Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene- 3-carbonitriles using squaramide as the catalyst

Article abstract of DOI:10.1016/j.tetasy.2012.09.011

The organocatalyzed enantioselective synthesis of a series of chiral 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles was achieved using bifunctional squaramides as the catalysts. The tandem Michael addition-cyclization reaction of cyclohexane

Full text of DOI:10.1016/j.tetasy.2012.09.011

Tetrahedron: Asymmetry 23 (2012) 1343–1349
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Tetrahedron: Asymmetry
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Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-
3-carbonitriles using squaramide as the catalyst
⇑
Yu Gao, Da-Ming Du
School of Chemical Engineering and Environment, Beijing Institute of Technology, Beijing 100081, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2012
Accepted 13 September 2012
The organocatalyzed enantioselective synthesis of a series of chiral 2-amino-5,6,7,8-tetrahydro-5-oxo-
4H-chromene-3-carbonitriles was achieved using bifunctional squaramides as the catalysts. The tandem
Michael addition–cyclization reaction of cyclohexane-1,3-diones and benzylidenemalononitriles gave the
corresponding products in excellent yields (up to 99%) and moderate to good enantioselectivities (up to
83% ee). This investigation provides an efficient and useful process for the synthesis of chiral 2-amino-
4H-chromenes.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
OMe
Chromene derivatives, which occurred widely in natural com-
pounds,1 are one of the most important heterocyclic compounds.
The chromene moiety frequently possesses efficient biological
activities and pharmacological properties, such as spasmolytic,
diuretic, anticoagulant, anticancer, and antianaphylactic activi-
ties.2 Among the different types of chromene derivatives, 2-ami-
no-4H-chromenes are popular compounds that exist in drugs.
Some representative biologically active 2-amino-4H-chromene
derivatives are listed in Figure 1.3
OMe
MeO
Br
O
CN
CN
O
NH2
Me2N
O
NH2
anticancer activity
nanomolar inhibitor of EAAT 1
O
NH2
Due to their usefulness, methods for the synthesis of 2-amino-
4H-chromenes have been developed.4 The asymmetric synthesis of
4H-chromene derivatives has seen great improvements. To the
best of our knowledge, there are two different types of methods
for the asymmetric synthesis of 2-amino-4H-chromene scaffolds.
The first type utilizes transition metal complexes as catalysts. For
example, Feng et al. reported the asymmetric synthesis of 2-ami-
no-4H-chromene derivatives with moderate to good yields and
with high enantioselectivities.5 The second type are organocata-
lyzed methods with bifunctional thioureas. Several reports using
thiourea catalysts have been developed since 2008.6 In 2009, Xie
et al. reported the asymmetric synthesis of functionalized 2-ami-
no-4H-chromene derivatives catalyzed by 9-amino-9-deoxyepiqu-
inine in combination with (R)-1,10-binaphth-2,20-diylhydrogen
phosphate.7
2-amino-4H-
chromene
O
Ar
EtO2C
CO2Et
CN
Br
CO2Et
NH2
O
NH2
O
antibacterial activity
Bcl-2 inhibitor
Figure 1. 2-Amino-4H-chromene and representative derivatives exhibiting biolog-
ical activity.
thiourea and squaramide organocatalysts for the synthesis of func-
tionalized chiral compounds, we have recently succeeded in devel-
oping an organocatalyzed enantioselective tandem Michael
addition–cyclization of malononitrile to nitroalkenes for the direct
synthesis of chiral 2-amino-4-(nitromethyl)-4H-chromene-3-car-
bonitriles.12 To further extend this methodology for the synthesis
of other chiral heterocyclic compounds, we want to develop a facile
method for the asymmetric synthesis of 2-amino-5,6,7,8-tetrahy-
dro-5-oxo-4H-chromene-3-carbonitriles catalyzed by these organ-
ocatalysts. During the preparation of our manuscript, Wang et al.
reported a one-pot enantioselective synthesis of functionalized
In recent years, thioureas8,9 and squaramides10,11 have emerged
as important hydrogen-bonding organocatalysts for the prepara-
tion of enantiomerically enriched compounds. As part of our ongo-
ing project on the synthesis and application of hydrogen-bonding
⇑
Corresponding author. Tel./fax: +86 10 68914985.
E-mail address: dudm@bit.edu.cn (D.-M. Du).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.09.011

1344
Y. Gao, D.-M. Du / Tetrahedron: Asymmetry 23 (2012) 1343–1349
pyranocoumarins and 2-amino-4H-chromenes using tertiary
amine-thioureas as the organocatalysts.6e Although the previous
work has reported bifunctional thioureas can catalyze a tandem
asymmetric Michael addition–cyclization reaction for the synthe-
sis of chiral 2-amino-4H-chromenes, the asymmetric synthesis of
these important chromenes is still lacking. Herein we report a
bifunctional squaramide catalyzed Michael addition–cyclization
sequence for the asymmetric synthesis of 2-amino-5,6,7,8-tetrahy-
dro-5-oxo-4H-chromene-3-carbonitriles.
carried out in CH2Cl2 at 0 °C for 5 h, product 11a was obtained in a
higher enantioselectivity and good yield (Table 1, entry 9). If the
reaction temperature was decreased to ꢀ20 °C, the enantioselec-
tivity decreased (Table 1, entry 10). No matter the loading of
catalyst, whether it was decreased to 2 mmol % or increased to
10 mmol %, it did not give a better enantioselectivity (Table 1,
entries 11 and 12).
For further optimization of the reaction condition, we next fo-
cused on the solvent effects. The screening results are summarized
in Table 2. It was found that, besides CH2Cl2, similar yields could
also be obtained in toluene, chlorobenzene, xylene, CH3CN, THF,
ClCH2CH2Cl, and CHCl3 (Table 2, entries 2–8). Variation of the sol-
vents had a pronounced effect on the enantioselectivity of the reac-
tion. CH3CN was the worst solvent for this reaction with 90% yield
and 19% ee (Table 2, entry 5). THF was the best solvent, and the
product was obtained in excellent yield and moderate enantiose-
lectivity (Table 2, entry 6). Additionally, a slightly better enantiose-
lectivity was obtained when 4 Å MS was added (Table 2, entry 9).
With the optimized reaction conditions in hand, we then
screened the substrate scope of this reaction and the results are
summarized in Table 3. A series of benzylidenemalononitrile deriv-
atives 10 reacted with 5,5-dimethylcyclohexane-1,3-dione to afford
the corresponding 2-amino-5,6,7,8-tetrahydro-7,7-dimethyl-5-
oxo-4H-chromene-3-carbonitriles 11 in excellent yields with mod-
erate to good enantioselectivities. As shown in Table 3, different
substituted groups on the phenyl ring had pronounced effects on
the enantioselectivity of this reaction: for para-bromobenzylidene-
malononitrile, the enantioselectivity was 83% ee (Table 3, entry 4),
and for para-nitrobenzylidene-malononitrile, the enantioselectivity
was only 42% ee (Table 3, entry 6). The position of the substituent on
2. Results and discussion
Initially, we adopted the synthesis of 2-amino-5,6,7,8-tetrahy-
dro-7,7-dimethyl-5-oxo-4H-chromene-3-carbonitrile 11a from
the tandem Michael addition–cyclization of 5,5-dimethylcyclohex-
ane-1,3-dione 9 and benzylidenemalononitrile 10a as the model
reaction. Several thiourea and squaramide organocatalysts
1–8 (Fig. 2), which were readily prepared according to previous
reports,9a,c,11c,f,13 were first screened at room temperature. The
results are presented in Table 1. In these catalysts, we found that
the thiourea catalysts 1 and 2 gave very poor enantioselectivities
(Table 1, entries 1 and 2). This result indicates that thiourea cata-
lysts are not good for this reaction. Next, we tried to evaluate the
catalytic performance of squaramide organocatalysts 3–8. These
squaramide catalysts performed much better than the thioureas.
Catalyst 4 bearing a tertiary amine and a 3,5-bis(trifluoromethyl)
group on the aromatic ring gave the best enantioselectivity, and
the desired product was obtained in 93% yield and 53% ee at room
temperature after 45 min (Table 1, entry 4). We next evaluated the
effect of temperature and catalyst loading. When the reaction was
CF3
H
H
N
H
N
N
S
F3C
OCH3
F3C
N
H
N
H
S
N
N
CF3
N
2
1
CF3
O
O
CF3
O
O
H
N
F3C
N
H
HN
F3C
N
N
OCH3
H
H
N
3
4
O
O
F3C
O
O
F3C
H
N
H
N
H
HN
N
N
H
HN
N
OCH3
N
6
5
CF3
O
O
O
O
N
H
N
N
NH
HN
F3C
N
N
H
HN
H
H
H3CO
OCH3
N
N
8
7
Figure 2. Thiourea and squaramide organcatalysts.

Y. Gao, D.-M. Du / Tetrahedron: Asymmetry 23 (2012) 1343–1349
1345
Table 1
Table 3
Evaluation of the bifunctional organocatalysta
Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4H-
NH2
chromene-3-carbonitrilesa
NH2
CN
O
O
O
CN
R
CN
O
catalyst
CH2Cl2, rt, 45 min
5 mol% catalyst 4
*
CN
+
R
CN
+
THF, 4 Å MS
0 °C, 5 h
O
O
CN
10
O
O
9
10a
Loading (mol %)
11a
11
9
Entry
Catalyst
Yieldb (%)
eec (%)
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
4
4
4
4
5
5
5
5
5
5
5
5
5
97
99
97
93
94
89
94
97
98
95
82
99
18
ꢀ5
37
53
40
1
2
3
4
5
6
7
8
C6H5
11a
11b
11c
11d
11e
11f
11g
11h
11i
99
95
97
96
97
94
99
98
90
94
—
67
58
55
83
68
42
51
65
59
54
—
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-NO2C6H4
2-ClC6H4
2-MeC6H4
3,4-(MeO)2C6H3
2-Naphthyl
EtO
22
ꢀ40
22
9d
10e
11d
12d
62
52
56
47
9
10
11
5
2
10
11j
11k
a
Unless noted otherwise, reactions were carried out with 5,5-dimethylcyclo-
a
Unless noted otherwise, reactions were carried out with 5,5-dimethylcyclo-
hexane-1,3-dione 9 (0.25 mmol), benzylidenemalononitrile 10 (0.25 mmol), and
hexane-1,3-dione 9 (0.25 mmol) and benzylidenemalononitrile 10a (0.25 mmol) in
30 mg 4 Å MS in THF at 0 °C for 5 h.
2 mL of CH2Cl2 at room temperature.
b
Isolated yields after silica gel chromatography.
Determined by HPLC analysis on a Daicel Chiralpak IA column.
b
Isolated yields after silica gel chromatography.
Determined by HPLC analysis on a Daicel Chiralpak IA column.
Reactions were carried out at 0 °C for 5 h.
Reactions were carried out at ꢀ20 °C for 24 h.
c
c
d
e
Table 4
Enantioselective synthesis of 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-
carbonitrilesa
NH2
Table 2
CN
R
O
Evaluation of solvent effectsa
NH2
O
4
5 mol% catalyst
CN
CN
O
R
O
+
5 mol% catalyst 4
THF, 4Å MS
0 °C, 5 h
CN
CN
10
O
+
*
O
solvent
0 °C, 5 h
CN
12
O
13
O
Entry
R
Product
Yieldb (%)
eec (%)
11a
9
10a
Solvent
1
2
3
4
5
6
7
8
9
10
C6H5
13a
13b
13c
13d
13e
13f
13g
13h
13i
84
91
98
94
99
91
93
99
94
99
55
42
53
49
54
31
49
49
52
46
Entry
Yieldb (%)
eec (%)
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-NO2C6H4
2-ClC6H4
2-MeC6H4
1
2
3
4
5
6
7
8
9d
CH2Cl2
Toluene
Chlorobenzene
Xylene
CH3CN
THF
ClCH2CH2Cl
CHCl3
98
88
98
87
90
98
95
98
98
62
48
49
51
19
65
53
59
67
3,4-(MeO)2C6H3
2-Naphthyl
13j
THF
a
Unless noted otherwise, reactions were carried out with cyclohexane-1,3-dione
a
12 (0.25 mmol), benzylidenemalononitrile 10 (0.25 mmol), and 30 mg 4 Å MS in
THF at 0 °C for 5 h.
Unless noted otherwise, reactions were carried out with 5,5-dimethylcyclo-
hexane-1,3-dione 9 (0.25 mmol) and benzylidenemalononitrile 10a (0.25 mmol) at
b
Isolated yields after silica gel chromatography.
0 °C for 5 h.
c
b
Determined by HPLC analysis on a Daicel Chiralpak IA column.
Isolated yields after silica gel chromatography.
Determined by HPLC analysis on a Daicel Chiralpak IA column.
4 Å MS (30 mg) was used.
c
d
5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitriles 13 were
obtained in excellent yields with slightly lower enantioselectivities
due to the lack of two methyl groups. As shown in Table 4, a similar
tendency of the substituent effect on the enantioselectivities was
observed.
On the basis of the experimental results described above, a cat-
alytic activation mode for the asymmetric induction in this cata-
lytic system is hypothesized and shown in Figure 3. We envision
that the chiral squaramide 4 acts as a bifunctional catalyst. The
cyclohexane-1,3-dione is deprotonated by the basic nitrogen atom
of the tertiary amine. Meanwhile, the benzylidenemalononitrile is
activated by the squaramide moiety via double hydrogen bonding
between the NH groups and the CN group. The deprotonated cyclo-
hexane-1,3-dione attacks the benzylidenemalononitrile from the
Si-face to afford the (R)-configured stereocenter; the final product
is formed after the following cyclization step.
the phenyl ring also affected the enantioselectivity. The ortho-
substituted compounds gave slightly lower enantioselectivities
than the para-substituted compounds (Table 3, entry 7 vs entry 3,
entry 8 vs entry 5). We tried several methods to synthesize alkyl-
substituted methylenemalononitriles, but all trials were unsuccess-
ful in giving the corresponding products. A commercially available
ethoxymethylenemalononitrile was used as the substrate, but the
Michael addition–cyclization reaction did not take place (Table 3 en-
try 11).
Encouraged by the above results, we investigated further the
tandem Michael addition–cyclization of cyclohexane-1,3-dione
12 to benzylidenemalononitriles 10 catalyzed by catalyst 4 under
the optimal conditions. The results are shown in Table 4. The same
substrate scope was explored and the corresponding 2-amino-

1346
Y. Gao, D.-M. Du / Tetrahedron: Asymmetry 23 (2012) 1343–1349
melting point apparatus and are uncorrected. 1H NMR spectra were
N
CF3
recorded with a Varian Mercury-plus 400 MHz spectrometer. 13C
NMR spectra were recorded at 100 MHz. Infrared spectra were ob-
tained with a Perkin Elmer Spectrum One spectrometer. Optical
rotations were measured with a WZZ-3 polarimeter at the indi-
cated concentration with units of g/100 mL. The enantiomeric ex-
cesses of the products were determined by chiral HPLC using an
Agilent 1200 LC instrument with Daicel Chiralpak IA column. The
absolute configurations of the known products were assigned by
HPLC and by comparison of the specific rotations with the reported
data,6e and those of other products were assigned by analogy.
O
O
OCH3
CF3
N
N
H
H
H
N
N
H
N
O
O
Si-face attack
4.2. General procedure for the asymmetric synthesis of 2-
amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-carbonitrile
derivatives
Figure 3. Proposed catalytic activation mode for the asymmetric induction.
In addition, we investigated the asymmetric Michael addition–
cyclization of cyclopentane-1,3-dione and 4-hydroxycoumarin to
benzylidenemalononitrile under the optimal conditions. The re-
sults are listed in Scheme 1. Comparable high yields were obtained
in these two cases. 4-Hydroxycoumarin gave much lower enanti-
oselectivity than cyclopentane-1,3-dione due to its higher
reactivity.
To a solution of benzylidenemalononitrile 10 (0.25 mmol) and
catalyst 4 (5 mmol %) in THF (2.0 mL) at 0 °C, 4 Å MS (30 mg) was
added. Next, cyclohexane-1,3-dione 9 or 12 (0.25 mmol) was
added. The reaction mixture was stirred for 5 h at 0 °C. After the
reaction was complete, the solvent was removed under vacuum
and the crude product was purified by column chromatography
on silica gel to afford the corresponding products.
4.2.1. (R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-5-oxo-4-
phenyl-4H-chromene-3-carbonitrile 11a6e
NH2
CN
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (72.6 mg, 99% yield); mp
O
CN
4
5 mol% catalyst
O
+
Ph
CN
207–208 °C. ½a 2D5
¼ þ35:5 (c 0.53, acetone); HPLC (Daicel Chiralpak
ꢁ
THF, 4Å MS
0 °C, 5 h
O
IA column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min,
detection at 254 nm): major enantiomer tR = 7.0 min, minor enan-
tiomer tR = 8.3 min, 67% ee. 1H NMR (400 MHz, DMSO-d6): d = 7.29
(t, J = 7.4 Hz, 2H, ArH), 7.13–7.20 (m, 3H, ArH), 7.02 (s, 2H, NH2),
4.16 (s, 1H, CH), 2.52(AB quartet, J = 17.6 Hz, 2H, CH2), 2.25 (d,
J = 16.4 Hz, 1H, CH2), 2.10 (d, J = 16.0 Hz, 1H, CH2), 1.04 (s, 3H,
CH3), 0.95 (s, 3H, CH3) ppm. 13C NMR (100 MHz, DMSO-d6):
d = 195.5, 162.4, 158.4, 144.6, 128.2, 127.1, 126.5, 119.6, 112.7,
58.2, 49.9, 39.6, 35.5, 31.7, 28.3, 26.7 ppm.
O
14
10a
15
89 % yield
32 % ee
NH2
CN
Ph
O
O
OH
O
CN
5 mol% catalyst 4
+
CN
THF, 4Å MS
0 °C, 5 h
O
O
17
4.2.2. (R)-2-Amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydro-7,7-
dimethyl-5-oxo-4H-chromene-3-carbonitrile 11b
10a
16
91 % yield
6 % ee
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (74.1 mg, 95% yield); mp
Scheme 1. The asymmetric Michael addition–cyclization of cyclopentane-1,3-
dione and 4-hydroxycoumarin with benzylidenemalononitrile. The asymmetric
Michael addition–cyclization of cyclopentane-1,3-dione and 4-hydroxycoumarin
with benzylidenemalononitrile.
193–194 °C (lit.14 mp 191–193 °C racemic). ½a 2D5
¼ þ39:6 (c 0.53,
ꢁ
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 13.2 min, minor enantiomer tR = 16.1 min, 58%
ee. 1H NMR (400 MHz, DMSO-d6): d = 7.16–7.20 (m, 2H, ArH),
7.11 (t, J = 8.8 Hz, 2 H, ArH), 7.03 (s, 2H, NH2), 4.20 (s, 1H, CH),
2.51 (s, 2H, CH2), 2.25 (d, J = 16.0 Hz, 1H, CH2), 2.11 (d,
J = 16.0 Hz, 1H, CH2), 1.04 (s, 3H, CH3), 0.95 (s, 3H, CH3) ppm. 13C
NMR (100 MHz, DMSO-d6): d = 195.6, 162.4, 160.8 (d,
3. Conclusion
We have developed an efficient organocatalyzed Michael addi-
tion–cyclization of cyclohexane-1,3-diones to benzylidenemalono-
nitriles using a chiral bifunctional squaramide organocatalyst. The
desired chiral 2-amino-5,6,7,8-tetrahydro-5-oxo-4H-chromene-3-
carbonitriles were obtained with excellent yields (up to 99%) and
moderate to good enantioselectivities (up to 83% ee) under mild
conditions. This hydrogen-bonding squaramide organocatalysis
route provides a facile method to access chiral functionalized chro-
mene derivatives.
3
1JCF = 241.0 Hz), 158.4, 140.9, 129.0 (d, JCF = 8.0 Hz), 119.6, 114.9
(d, 2JCF = 21.2 Hz), 112.5, 58.1, 49.9, 39.6, 34.9, 31.7, 28.3, 26.8 ppm.
4.2.3. (R)-2-Amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-7,7-
dimethyl-5-oxo-4H-chromene-3-carbonitrile 11c
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (80.0 mg, 97% yield); mp
211–212 °C (lit.14 mp 209–211 °C, racemic). ½a 2D5
¼ þ39:6 (c 0.45,
ꢁ
4. Experimental
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 13.6 min, minor enantiomer tR = 17.6 min, 55%
ee. 1H NMR (400 MHz, DMSO-d6): d = 7.34 (d, J = 8.4 Hz, 2H, ArH),
7.16 (d, 2H, J = 8.0 Hz, ArH), 7.05 (s, 2H, NH2), 4.19 (s, 1H, CH),
2.50 (s, 2H, CH2), 2.24 (d, J = 16.0 Hz, 1H, CH2), 2.10 (d,
4.1. General remarks
Commercially available compounds were used without further
purification. Column chromatography was carried out with silica
gel (200–300 mesh). Melting points were measured with a XT-4

Y. Gao, D.-M. Du / Tetrahedron: Asymmetry 23 (2012) 1343–1349
1347
J = 16.0 Hz, 1H, CH2), 1.04 (s, 3H, CH3), 0.95 (s, 3H, CH3) ppm. 13C
NMR (100 MHz, DMSO-d6): d = 195.5, 162.5, 158.4, 143.6, 131.0,
129.0, 128.2, 119.4, 112.3, 57.7, 49.9, 39.6, 35.0, 31.7, 28.2,
26.8 ppm.
132.0, 129.9, 129.3, 128.1, 127.3, 119.2, 111.7, 56.8, 49.9, 39.6,
32.8, 31.7, 28.3, 26.8 ppm.
4.2.8. (R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(2-meth-
ylphenyl)-5-oxo-4H-chromene-3-carbonitrile 11h
4.2.4. (R)-2-Amino-4-(4-bromophenyl)-5,6,7,8-tetrahydro-7,7-
dimethyl-5-oxo-4H-chromene-3-carbonitrile 11d
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (75.9 mg, 98% yield); mp
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (89.3 mg, 96% yield); mp
205–206 °C (lit.14 mp 212–214 °C, racemic). ½a 2D5
¼ þ37:0 (c 0.74,
ꢁ
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 6.1 min, minor enantiomer tR = 7.9 min, 65% ee.
1H NMR (400 MHz, DMSO-d6): d = 7.09–7.13 (m, 2H, ArH), 7.02–
7.06 (m, 1H, ArH), 6.94 (s, 3H, ArH + NH2), 4.47 (s, 1H, CH), 2.52
(s, 2H, CH2), 2.46 (s, 3H, CH3), 2.24 (d, J = 16.0 Hz, 1H, CH2), 2.07
(d, J = 16.0 Hz, 1H, CH2), 1.05 (s, 3H, CH3), 0.96 (s, 3H, CH3) ppm.
13C NMR (100 MHz, DMSO-d6): d = 195.6, 162.4, 158.2, 143.5,
134.7, 129.8, 127.2, 126.3, 126.1, 119.7, 113.4, 58.2, 49.9, 39.6,
31.8, 30.8, 28.4, 26.7, 19.0 ppm.
207–208 °C (lit.14 mp 205–207 °C racemic). ½a 2D5
¼ þ39:2 (c 0.49,
ꢁ
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 13.9 min, minor enantiomer tR = 17.9 min, 83%
ee. 1H NMR (400 MHz, DMSO-d6): d = 7.48 (d, J = 8.4 Hz, 2H, ArH),
7.11 (d, J = 8.4 Hz, 2H, ArH), 7.07 (s, 2H, NH2), 4.18 (s, 1H, CH),
2.51 (s, 2H, CH2), 2.25 (d, J = 16.0 Hz, 1H, CH2), 2.10 (d,
J = 16.4 Hz, 1H, CH2), 1.03 (s, 3H, CH3), 0.95 (s, 3H, CH3) ppm. 13C
NMR (100 MHz, DMSO-d6): d = 195.5, 162.5, 158.4, 144.1, 131.1,
129.4, 119.5, 112.2, 57.6, 49.8, 39.6, 35.1, 31.7, 28.2, 26.8 ppm.
4.2.9. (R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(3,4-di-
methoxyphenyl)-5-oxo-4H-chromene-3-carbonitrile 11i
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (79.6 mg, 90% yield); mp
4.2.5. (R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(4-meth-
ylphenyl)-5-oxo-4H-chromene-3-carbonitrile 11e
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (74.8 mg, 97% yield); mp
194–195 °C (lit.16 mp 191–193 °C, racemic). ½a 2D5
¼ þ21:1 (c 0.92,
ꢁ
217–218 °C (lit.15 mp 218–219 °C, racemic). ½a 2D5
ꢁ
¼ þ22:1 (c 0.97,
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 11.0 min, minor enantiomer tR = 14.1 min, 64%
ee. 1H NMR (400 MHz, DMSO-d6): d = 6.97 (s, 2H, NH2), 6.86 (d,
J = 8.0 Hz, ArH), 6.68 (s, 1H, ArH), 6.65 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz,
1H, ArH), 4.12 (s, 1H, CH), 3.71 (s, 3H, OCH3), 3.70 (s, 3H, OCH3),
2.51 (AB quartet, J = 17.6 Hz, 2H, CH2), 2.26 (d, J = 16.0 Hz, 1H,
CH2), 2.11(d, J = 16.0 Hz, 1H, CH2), 1.04 (s, 3H, CH3), 0.98 (s, 3H,
CH3) ppm. 13C NMR (100 MHz, DMSO-d6): d = 195.6, 162.2, 158.3,
148.4, 147.5, 137.3, 119.7, 119.1, 112.8, 111.7, 111.0, 58.5, 55.40,
55.37, 49.9, 39.6, 35.0, 31.7, 28.4, 26.6 ppm.
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 11.9 min, minor enantiomer tR = 15.4 min, 68%
ee. 1H NMR (400 MHz, DMSO-d6): d = 7.08 (d, J = 8.0 Hz, 2H, ArH),
7.02 (d, J = 8.0 Hz, 2H, ArH), 6.96 (s, 2H, NH2), 4.12 (s, 1H, CH),
2.50 (AB quartet, J = 17.2 Hz, 2H, CH2), 2.22–2.26 (m, 3H, CH2,
CH3), 2.08 (d, J = 16.4 Hz, 1H, CH2), 1.03 (s, 3H, CH3), 0.95 (s, 3H,
CH3) ppm. 13C NMR (100 MHz, DMSO-d6): d = 195.5, 162.2, 158.3,
141.7, 135.5, 128.8, 127.0, 119.6, 112.8, 58.4, 49.9, 39.6, 35.1,
31.7, 28.3, 26.7, 20.5 ppm.
4.2.6. (R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(4-nitro-
phenyl)-5-oxo-4H-chromene-3-carbonitrile 11f
4.2.10. (R)-2-Amino-5,6,7,8-tetrahydro-7,7-dimethyl-4-(2-
naphthyl)-5-oxo-4H-chromene-3-carbonitrile 11j
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (79.3 mg, 94% yield); mp
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (81.0 mg, 94% yield); mp
175–176 °C (lit.14 mp 179–180 °C, racemic). ½a 2D5
ꢁ
¼ þ25:0 (c 0.93,
257–258 °C (lit.17 mp 258–260 °C, racemic). ½a 2D5
¼ þ73:7 (c 0.92,
ꢁ
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 23.3 min, minor enantiomer tR = 32.8 min, 42%
ee. 1H NMR (400 MHz, DMSO-d6): d = 8.18 (d, J = 8.8 Hz, 2H, ArH),
7.45 (d, J = 8.8 Hz, 2H, ArH), 7.18 (s, 2H, NH2), 4.37 (s, 1H, CH),
2.54 (s, 2H, CH2), 2.27 (d, J = 16.0 Hz, 1H, CH2), 2.12 (d,
J = 16.4 Hz, 1H, CH2), 1.05 (s, 3H, CH3), 0.96 (s, 3H, CH3) ppm. 13C
NMR (100 MHz, DMSO-d6): d = 195.6, 163.0, 158.5, 152.2, 146.2,
128.5, 123.6, 119.2, 111.7, 56.9, 49.8, 39.6, 35.6, 31.7, 28.2,
26.8 ppm.
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 19.2 min, minor enantiomer tR = 24.6 min, 54%
ee. 1H NMR (400 MHz, DMSO-d6): d = 8.37 (d, J = 8.0 Hz, 1H, ArH),
7.90–7.92 (m, 1H, ArH), 7.77 (d, J = 8.0 Hz, 1H, ArH), 7.43–7.58
(m, 3H, ArH), 7.24 (d, J = 7.2 Hz, 1H, ArH), 6.96 (s, 2H, NH2), 5.14
(s, 1H, CH), 2.59 (s, 2H, CH2), 2.24 (d, J = 16.0 Hz, 1H, CH2), 2.06
(d, J = 16.0 Hz, 1H, CH2), 1.05 (s, 3H, CH3), 0.99 (s, 3H, CH3) ppm.
13C NMR (100 MHz, DMSO-d6): d = 195.6, 162.7, 158.3, 133.2,
130.7, 128.3, 126.9, 125.7, 125.6, 125.5, 123.5, 119.5, 113.3, 58.8,
49.9, 39.6, 31.7, 28.3, 26.9 ppm.
4.2.7. (R)-2-Amino-4-(2-chlorophenyl)-5,6,7,8-tetrahydro-7,7-
dimethyl-5-oxo-4H-chromene-3-carbonitrile 11g
4.2.11. (R)-2-Amino-5,6,7,8-tetrahydro-5-oxo-4-phenyl-4H-
chromene-3-carbonitrile 13a6e
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (80.9 mg, 99% yield); mp
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (55.7 mg, 84% yield); mp
216–217 °C (lit.14 mp 214–215 °C, racemic).
½
a 2D5
ꢁ
¼ þ47:3 (c
0.77, acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-
propanol = 80:20, flow rate 1.0 mL/min, detection at 254 nm):
major enantiomer tR = 7.3 min, minor enantiomer tR = 8.8 min,
51% ee. 1H NMR (400 MHz, DMSO-d6): d = 7.36 (d, J = 8.0 Hz,
1H, ArH), 7.27 (t, J = 6.8 Hz, 1H, ArH), 7.16–7.22 (m, 2H, ArH),
7.03 (s, 2H, NH2), 4.70 (s, 1H, CH), 2.52 (AB quartet,
J = 17.2 Hz, 2H, CH2), 2.25 (d, J = 16.0 Hz, 1H, CH2), 2.08 (d,
J = 16.0 Hz, 1H, CH2), 1.04 (s, 3H, CH3), 0.98 (s, 3H, CH3) ppm.
13C NMR (100 MHz, DMSO-d6): d = 195.4, 163.0, 158.6, 141.5,
213–214 °C. ½a 2D5
¼ þ54:7 (c 0.74, acetone); HPLC (Daicel Chiralpak
ꢁ
IA column, n-hexane/2-propanol = 90:10, flow rate 1.0 mL/min,
detection at 254 nm): major enantiomer tR = 16.1 min, minor enan-
tiomer tR = 19.8 min, 55% ee. 1H NMR (400 MHz, DMSO-d6):
d = 7.28 (t, J = 7.2 Hz, 2H, ArH), 7.14–7.19 (m, 3H, ArH), 6.99 (s,
2H, NH2), 4.19 (s, 1H, CH), 2.62 (s, 2H, CH2), 2.21–2.31 (m, 2H,
CH2), 1.87–1.98 (m, 2H, CH2) ppm. 13C NMR (100 MHz, DMSO-
d6): d = 195.8, 164.4, 158.4, 144.7, 128.2, 127.0, 126.4, 119.7,
113.7, 58.2, 36.3, 35.4, 26.4, 19.7 ppm.

1348
Y. Gao, D.-M. Du / Tetrahedron: Asymmetry 23 (2012) 1343–1349
4.2.12. (R)-2-Amino-4-(4-fluorophenyl)-5,6,7,8-tetrahydro-5-
oxo-4H-chromene-3-carbonitrile 13b6e
ee. 1H NMR (400 MHz, DMSO-d6): d = 8.16 (d, J = 8.4 Hz, 2H, ArH),
7.47 (d, J = 8.4 Hz, 2H, ArH), 7.18 (s, 2H, NH2), 4.37 (s, 1H, CH),
2.64 (s, 2H, CH2), 2.23–2.37 (m, 2H, CH2), 1.91–1.99 (m, 2H, CH2)
ppm. 13C NMR (100 MHz, DMSO-d6): d = 195.8, 165.0, 158.5,
152.2, 146.1, 128.5, 123.5, 119.3, 112.7, 56.9, 36.1, 35.5, 26.5,
19.7 ppm.
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (64.6 mg, 91% yield); mp
211–212 °C. ½a 2D5
¼ þ42:9 (c 1.03, acetone); HPLC (Daicel Chiralpak
ꢁ
IA column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min,
detection at 254 nm): major enantiomer tR = 7.6 min, minor enan-
tiomer tR = 8.6 min, 42% ee. 1H NMR (400 MHz, DMSO-d6): d = 7.20
(t, J = 6 Hz, 2H, ArH), 7.10 (t, J = 8.0 Hz, 2H, ArH), 7.02 (s, 2H, NH2),
4.21 (s, 1H, CH), 2.61 (s, 2H, CH2), 2.22–2.34 (m, 2H, CH2), 1.88–
1.98 (m, 2H, CH2) ppm. 13C NMR (100 MHz, DMSO-d6): d = 195.8,
4.2.17. (R)-2-Amino-4-(2-chlorophenyl)-5,6,7,8-tetrahydro-5-
oxo-4H-chromene-3-carbonitrile 13g
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (70.0 mg, 93% yield); mp
164.4, 160.8 (d, JC-F = 240.9 Hz), 158.4, 140.9, 128.9 (3JC-
213–214 °C (lit.18 mp 212–214 °C, racemic). ½a 2D5
¼ þ33:2 (c 0.86,
ꢁ
1
F = 8.1 Hz), 119.6, 114.9 (2JC-F = 21.2 Hz), 113.6, 58.0, 36.2, 34.7,
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 20.0 min, minor enantiomer tR = 23.0 min, 34%
ee. 1H NMR (400 MHz, DMSO-d6): d = 7.36 (d, J = 7.2 Hz, 1H, ArH),
7.26 (t, 1H, J = 7.0 Hz, 1H, ArH), 7.19 (t, J = 6.8 Hz, 2H, ArH), 7.01
(s, 2H, NH2), 4.71 (s, 1H, CH), 2.55–2.67 (m, 2H, CH2), 2.19–2.32
(m, 2H, CH2), 1.90–1.97 (m, 2H,CH2) ppm. 13C NMR (100 MHz,
DMSO-d6): d = 195.6, 165.0, 158.5, 141.7, 132.0, 129.7, 129.2,
128.0, 127.4, 119.2, 112.8, 56.8, 36.2, 32.6, 26.4, 19.8 ppm.
26.4, 19.7 ppm.
4.2.13. (R)-2-Amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydro-5-
oxo-4H-chromene-3-carbonitrile 13c6e
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (73.9 mg, 98% yield); mp
227–228 °C. ½a 2D5
¼ þ24:7 (c 0.85, acetone); HPLC (Daicel Chiralpak
ꢁ
IA column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min,
detection at 254 nm): major enantiomer tR = 7.7 min, minor enan-
tiomer tR = 9.1 min, 53% ee. 1H NMR (400 MHz, DMSO-d6): d = 7.34
(d, J = 8.0 Hz, 2H, ArH), 7.19 (d, J = 8.0 Hz, 2H, ArH), 7.05 (s, 2H,
NH2), 4.20 (s, 1H, CH), 2.61 (s, 2H, CH2), 2.22–2.34 (m, 2H, CH2),
1.88–1.96 (m, 2H, CH2) ppm. 13C NMR (100 MHz, DMSO-d6):
d = 195.7, 164.5, 158.4, 143.7, 131.0, 129.0, 128.2, 119.5, 113.3,
57.6, 36.2, 34.9, 26.4, 19.7 ppm.
4.2.18. (R)-2-Amino-5,6,7,8-tetrahydro-4-(2-methylphenyl)-5-
oxo-4H-chromene-3-carbonitrile 13h
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (69.4 mg, 99% yield); mp
195–196 °C. ½a 2D5
¼ þ32:7 (c 1.12, acetone); HPLC (Daicel Chiralpak
ꢁ
IA column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min,
detection at 254 nm): major enantiomer tR = 7.0 min, minor enan-
tiomer tR = 7.8 min, 49% ee. 1H NMR (400 MHz, DMSO-d6):
d = 7.02–7.13 (m, 3H, ArH), 6.96 (d, J = 7.2 Hz, 1H, ArH), 6.93 (s,
2H, NH2), 4.47 (s, 1H, CH), 2.60–2.67 (m, 2H, CH2), 2.46 (s, 3H,
CH3), 2.18–2.31 (m, 2H, CH2), 1.88–1.98 (m, 2H, CH2) ppm. 13C
NMR (100 MHz, DMSO-d6): d = 195.8, 164.3, 158.1, 143.6, 134.7,
129.7, 127.3, 126.4, 126.1, 119.7, 114.5, 58.1, 36.2, 31.0, 26.3,
4.2.14. (R)-2-Amino-4-(4-bromophenyl)-5,6,7,8-tetrahydro-5-
oxo-4H-chromene-3-carbonitrile 13d6e
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (81.5 mg, 94% yield); mp
234–235 °C. ½a 2D5
¼ þ29:5 (c 0.80, acetone); HPLC (Daicel Chiralpak
ꢁ
IA column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min,
detection at 254 nm): major enantiomer tR = 8.0 min, minor enan-
tiomer tR = 9.6 min, 49% ee. 1H NMR (400 MHz, DMSO-d6): d = 7.47
(d, J = 8.0 Hz, 2H, ArH), 7.13 (d, J = 8.0 Hz, 2H, ArH), 7.05 (s, 2H,
NH2), 4.19 (s, 1H, CH), 2.61 (s, 2H, CH2), 2.22–2.33 (m, 2H, CH2),
1.88–1.96 (m, 2H, CH2) ppm. 13C NMR (100 MHz, DMSO-d6):
d = 195.7, 164.5, 158.4, 144.1, 131.1, 129.4, 119.5, 113.2, 57.5,
36.2, 35.0, 26.4, 19.7 ppm.
19.8, 19.0 ppm. HRMS (ESI): m/z calculated for
C17H17N2O2
[M+H]+ 281.12845, found 281.12791.
4.2.19. (R)-2-Amino-5,6,7,8-tetrahydro-4-(3,4-dimethoxy-
phenyl)-5-oxo-4H-chromene-3-carbonitrile 13i
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (76.9 mg, 94% yield); mp
227–228 °C (lit.16 mp 227–229 °C, racemic). ½a 2D5
¼ þ24:9 (c 0.85,
ꢁ
4.2.15. (R)-2-Amino-5,6,7,8-tetrahydro-4-(4-methylphenyl)-5-
oxo-4H-chromene-3-carbonitrile 13e
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 10.8 min, minor enantiomer tR = 15.2 min, 53%
ee. 1H NMR (400 MHz, DMSO-d6): d = 6.94 (s, 2H, NH2), 6.85 (d,
J = 8.4 Hz, 1H, ArH), 6.72 (s, 1H, ArH), 6.63–6.65 (m, 1H, ArH),
4.15 (s, 1H, CH), 3.72 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 2.61 (s,
2H, CH2), 2.28 (s, 2H, CH2), 1.87–1.98 (m, 2H, CH2) ppm. 13C NMR
(100 MHz, DMSO-d6): d = 195.8, 164.1, 158.3, 148.4, 147.5, 137.3,
119.8, 118.9, 113.9, 111.8, 111.1, 58.3, 55.45, 55.40, 36.3, 34.8,
26.4, 19.8 ppm.
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (69.6 mg, 99% yield); mp
225–226 °C (lit.18 mp 214–216 °C, racemic). ½a 2D5
¼ þ36:0 (c 0.85,
ꢁ
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 6.7 min, minor enantiomer tR = 7.9 min, 54% ee.
1H NMR (400 MHz, DMSO-d6): d = 7.07 (d, J = 7.8 Hz, 2H, ArH),
7.03 (d, J = 8.0 Hz, 2H, ArH), 6.95 (s, 2H, NH2), 4.14 (s, 1H, CH),
2.60 (s, 2H, CH2), 2.20–2.32 (m, 5H, CH2 + CH3), 1.86–1.95 (m, 2H,
CH2) ppm. 13C NMR (100 MHz, DMSO-d6): d = 195.7, 164.1, 158.4,
141.8, 135.5, 128.8, 126.8, 127.0, 113.9, 58.3, 36.3, 35.0, 26.4,
20.5, 19.7 ppm.
4.2.20. (R)-2-Amino-5,6,7,8-tetrahydro-4-(2-naphthyl)-5-oxo-
4H-chromene-3-carbonitrile 13j
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (66.1 mg, 99% yield); mp
4.2.16. (R)-2-Amino-5,6,7,8-tetrahydro-4-(4-nitrophenyl)-5-
oxo-4H-chromene-3-carbonitrile 13f
254–255 °C (lit.17 mp 254–255 °C, racemic). ½a 2D5
¼ þ61:5 (c 0.78,
ꢁ
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 26.1 min, minor enantiomer tR = 28.6 min, 45%
ee. 1H NMR (400 MHz, DMSO-d6-d6): d = 8.39 (d, J = 8.0 Hz, 1H,
ArH), 7.91 (d, J = 7.6 Hz, 1H, ArH), 7.77 (d, J = 8.0 Hz, 1H, ArH),
7.51–7.58 (m, 2H, ArH), 7.44 (t, J = 7.2 Hz, 1H, ArH), 7.25 (d,
J = 6.8 Hz, 1H, ArH), 6.94 (s, 2H, NH2), 5.15 (s, 1H, CH), 2.62–2.75
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (76.8 mg, 99% yield); mp
233–234 °C (lit.18 mp 235–236 °C, racemic). ½a 2D5
¼ þ42:2 (c 1.02,
ꢁ
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 80:20, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 12.3 min, minor enantiomer tR = 18.0 min, 31%

Y. Gao, D.-M. Du / Tetrahedron: Asymmetry 23 (2012) 1343–1349
1349
Bunch, L. J. Med. Chem. 2009, 52, 912; (c) Grée, D.; Vorin, S.; Manthati, V. L.;
Caijo, F.; Viault, G.; Manero, F.; Juin, P.; Grée, R. Tetrahedron Lett. 2008, 49,
3276; (d) Kumar, D.; Reddy, V. B.; Sharad, S.; Dube, U.; Kapur, S. Eur. J. Med.
Chem. 2009, 44, 3805.
(m, 2H, CH2), 2.18–2.32 (m, 2H, CH2), 1.91–2.01 (m, 2H, CH2) ppm.
13C NMR (100 MHz, DMSO-d6): d = 195.8, 164.7, 158.4, 141.9,
133.2, 130.7, 128.3, 126.8, 125.7, 125.5, 124.9, 123.6, 119.6,
114.4, 58.7, 36.3, 30.0, 26.5, 19.8 ppm.
4. For selected examples, see: (a) Ballini, R.; Bosica, G.; Conforti, M. L.; Maggi, R.;
Mazzacani, A.; Righi, P.; Sartori, G. Tetrahedron 2001, 57, 1395; (b)
Abdolmohammadi, S.; Balalaie, S. Tetrahedron Lett. 2007, 48, 3299; (c) Gao, S.;
Tsai, C. H.; Tseng, C.; Yao, C.-F. Tetrahedron 2008, 64, 9143; (d) Kumaravel, K.;
Vasuki, G. Green Chem. 2009, 11, 1945; (e) Khurana, J. M.; Kumar, S. Tetrahedron
Lett. 2009, 50, 4125; (f) Elinson, M. N.; Ilovaisky, A. I.; Merkulova, V. M.;
Belyakov, P. A.; Chizhov, A. O.; Nikishin, G. I. Tetrahedron 2010, 66, 4043; (g)
Moafi, L.; Ahadi, S.; Bazgir, A. Tetrahedron Lett. 2010, 51, 6270; (h)
Boominathan, M.; Nagaraj, M.; Muthusubramanian, S.; Krishnakumar, R. V.
Tetrahedron 2011, 67, 6057.
5. (a) Dong, Z.; Liu, X.; Feng, J.; Wang, M.; Lin, L.; Feng, X. Eur. J. Org. Chem. 2011,
137; (b) Chen, W.; Cai, Y.; Fu, X.; Liu, X.; Lin, L.; Feng, X. Org. Lett. 2011, 13, 4910.
6. (a) Wang, X. S.; Yang, G. S.; Zhao, G. Tetrahedron: Asymmetry 2008, 19, 709; (b)
Gogoi, S.; Zhao, C.-G. Tetrahedron Lett. 2009, 50, 2252; (c) Ding, D. R.; Zhao, C. G.
Tetrahedron Lett. 2010, 51, 1322; (d) Ramireddy, N.; Abbaraju, S.; Zhao, C.-G.
Tetrahedron Lett. 2011, 52, 6792; (e) Zhang, G.; Zhang, Y. H.; Yan, J. X.; Chen, R.;
Wang, S. L.; Ma, Y. X.; Wang, R. J. Org. Chem. 2012, 77, 878; (f) Ren, Q.; Gao, Y. J.;
Wang, J. Chem. Eur. J. 2010, 16, 13594; (g) Ren, Q.; Siau, W.-Y.; Du, Z.; Zhang, K.;
Wang, J. Chem. Eur. J. 2011, 17, 7781; (h) Du, Z.; Siau, W.-Y.; Wang, J.
Tetrahedron Lett. 2011, 52, 6137; (i) Yang, G.; Luo, C.; Mu, X.; Wang, T.; Liu, X.-Y.
Chem. Commun. 2012, 48, 5880; (j) Muramulla, S.; Zhao, C.-G. Tetrahedron Lett.
2011, 52, 3905; (k) Li, W. J.; Liu, H.; Jiang, X. F.; Wang, J. ACS Catal. 2012, 2, 1535.
7. Xie, J. W.; Huang, X.; Fan, L. P.; Xu, D. C.; Li, X. S.; Su, H.; Wen, Y. H. Adv. Synth.
Catal. 2009, 351, 3077.
4.2.21. (R)-2-Amino-4,5,6,7-tetrahydro-5-oxo-4-phenyl-cyclo-
penta[b]pyran-3-carbonitrile 15
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (56.3 mg, 89% yield); mp
187–188 °C (lit.19 mp 192–194 °C, racemic). ½a 2D5
¼ þ6:9 (c 1.15,
ꢁ
acetone); HPLC (Daicel Chiralpak IA column, n-hexane/2-propa-
nol = 90:10, flow rate 1.0 mL/min, detection at 254 nm): major
enantiomer tR = 20.1 min, minor enantiomer tR = 24.4 min, 32%
ee. 1H NMR (400 MHz, DMSO-d6): d = 7.30 (t, J = 7.2 Hz, 2H, ArH),
7.18–7.23 (m, 3H, ArH), 7.20 (s, 2H, NH2), 4.19 (s, 1H, CH), 2.68–
2.82 (m, 2H, CH2), 2.36–2.38 (m, 2H, CH2) ppm. 13C NMR
(100 MHz, DMSO-d6): d = 201.0, 176.2, 159.4, 142.6, 128.3, 127.6,
126.8, 119.7, 116.8, 57.5, 35.5, 33.4, 24.5 ppm.
4.2.22. (R)-2-Amino-5-oxo-4-phenyl-4H,5H-pyrano[3,2-c]chro-
mene-3-carbonitrile 176e
Prepared according to the general procedure, the title com-
pound was obtained as a white solid (72.6 mg, 99% yield); mp
8. For selected reviews, see: (a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299; (b)
Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520; (c) Connon, S.
J. Chem. Eur. J. 2006, 12, 5418; (d) Siau, W.-Y.; Wang, J. Catal. Sci. Technol. 2011,
1, 1298.
256–257 °C. ½a 2D5
¼ þ1:1 (c 0.75, acetone); HPLC (Daicel Chiralpak
ꢁ
IA column, n-hexane/2-propanol = 80:20, flow rate 1.0 mL/min,
detection at 254 nm): major enantiomer tR = 8.1 min, minor enan-
tiomer tR = 8.8 min, 6% ee. 1H NMR (400 MHz, DMSO-d6): d = 7.90
(d, J = 8.0 Hz, 1H, ArH), 7.71 (t, J = 7.8 Hz, 1H, ArH), 7.41–7.51 (m,
4H, ArH), 7.25–7.33 (m, 5H, ArH + NH2) ppm. 13C NMR (100 MHz,
DMSO-d6): d = 159.4, 157.9, 153.3, 152.0, 143.3, 132.8, 128.4,
127.6, 127.0, 124.6, 122.4, 119.2, 116.5, 112.9, 103.9, 57.9,
36.9 ppm.
9. For selected examples, see: (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672; (b) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto,
Y. J. Am. Chem. Soc. 2005, 127, 119; (c) McCooey, S. H.; Connon, S. J. Angew.
Chem., Int. Ed. 2005, 44, 6367; (d) Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun.
2005, 35, 4481; (e) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170;
(f) Cao, C.; Ye, M.; Sun, X.; Tang, Y. Org. Lett. 2006, 8, 2901; (g) Liu, K.; Cui, H.-F.;
Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Org. Lett. 2007, 9, 923; (h) Rabalakos, C.;
Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 13524; (i) Wang, C.-J.; Zhang, Z.-H.;
Dong, X.-Q.; Wu, X.-J. Chem. Commun. 2008, 1431; (j) Zhou, W. M.; Liu, H.; Du,
D. M. Org. Lett. 2008, 10, 2817.
10. For reviews of squaramides, see: (a) Alemán, J.; Parra, A.; Jiang, H.; Jørgensen, K.
A. Chem. Eur. J. 2011, 17, 6890; (b) Storer, R. I.; Aciro, C.; Jones, L. H. Chem. Soc.
Rev. 2011, 40, 2330.
Acknowledgments
11. For selected examples of squaramide-catalyzed asymmetric reactions, see: (a)
Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416; (b)
Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed. 2010, 49, 153; (c)
Yang, W.; Du, D. M. Org. Lett. 2010, 12, 5450; (d) Xu, D. Q.; Wang, Y.-F.; Zhang,
W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y. Chem. Eur. J. 2010, 16, 4177; (e)
Dai, L.; Wang, S.-X.; Chen, F.-E. Adv. Synth. Catal. 2010, 352, 2137; (f) Yang, W.;
Du, D. M. Chem. Commun. 2011, 47, 12706; (g) Yang, W.; Du, D. M. Adv. Synth.
Catal. 2011, 353, 1241; (h) Pansare, S. V.; Paul, E. K. Chem. Commun. 2011, 47,
1027; (i) Min, C.; Han, X.; Liao, Z.; Wu, X.; Zhou, H.-B.; Dong, C. Adv. Synth. Catal.
2011, 353, 2715; (j) Bae, H. Y.; Some, S.; Lee, J. H.; Kim, J.-Y.; Song, M. J.; Lee, S.;
Zhang, Y. J.; Song, C. E. Adv. Synth. Catal. 2011, 353, 3196; (k) Yang, W.; Jia, Y.;
Du, D. M. Org. Biomol. Chem. 2012, 10, 332.
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21272024), the Science and
Technology Innovation Program of Beijing Institute of Technology
(Grant No. 2011CX01008), and the Development Program for Dis-
tinguished Young and Middle-aged Teachers of Beijing Institute
of Technology.
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