢁ
CHCl3), 41% ee. 1H NMR (Acetone-d6, 400 MHz): d 3.78 (s, 3H),
4.35 (br s, 1H), 4.72 (dd, J = 4.8, 12.0 Hz, 1H), 4.84 (dd, J = 4.8,
12.0 Hz, 1H), 6.41 (br s, 2H), 6.89 (d, J = 8.4 Hz, 1 Harom), 6.95
(s, 1 Harom), 6.98 (d, J = 9.2 Hz, 1 Harom). 13C NMR (Acetone-
d6, 100.6 MHz): d 37.4, 53.5, 57.0, 82.1, 114.2, 116.8, 119.1,
120.6, 122.2, 145.6, 158.5, 164.4. HRMS (ESI) m/z calcd for
4.2.2. (R)-2-Amino-6-fluoro-4-nitromethyl-4H-chromene-3-
carbonitrile 5b
Yellow solid, >99% yield, mp 154–155 °C, ½a D25
ꢁ
¼ ꢀ26:0 (c 1.0,
4.33 (t,
CHCl3), 74% ee. 1H NMR (DMSO-d6, 400 MHz):
d
C
12H10N3O4 [MꢀH]ꢀ: 260.0677, found 260.0680. HPLC analysis
J = 4.8 Hz, 1H), 4.70 (dd, J = 4.8, 12.4 Hz, 1H), 4.86 (dd, J = 4.8,
12.4 Hz, 1H), 7.07 (dd, J = 4.8, 8.8 Hz, 1 Harom), 7.17 (dt, J = 2.8,
8.8 Hz, 1 Harom), 7.21 (br s, 2H), 7.29 (dd, J = 2.8, 9.2 Hz, 1 Harom).
13C NMR (DMSO-d6, 100.6 MHz): d 34.6, 49.3, 80.3, 114.6 (d,
J = 24.3 Hz), 115.9 (d, J = 23.7 Hz), 117.8 (d, J = 8.6 Hz), 119.6,
121.2 (d, J = 8.3 Hz), 145.8, 158.2 (d, J = 240.6 Hz), 162.0. HPLC
analysis (Chiralpak AD-H column, hexane:2-propanol = 80:20, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 9.99 (minor) and
12.15 min (major).
(Chiralpak AD-H column, hexane:2-propanol = 80:20, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 12.16 (minor) and
13.25 min (major).
4.2.8. (R)-2-Amino-6-methyl-4-nitromethyl-4H-chromene-3-
carbonitrile 5h
Yellow solid, 92% yield, mp 156–157 °C, ½a D25
¼ ꢀ25:0 (c 1.5,
ꢁ
CHCl3), 57% ee. 1H NMR (DMSO-d6, 400 MHz): d 2.26 (s, 3H), 4.25
(br s, 1H), 4.67 (br s, 1H), 4.76 (br s, 1H), 6.91 (d, J = 6.8 Hz, 1 Har-
om), 7.14 (br s, 2H + 2 Harom). 13C NMR (DMSO-d6, 100.6 MHz): d
20.2, 34.6, 49.8, 80.7, 115.8, 119.0, 119.8, 128.3, 129.5, 133.8, 147.3,
162.2. HPLC analysis (Chiralpak AD-H column, hexane:2-propa-
nol = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm):
Rt = 9.19 (minor) and 10.54 min (major).
4.2.3. (R)-2-Amino-6-chloro-4-nitromethyl-4H-chromene-3-
carbonitrile 5c
Yellow solid, 92% yield, mp 182–183 °C, ½a D25
¼ ꢀ40:5 (c 1.2,
ꢁ
CHCl3), 62% ee. 1H NMR (DMSO-d6, 400 MHz): d 4.33 (br s, 1H),
4.70 (d, J = 8.8 Hz, 1H), 4.88 (d, J = 8.8 Hz, 1H), 7.06 (d, J = 8.0 Hz,
1 Harom), 7.25 (br s, 2H), 7.37 (d, J = 7.2 Hz, 1 Harom), 7.51 (s, 1
Harom). 13C NMR (DMSO-d6, 100.6 MHz): d 34.3, 49.5, 80.3,
117.9, 119.4, 121.5, 122.0, 128.2, 128.9, 148.3, 161.8. HPLC analysis
(Chiralpak AD-H column, hexane:2-propanol = 80:20, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 10.47 (minor) and
13.72 min (major).
4.2.9. (R)-2-Amino-7-methyl-4-nitromethyl-4H-chromene-3-
carbonitrile 5i
Yellow solid, 82% yield, mp 153–155 °C, ½a D25
¼ ꢀ35:0 (c 1.0,
ꢁ
CHCl3), 62% ee. 1H NMR (Acetone-d6, 400 MHz): d 2.34 (s, 3H),
4.35 (t, J = 4.8 Hz, 1H), 4.69 (dd, J = 5.6, 12.0 Hz, 1H), 4.81 (dd,
J = 4.8, 12.0 Hz, 1H), 6.45 (br s, 2H), 6.88 (s, 1 Harom), 7.04 (d,
J = 7.6 Hz, 1 Harom), 7.25 (d, J = 7.6 Hz, 1 Harom). 13C NMR (Ace-
tone-d6, 100.6 MHz): d 21.9, 36.8, 54.1, 82.3, 118.3, 118.5, 120.5,
127.7, 129.8, 141.4, 151.5, 164.2. HRMS (ESI) m/z calcd for
4.2.4. (R)-2-Amino-6-bromo-4-nitromethyl-4H-chromene-3-
carbonitrile 5d
Yellow solid, 94% yield, mp 181–182 °C, ½a D25
ꢁ
¼ ꢀ10:0 (c 0.8,
4.33 (t,
CHCl3), 76% ee. 1H NMR (DMSO-d6, 400 MHz):
d
C
12H10N3O3 [MꢀH]ꢀ: 244.0727, found 244.0734. HPLC analysis
J = 4.4 Hz, 1H), 4.70 (dd, J = 4.4, 12.4 Hz, 1H), 4.88 (dd, J = 4.8,
12.8 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1 Harom), 7.25 (br s, 2H), 7.48 (d,
J = 8.8 Hz, 1 Harom), 7.63 (s, 1 Harom). 13C NMR (DMSO-d6,
100.6 MHz): d 34.2, 49.6, 80.3, 116.1, 118.3, 119.4, 121.9, 130.8,
131.8, 148.7, 161.8. HPLC analysis (Chiralpak AD-H column,
(Chiralpak AD-H column, hexane:2-propanol = 80:20, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 9.27 (minor) and
10.97 min (major).
4.2.10. (R)-2-Amino-8-methyl-4-nitromethyl-4H-chromene-3-
hexane:2-propanol = 80:20,
flow
rate = 1.0 mL/min,
wave-
carbonitrile 5j
length = 254 nm): Rt = 11.31 (minor) and 15.12 min (major).
Yellow solid, 85% yield, mp 125–126 °C, ½a D25
¼ ꢀ16:7 (c 1.0,
ꢁ
CHCl3), 67% ee. 1H NMR (Acetone-d6, 400 MHz): d 2.27 (s, 3H),
4.35 (t, J = 5.6 Hz, 1H), 4.66 (dd, J = 6.0, 12.0 Hz, 1H), 4.77 (dd,
J = 5.2, 12.0 Hz, 1H), 6.51 (br s, 2H), 7.08 (t, J = 7.6 Hz, 1 Harom),
7.16 (d, J = 8.0 Hz, 1 Harom), 7.19 (d, J = 7.2 Hz, 1 Harom). 13C
NMR (Acetone-d6, 100.6 MHz): d 16.5, 37.4, 54.1, 82.4, 120.5,
121.2, 126.3, 127.5, 127.6, 132.3, 150.0, 164.3. HRMS (ESI) m/z
calcd for C12H10N3O3 [MꢀH]ꢀ: 244.0727, found 244.0734. HPLC
analysis (Chiralpak AD-H column, hexane:2-propanol = 80:20, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 7.85 (minor) and
9.41 min (major).
4.2.5. (R)-2-Amino-6,8-dibromo-4-nitromethyl-4H-chromene-
3-carbonitrile 5e
Yellow solid, 85% yield, mp 172–174 °C, ½a D25
¼ ꢀ10:0 (c 1.0,
ꢁ
CHCl3), 95% ee. 1H NMR (DMSO-d6, 400 MHz): d 4.38 (br s, 1H),
4.73 (br s, 1H), 4.89 (br s, 1H), 7.39 (br s, 2H), 7.66 (s, 1 Harom),
7.87 (s, 1 Harom). 13C NMR (DMSO-d6, 100.6 MHz): d 34.6, 50.0,
80.2, 110.5, 116.2, 119.0, 123.5, 130.4, 134.3, 145.9, 161.4. HPLC
analysis (Chiralpak AD-H column, hexane:2-propanol = 80:20, flow
rate = 1.0 mL/min, wavelength = 254 nm): Rt = 30.10 (minor) and
34.86 min (major).

K. Hu et al. / Tetrahedron: Asymmetry 24 (2013) 953–957
957
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4.2.11. (R)-3-Amino-1-nitromethyl-1H-benzo[f]chromene-2-
carbonitrile 5k
Yellow solid, 84% yield, mp 157–159 °C, ½a D25
ꢁ
¼ ꢀ45:0 (c 1.5,
4.76 (d,
CHCl3), 81% ee. 1H NMR (DMSO-d6, 400 MHz):
d
J = 4.0 Hz, 2H), 4.99 (br s, 1H), 7.23 (d, J = 8.8 Hz, 1 Harom), 7.30
(br s, 2H), 7.53 (t, J = 7.6 Hz, 1 Harom), 7.65 (t, J = 7.6 Hz, 1 Harom),
7.94 (d, J = 8.8 Hz, 1 Harom), 7.98 (d, J = 8.0 Hz, 1 Harom), 8.07 (d,
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79.8, 112.0, 116.6, 119.8, 122.2, 125.2, 127.7, 128.8, 129.5, 130.6,
147.8, 162.3. HPLC analysis (Chiralpak AD-H column, hexane:2-
propanol = 80:20, flow rate = 1.0 mL/min, wavelength = 254 nm):
Rt = 12.55 (major) and 14.27 min (minor).
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We are grateful to the National Natural Science Foundation of
China (No. 20972070, 21121002), the National Basic research Pro-
gram of China (973 program 2010CB833300), Program for New
Century Excellent Talents in University (NCET-11-0265) and the
Key laboratory of Elemento-Organic Chemistry for generous finan-
cial support for our programs.
15. For selected examples, see (a) Kolla, S. R.; Lee, Y. R. Tetrahedron 2012, 68, 226;
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