Organocatalyzed Enantioselective Synthesis of 2-Amino-4H-chromene Derivatives

Article abstract of DOI:10.1002/jhet.2641

Optically active 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylates, 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles, and 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles were synthesized. Using cinchona alkaloid-derived bifunctional catalysts, the corresponding 2-amino-4H-chromene derivatives were obtained in high yields and moderate to high ee values (up to 82% ee) from the tandem Michael addition–cyclization reaction between 1,3-cyclohexanediones or 1,2-cyclohexanediones and (E)-3-aryl-2-cyanoacrylate or alkylidene malononitrile derivatives.

Full text of DOI:10.1002/jhet.2641

Month 2016
Organocatalyzed Enantioselective Synthesis of 2-Amino-4H-chromene
Derivatives
*
Naresh Ramireddy, Santhi Abbaraju, Derong Ding, Hadi Arman, and John C.-G. Zhao
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-0698, USA
*
E-mail: cong.zhao@utsa.edu
Received May 6, 2014
DOI 10.1002/jhet.2641
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Optically active 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylates, 2-amino-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitriles, and 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles
were synthesized. Using cinchona alkaloid-derived bifunctional catalysts, the corresponding 2-amino-4H-
chromene derivatives were obtained in high yields and moderate to high ee values (up to 82% ee) from the
tandem Michael addition–cyclization reaction between 1,3-cyclohexanediones or 1,2-cyclohexanediones and
(E)-3-aryl-2-cyanoacrylate or alkylidene malononitrile derivatives.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
similar derivatives [13]; however, the enantioselective ver-
sion of this reaction was seldom explored [8a] prior to our
initial study [12].
Chromene is an important structural motif that can be
found in many natural products, such as tocopherols, flavo-
noids, and anthocyanins, which possess many biological
activities [1]. Moreover, polyfunctionalized chromenes also
play an important role in the field of medicinal chemistry
because these compounds frequently display various
biological activities, such as anticancer, anticoagulant,
spasmolytic, diuretic, anti-anaphylactic, antibacterial, and
fungicidal activities [2]. Because of their biological signifi-
cance, recently, there has been considerable interest in
developing high enantioselective methods for the synthesis
of these compounds, especially the 2-amino-4H-chromene
derivatives [3–10], and several organocatalytic methods
have been reported in recent years [4–10]. Our group is
interested in developing enantioselective methods for the
synthesis of substituted pyrans and thiopyrans [11,12].
Herein, we wish to disclose a detailed study of the synthesis
of 2-amino-5,6,7,8-tetrahydro-4H-chromene derivatives.
Synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carboxylates. Because Brønsted base is a good catalyst
for the racemic reaction [13], it is conceivable that
asymmetric induction may be achieved in the synthesis if a
chiral Brønsted base is used as the catalyst [14]. Thus,
using 5,5-dimethylcyclohexane-1,3-dione (dimedone, 2a),
and (E)-ethyl 2-cyano-3-phenylacrylate (3a) as the model
substrates, we first screened some common chiral
bifunctional Brønsted bases (Fig. 1) as the catalyst for their
ability in inducing the desired enantioselectivity in the
synthesis of ethyl 2-amino-7,7-diemthyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carboxylate (4a). The results are
summarized in Table 1.
As is evident from the data in Table 1, when quinine-
derived thiourea 1a (10 mol %) was used as the catalyst
in toluene at room temperature, the desired chromenone
product 4a was obtained in an excellent yield of 92%
(entry 1). The formation of 4a was confirmed by comparing
its 1H and 13C NMR spectroscopic data with those reported
data [3]. The ee value of this product was determined to be
72% (entry 1). Similarly, excellent yield of 4a and good ee
values were obtained with the dihydroquinine-derived thio-
urea 1b (entry 2) and cinchonidine thiourea 1c (entry 3).
When quinidine thiourea (1d) and cinchonine thiourea
(1e), the pseudo-enantiomers of 1a and 1c, respectively,
were applied under the aforementioned conditions, slightly
lower ee values were obtained for the opposite enantiomeric
product, but the yields remained high (entries 4–5). In
contrast, when quinine (1f) was used as the catalyst, the de-
sired product 4a was obtained in a high yield (94%),
but with a much inferior ee value (22%, entry 6). Similarly,
RESULTS AND DISCUSSION
Our approach for the assembly of these 2-amino-4H-
chromene derivatives was based on a tandem Michael
cyclization reaction between a cycloketone nucleophile
(1,3-cyclohexanediones or 1,2-cyclohexanediones) and
arylidenemalononitriles or 3-aryl-2-cyanoacrylates. The
cyclization reaction between cyclohexane-1,3-diones and
other 1,3-dicarbonyl compounds and benzylidenemalo-
nonitriles in the presence of a suitable base was used in
the literature for the synthesis of racemic 2-amino-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles
and
© 2016 Wiley Periodicals, Inc.

N. Ramireddy, S. Abbaraju, D. Ding, H. Arman, and J. C.-G. Zhao
Vol 9999
cupreine (1g) is also a highly reactive but poorly
enantioselective catalyst (entry 7). These results indicate
that the thiourea moiety is essential for achieving good
enantioselectivity in this reaction. As an additional
evidence of this, the Takemoto thiourea (1j) [14c] also led
to a much better ee value of 4a (57% ee, entry 8) than 1f
and 1g. When quinine squaramide (1k) was applied, the
product was obtained in 61% ee (entry 9). Thus, this screen
identified quinine thiourea (1a) and dihydroquinine
thiourea (1b) as the best catalysts for this reaction. Because
1a is more easily accessible than 1b, it was adopted for
further reaction condition optimizations.
Firstly, the effects of solvent on the reaction were evalu-
ated. It was found that, besides toluene, similar but slightly
diminished enantioselectivities may also be obtained in
xylene, benzene, dimethoxyethane (DME), and ether
(entries 10–13). Other common organic solvents, such as
tetrahydrofuran (THF) (entry 14) and CH2Cl2 (entry 15),
led to slightly inferior ee values of the product. Addition-
ally, slightly lower product yields were obtained in ethereal
solvents like DME and Et2O (entries 12–13). Thus, toluene
was identified as the best solvent for this reaction.
Figure 1. Structure of the catalysts screened in the study [Ar = 3,5-
(CF3)2C6H3-].
Table 1
Catalyst screening and reaction condition optimizations.a
Entry
Solvent
Catalyst
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Xylene
Benzene
DME
Et2O
THF
CH2Cl2
Toluene
Toluene
1a
1b
1c
1d
1e
1f
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
4.5
4.5
92
93
90
91
90
94
91
84
91
91
90
86
85
90
93
92
74
72
72
70
62d
66d
22
14
57d
61
71
70
71
70
68
62
79
77
1g
1j
9
1k
1a
1a
1a
1a
1a
1a
1a
1a
10
11
12
13
14
15
16e
17f
aUnless otherwise indicated, all reactions were conducted with dimedone (2a, 0.10 mmol), (E)-ethyl 2-cyano-3-phenylacrylate (3a, 0.12 mmol), and the
catalyst (0.010 mmol, 10 mol %) in the specified solvent (0.5 mL) at room temperature.
bYield of isolated product after column chromatography.
cDetermined by HPLC analysis on a ChiralCel OD-H column.
dThe opposite enantiomer was obtained in excess.
eThe reaction was conducted at 0°C.
fThe reaction was conducted at À15°C.
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DOI 10.1002/jhet

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Enantioselective Synthesis of 2-Amino-4H-chromene Derivatives
Secondly, the influence of temperature on this reaction
was investigated. When the reaction was performed at 0°C,
the ee value was improved to 79% at a slight expense of
the reaction rate (entry 16). Further decrease of the
reaction temperature to À15°C showed no enhancement
in the ee value but with a further decrease of the reaction
rate (entry 17).
With the optimized reaction conditions at hand, we then
studied the substrate scope of this reaction, and the results
are compiled in Table 2. As the results in Table 2 show,
different ester alkyl groups on the (E)-2-cyano-3-
phenylacrylates (3) have some effects on the enan-
tioselectivity of this reaction: The ee value of the product
4 increases from 69 to 80% when the ester alkyl group is
changed from a methyl to an isopropyl group (entries
1–3). These increases are most likely because of the steric
effects [10]. Because the isopropyl group leads to the
highest product ee value, it was chosen for further study.
Similarly, the electronic nature of the substituent on the
phenyl ring of 3 influences the enantioselectivity of this re-
action. Electron-withdrawing groups on the para position
of the phenyl ring result in lower ee values: The stronger
the electron-withdrawing capacity of the substituent, the
lower the product ee value (entries 4–8). Strong electron-
withdrawing groups, such as the cyano and nitro groups,
also lead to diminished product yields (entries 7 and 8).
In contrast, electron-donating groups like methyl and
methoxy groups lead to slightly higher ee values of the
product as compared to the unsubstituted phenyl group
(entries 9 and 10). The electronic effects of the substituents
may be able to change the hydrogen bonding capability of
the cyano and carbonyl groups in 3, which, in turn, leads to
the changes in the product ee values. A similar phenome-
non has been observed before in a similar reaction [7a].
The position of the substituent on the phenyl ring also af-
fects the enantioselectivity. While meta-substituted 3 gives
similar results as the para-substituted ones (entries 11 vs.
entry 6; entry 13 vs. entry 10), ortho-substituted com-
pounds yield much lower ee values of the products (entry
12 vs. entries 6 and 11; entry 14 vs. entries 10 and 13).
The drop in the enantioselectivity in the ortho-substituted
benzylidenecyanoacetates is most likely because of steric
effects. Besides phenyl substituted 2-cyanoacrylates, 1-
naphthyl (entry 15) and 2-thienyl (entry 16) substituted 2-
cyanoacrylates are also good substrates for this reaction,
and the corresponding products were obtained in 65%
Table 2
Enantioselective synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylates.a
Entry
R1
R2
4
Time (h)
Yieldb (%)
eec (%)
1d
2e
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Ph
Ph
Ph
a
b
c
d
e
4.5
4
4.5
4
4
4.5
3
2.5
4.5
6.5
4.5
3.5
6.5
6.5
7.5
11
4.5
92
90
85
88
85
91
75
72
85
84
90
85
86
82
81
67
83
79
69
80
74
4-FC6H4
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
3-BrC6H4
2-BrC6H4
3-MeOC6H4
2-MeOC6H4
1-napthyl
2-thienyl
Ph
76
f
75
g
h
i
j
k
l
n
m
o
p
q
66f
65f
82f
80
74
20f
74
51f
65f
76f
70f
aUnless otherwise specified, all reactions were conducted with cyclohexane-1,3-dione (2, 0.10 mmol), alkylidenecyanoacetate (3, 0.12 mmol, unless
otherwise indicated, R3 = i-Pr), and catalyst 1a (0.010 mmol, 10 mol %) in toluene (0.5 mL) at 0°C.
bYield of isolated product after column chromatography.
cDetermined by HPLC analysis on a ChiralCel OD-H column.
dR3 = Et.
eR3 = Me.
fDetermined by HPLC analysis on a ChiralPak AD-H column.
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N. Ramireddy, S. Abbaraju, D. Ding, H. Arman, and J. C.-G. Zhao
Vol 9999
and 76% ee, respectively. Unsubstituted 1,3-
cyclohexanedione is also a good substrate for this reaction
(entry 17). As the results show, the two methyl groups at
the C-5 of the dione have some beneficial effects on the
enantioselectivity but not on the reactivity (entry 3 vs.
entry 17).
The stereochemistry of the newly formed stereogenic
center in the product 4 was determined by X-ray crys-
tallographic analysis of compound 4a (Fig. 2) [15].
According to the X-ray data, the S-configuration is
assigned to the major enantiomeric product formed in
this reaction.
Synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-
carbonitirile. We then focused our attention in synthesizing
2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile
derivatives using 1,3-diones and benzylidenemalononitriles
[16]. Using dimedone (2a) and benzylidenemalononitrile
(5a) as the model substrates, we first screened the
catalysts. The results are summarized in Table 3. As
shown in Table 3, all the cinchona alkaloid-derived
thiourea catalysts 1a-e (10mol % loading) were able to
produce the desired product 6a in high yields in much
shorter reaction times as compared with that of (E)-ethyl
2-cyano-3-phenylacrylate (3a, Table 1). However, only
low enantioselectivities were obtained (entries 1–4).
Takemoto thiourea catalyst 1j also gave the desired
product 6a in only 18% ee (entry 5). It should be
pointed that the opposite enantiomer was obtained as the
major enantiomer when catalysts 1d-e and 1j were used.
Figure 2. Oak Ridge thermal ellipsoid plot O-substituted drawing of
compound 4a [15]. [Color figure can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
Table 3
Catalyst screening and reaction condition optimizations.a
Entry
Solvent
Catalyst
Time (min)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
CH2Cl2
THF
1a
1c
1d
1e
1j
25
25
25
25
25
25
25
25
25
25
25
60
180
97
97
94
96
91
98
97
96
99
98
92
96
88
31
31
26d
24d
18d
60
58
62
52
58
56
62
62
1k
1l
1k
1k
1k
1k
1k
1k
9
10
11
12e
13f
Et2O
xylene
xylene
aUnless otherwise specified, all reactions were conducted with dimedone (2a, 0.10 mmol), benzylidenemalononitrile (5a, 0.12 mmol), and the catalyst
(0.0025 mmol, 2.5 mol %) in the specified solvent (0.5 mL) at room temperature.
bYield of isolated product after column chromatography.
cDetermined by HPLC analysis on a Chiral IB column.
dThe opposite enantiomer was obtained in excess.
eThe reaction was conducted using 1.0 mol % of the catalyst.
fThe reaction was conducted at 0°C.
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Enantioselective Synthesis of 2-Amino-4H-chromene Derivatives
Table 4
Enantioselective synthesis of 2-amino-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles.a
Entry
R1
R2
6
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Ph
4-FC6H4
a
b
c
d
e
1
1
1
0.75
1
0.75
1.5
2.5
1
98
96
96
98
92
94
91
74
93
95
86
82
90
63
62
54
53
54
31
36
64
60
0
51
45
51
48
52
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
3-BrC6H4
2-BrC6H4
3-MeOC6H4
2-MeOC6H4
2-thienyl
f
g
h
i
j
k
l
9
10
11
12
13
14
1
1.5
1.5
2
m
n
Ph
4.5
aUnless otherwise specified, all reactions were conducted with cyclohexane-1,3-dione (2, 0.10 mmol), benzylidene malononitrile (5, 0.12 mmol), and
catalyst 1k (0.0010 mmol, 1.0 mol %) in the specified solvent (0.5 mL) at room temperature.
bYield of isolated product after column chromatography.
cDetermined by HPLC analysis on a ChiralPak IB column.
Nonetheless, when a quinine-derived squaramide catalyst
1k was used, compound 6a was obtained in a much
improved ee value of 60% (entry 6). Similarly, an
improved ee value was also obtained with the
cinchonidine-derived squaramide catalyst 1l (entry 7).
These results show that cinchona alkaloid-derived
squaramides are much better than their corresponding
thioureas for benzylidenemalononitrile substrate in terms
of enantioselectivities.
An electron-withdrawing group on the para position leads
to a lower product ee value (entries 2–6), while an electron-
donating group (methyl or methoxy) on the para position
The solvent used in this reaction was then further opti-
mized using the best catalyst 1k (entries 8–11). A slightly
higher ee value of 62% was obtained in xylene (entry 8);
however, common organic solvents CH2Cl2, THF, and
Et2O all led to slightly lower product ee values (entries
9–11). When the catalyst loading was reduced to 1.0 mol
%, there was no change to both the yield and ee value of
the product, although the reaction took a little longer time
for completion (entry 12). Lowering the reaction tempera-
ture to 0°C did not affect the ee value of the product but
had a negative effect on the reaction rate (entry 13).
The scope of this reaction was then evaluated under the
optimized reaction conditions using different benzylidene-
malononitriles (5) and cyclohexane-1,3-diones (2). The
results are summarized in Table 4.
As the data in Table 4 show, this reaction exhibits a
very similar trend in terms of the effect of the
benzylidenemalononitrile para substituent on the product
ee values as (E)-ethyl 2-cyano-3-arylacrylates (Table 2):
Figure 3. Oak Ridge thermal ellipsoid plot O-substituted drawing of
compound 6a[17]. [Color figure can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
Journal of Heterocyclic Chemistry
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N. Ramireddy, S. Abbaraju, D. Ding, H. Arman, and J. C.-G. Zhao
Vol 9999
leads to a better ee value (entries 7 and 8). An electron-
withdrawing or an electron-donating group on any position
other than the para of the phenyl ring lowers the
enantioselectivity of the reaction (entries 9–12), and the
effects are prominent as compared with (E)-ethyl 2-cy-
ano-3-arylacrylates [7a]. When the heterocyclic thiophen-
2-ylmethylidenemalononitrile was applied, the reaction
yielded the expected product 1m in 48% ee and 90% yield
(entry 13). Besides dimedone, unsubstituted cyclohexane
1,3-dione also gave the expected product in 63% yield
and in 52% ee value (entry 14).
The stereochemistry of the newly formed stereogenic
center in the product 6 was determined by X-ray crystallo-
graphic analysis of compound 6a (Fig. 3) [17]. According
to the X-ray data, the R-configuration is assigned to the
major enantiomeric product formed in this reaction. Appar-
ently, according to the X-ray data, compounds 4 and 6
have the same absolute configuration, which indicate that
the transition states responsible for the formation of these
compounds are similar.
Scheme 1. Proposed favored transition state for the formation of 4a.
A plausible mechanism is proposed to account for the
formation of the major enantiomer in these reactions. As
depicted in Scheme 1, the formation of (S)-4a may be ex-
plained by the proposed favored transition state, in which
the enolized dimedone is closely associated with the
quinuclidine backbone of the catalyst 1a through ionic in-
teractions, and hydrogen bonding and the orientation
of (E)-ethyl 2-cyano-3-phenylacrylate (3a) are controlled
by the thiourea moiety of the catalyst via hydrogen bonds.
The attack of the enolate from the back onto the Re face of
Table 5
Synthesis of racemic 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles.a
Entry
R
5/9
Solvent
Catalyst
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
a
a
a
a
a
a
a
a
a
a
b
c
d
e
f
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
EtOAc
acetone
EtOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DABCO
DBU
Et3N
27
30
38
48
72
24
28
27
29
30
24
30
23
22
25
20
26
32
75
43
67
29
0
K2CO3
NaHCO3
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
71
74
64
51
61
73
59
45
64
67
65
79
39
9
10
11
12
13
14
15
16
17
18
Ph
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
4-CH3C6H4
3-BrC6H4
thiophen-2-yl
CH3(CH2)5
g
h
i
aAll reactions were conducted with the indicated arylidenemalononitrile (2, 0.30 mmol), 1,2-cyclohexanedione (8, 0.32 mmol), and the catalyst
(0.030 mmol, 10 mol %,) in the specified solvent (1.5 mL) at room temperature.
bYield of isolated product after column chromatography.
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Enantioselective Synthesis of 2-Amino-4H-chromene Derivatives
Table 6
3a gives the intermediate 7, which undergoes further base-
catalyzed cyclization and tautomerization to give (S)-4a as
the major enantiomer. The formation of (R)-6a using 5a
and catalyst 1k may be interpreted in a similar manner.
Synthesis of 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitriles. 1,2-Diones are highly reactive compounds
and have found many applications in organic synthesis [18].
Nevertheless, they have been seldom used in organocatalyzed
reactions [19]. Previously, we and others have demonstrated
that 1,2-diones can be enolized and used as a nucleophile in
organocatalyzed reactions [19c–g]. On the basis of these
findings, we envisioned that cyclohexane-1,2-dione could
be used as a potential Michael donor in a tandem Michael
addition–cyclization reaction with benzylidenemalononitriles
for the synthesis of 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitriles, an isomer of compound 6, for
which a general synthesis was not available.
In order to demonstrate the feasibility of this reaction,
we first studied the racemic version of this reaction. We
adopted cyclohexane-1,2-dione (8) and benzylidenema-
lononitrile (5a) as the model substrates. As shown in
Table 5, when the reaction was carried out with 10mol %
1,4-diazabicyclo[2.2.2]octane as the base catalyst in
toluene at room temperature for 27 h (entry 1), the expected
product 9a was isolated in 75% yield. Similarly, 1,8-
diazabicyclo[5.4.0]undec-7-ene, Et3N, and K2CO3 can also
be applied to catalyze this reaction (entries 2–4), although
lower yields were obtained. However, when a weak base
NaHCO3 was applied as the catalyst, no desired product
could be obtained (entry 5). Further screening of the
solvents revealed that toluene (entry 1), CH2Cl2 (entry 6),
and THF (entry 7) are good solvents for this reaction, while
EtOAc, acetone, and EtOH (entries 8–10) are worse ones.
Several substituted benzylidenemalononitriles were then
applied as the substrate under the optimized conditions.
As shown in Table 6, acceptable to good yields (45–
73%) were obtained with benzylidenemalononitriles that
contain either an electron-withdrawing substituent (5b-e,
entries 11–14) or an electron-donating group (5f, entry
15) at the para position. A benzylidenemalononitrile with
a meta-bromo substituent (5g) also led to good results
(entry 16). Heterocyclic thiophen-2-ylmethylidenema-
lononitrile (5h) gave the highest yield of 79% of the
desired product (entry 17). Alkylidenemalononitrile 5i also
reacted to produce the expected product 9i, although the
reaction was sluggish, and the yield was lower (entry 18).
However, other 1,2-diones, such as butane-2,3-dione and
3-methylcyclopentane-1,2-dione, do not yield the expected
product (data not shown), with the former gives no product
at all and the latter some unidentified products.
Catalyst screening for the enantioselective synthesis of 9aa.
Time
(h)
Yieldb
(%)
eec
(%)
Entry
Solvent
Catalyst
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
Et2O
EtOAc
THF
CHCl3
CH3CN
EtOH
1a
1b
1c
1d
1f
1h
1m
1i
26
30
30
28
28
28
26
240
40
168
30
28
28
40
38
28
28
72
28
28
56
41
47
37
61
72
70
21
34
31
43
55
35
33
33
31
53
58
64
43
35
35
34
30d
16
3d
25d
1d
9
1j
27d
3
10
11
12
13
14
15
16
17
18e
19e
20f
1n
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
18
17
25
33
6
15
40
40
63
59
EtOH
toluene
toluene
aUnless otherwise indicated, all reactions were conducted with
benzylidenemalononitrile 5a (0.30 mmol), cyclohexane-1,2-dione (8,
0.32 mmol), and the catalyst (0.030 mmol, 10 mmol %) in the specified
solvent (1.5 mL) at room temperature.
bYield of isolated product after column chromatography.
cDetermined by HPLC analysis on a ChiralCel OD-H column.
dThe opposite enantiomer was obtained as the major product in these cases.
eThe reaction was conducted at 0°C.
fThe reaction was conducted at À15°C.
(5a) were, as the model substrates to screen, the catalysts
and optimize the reaction conditions. The data were col-
lected in Table 6.
As shown in Table 6, different cinchona alkaloid deriv-
atives (1a-d, 1f, 1h, and 1m) were screened using toluene
as the solvent at room temperature (entries 1–7). All of
these catalysts led to poor product ee values, with quinine
thiourea (1a), dihydroquinine thiourea (1b), and
cinchonidine thiourea (1c) yielding the highest product ee
values (entries 1–3). Similarly, poor enantioselectivities
were obtained with Takemoto thiourea catalysts 1i and 1j
and a diamine catalyst 1n (entries 8–10). On the basis of
these results, quinine thiourea (1a) was chosen as the cata-
lyst for further optimizations. Firstly, different organic
solvents were screened (entries 11–17). As the data indi-
cate, except for ethanol (entry 17), all the other solvents
screened gave lower ee values as compared with that of
Based on the earlier results, we then developed an
enantioselective synthesis of these 2-amino-4H-chromene
derivatives using chiral Brønsted bases (Fig. 1) as the cat-
alyst. Again, compound 8 and benzylidenemalononitrile
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Ramireddy, S. Abbaraju, D. Ding, H. Arman, and J. C.-G. Zhao
Vol 9999
Table 7
Enantioselective synthesis of 2-amino-8-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrilesa.
Entry
R
5/9
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
Ph
4-ClC6H4
4-BrC6H4
4-CNC6H4
4-NO2C6H4
3-BrC6H4
4-CH3C6H4
thiophen-2-yl
CH3(CH2)5
a
b
c
d
e
f
g
h
i
28
24
30
24
26
24
28
30
96
64
60
55
51
55
63
49
37
12
63
58
57
43
48
52d
50
47e
9d
aAll reactions were conducted with the benzylidenemalononitrile (5, 0.30 mmol), cyclohexane-1,2-dione (8, 0.32 mmol), and catalyst 1a (0.030 mmol,
10 mol %) in toluene (1.5 mL) at 0°C. The product stereochemistry was tentatively assigned.
bYield of isolated product after column chromatography.
cUnless otherwise specified, ee values were determined by HPLC analysis on a ChiralCel OD-H column.
dDetermined by HPLC analysis on a ChiralPak AD-H column.
eDetermined by HPLC analysis on a ChiralPak AS column.
toluene. Nonetheless, the attempt to increase the ee value
of the reaction at lower temperatures using ethanol failed
(entry 18). In contrast, the ee value of the product can be
increased to 63% by conducting the reaction using toluene
as the solvent at 0°C (entry 19). Further lowering the tem-
perature to À15°C had detrimental effect both on reactivity
and enantioselectivity of the reaction (entry 20).
Once the optimized reaction conditions were found, the
other benzylidenemalononitriles were applied to this reaction
under these conditions. The results are collected in Table 7.
As shown in Table 7, benzylidenemalononitriles with vari-
ous substituents all produce the desired product in mediocre
to good ee values (43–63% ee, entries 1–7). The yields
(49–64%) obtained are usually low because of the formation
of some unidentified products in the reaction. The heterocy-
clic thiophen-2-ylmethylidenemalononitrile also gives the
expected product in 47% ee and 37% yield (entry 8).
However, the alkylidenemalononitrile 5i reacts very slowly
and leads to poor ee value of the product (entry 9).
Because products 9 were mostly viscous liquids, we
were not able to obtain a suitable crystal for the X-ray crys-
tallographic analysis. Thus, the absolute stereochemistry of
the newly formed stereogenic center could not be deter-
mined in the same way as compounds 4 and 6. Instead,
the product stereochemistry was tentatively assigned as S
because of the similarity of the mechanism of this reaction
to those responsible for the formation of products 4 and 6
(Scheme 1).
CONCLUSION
In summary, we have realized the enantioselective syn-
thesis of several 2-amino-4H-chromene derivatives using
the cinchona alkaloid-derived bifunctional organocatalysts
via the tandem Michael addition–cyclization reaction
between 1,3-cyclohexanediones or 1,2-cyclohexanediones
and (E)-3-aryl-2-cyanoacrylate or alkylidenemalononitrile
derivatives. The optical purity of the products was found
to be highly substrate-dependent and catalyst-dependent.
EXPERIMENTAL
All reactions were carried out in oven-dried glass wires.
Solvents were dried using standard protocols. All
chemicals and reagents were used as received. The cata-
lysts were prepared according to the literature methods
[14]. H NMR (300 or 500 MHz) and 13C NMR (75 or
1
125 MHz, respectively) spectra were recorded at 25°C
using CDCl3 or DMSO-d6 as the solvent. Thin-layer chro-
matography (TLC) was performed with silica gel GF254
precoated on plastic plates, and spots were visualized with
UV. HPLC analysis was performed on an HPLC instru-
ment equipped with a ultraviolet–visible detector. High
resolution mass spectrum (HRMS) was recorded using
electrospray ionization technique with a time of flight ana-
lyzer. Elemental microanalysis was conducted by Atlantic
Microlab Inc. (Norcross, GA 30071).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Enantioselective Synthesis of 2-Amino-4H-chromene Derivatives
General procedure for the asymmetric synthesis of
compound 4.
3447, 3320, 2958, 1686, 1665, 1596, 1367, 1241. Anal.
calcd for C21H25NO4 : C, 70.96; H, 7.09; N, 3.94.
Found: C, 71.02; H, 7.01; N, 3.87. HPLC conditions:
ChiralCel OD-H, hexanes/i-PrOH = 80:20, flow rate= 0.7 mL/
min, UV detection at 254 nm.
A solution of 5,5-dimethylcyclohexane-
1,3-dione (2, 35.3mg, 0.10 mmol) and catalyst 1a
(5.9 mg. 0.010mmol, 10 mol %) in toluene (1.0 mL) was
stirred at 0°C for 15 min. To this solution was added
alkyl (E)-2-cyano-3-phenylacrylate (3, 0.12 mmol), and
the mixture was further stirred at 0°C until the reaction
was completed (TLC monitoring). The solvent was then
removed under reduced pressure, and the residue was
purified by silica gel chromatography (85:15 hexanes/
EtOAc) to afford the product 4.
(S)-Isopropyl 2-amino-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4d).
White
solid, yield 32.8 mg (88%), mp: 127–128°C, [α]2D5 =+32.1
1
(c =1.45, CH2Cl2, 74% ee). H NMR (300 MHz, CDCl3):
δ=0.96 (d, J= 6.2Hz, 6H), 1.09 (s, 3H), 1.22 (d, J=6.2Hz,
3H), 2.15 (d, J= 16.2 Hz, 1H), 2.23(d, J=16.2 Hz, 1H), 2.41
(s, 2H), 4.64 (s, 1H), 4.88 (septet, J=6.2Hz, 1H), 6.18 (br.
s, 2H), 6.83–6.89 (m, 2H), 7.18–7.22 (m, 2H) ppm; 13C
NMR (75 MHz, CDCl3): δ =22.0, 22.6, 27.8, 29.4, 32.6,
33.7, 41.0, 51.0, 67.3, 81.1, 114.4, 114.7, 116.7, 130.0,
141.9, 158.2, 159.7, 161.5, 162.9, 168.7, 196.6 ppm. υmax
(neat, cmÀ1): 3413, 3321, 2961, 1676, 1652, 1517, 1355,
1240, 1191, 1159. Anal. calcd. for C21H24FNO4 : C, 67.54;
H, 6.48; N, 3.75. Found: C, 67.67; H, 6.44; N, 3.82. HPLC
conditions: ChiralCel OD-H, hexanes/i-PrOH= 80:20, flow
rate= 0.7 mL/min, UV detection at 254nm.
(S)-Ethyl 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tet
rahydro-4H-chromene-3-carboxylate (4a).
White solid,
yield 31.3 mg (92%), mp: 160–161°C, [α]2D5 =+35.7 (c=1.4,
1
CH2Cl2, 79% ee). H NMR (500 MHz, CDCl3): δ= 0.89
(s, 3H), 1.02 (s, 3H), 1.08 (t, J = 7.5 Hz, 3H), 2.08 (d,
J = 16.2 Hz, 1H), 2.15 (d, J = 16.2 Hz, 1H), 2.35 (s, 2H),
3.92–3.99 (m, 2H), 4.62 (s, 1H), 6.10 (br. s, 2H), 7.02
(t, J = 7.0 Hz, 1H), 7.12 (t, J = 7.7 Hz, 2H), 7.18
(d, J = 7.2 Hz, 2H) ppm; 13C NMR (125 MHz,
CDCl3): δ= 14.5, 27.7, 29.3, 32.5, 34.1, 40.9, 51.0,
59.9, 81.1, 117.0, 126.3, 128.0, 128.5, 146.0, 158.5,
161.6, 169.4, 196.7 ppm. υmax (neat, cmÀ1): 3427,
3310, 2919, 1688, 1657, 1598, 1517, 1364, 1244.
Anal. calcd. for C20H23NO4 : C, 70.36; H, 6.79; N,
4.10. Found: C, 70.39; H, 6.91; N, 4.07. HPLC
conditions: ChiralCel OD-H, hexanes/i-PrOH = 80:20,
flow rate = 0.7 mL/min, UV detection at 254 nm.
(S)-Isopropyl 2-amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4e).
White
solid, yield 33.0 mg (85%), mp: 142–144°C, [α]2D5 =+10.6
1
(c =1.62, CH2Cl2, 76% ee). H NMR (300 MHz, CDCl3):
δ=0.97 (d, J= 6.0Hz, 6H), 1.09 (s, 3H), 1.22 (d, J=6.2Hz,
3H), 2.14 (d, J= 16.2 Hz, 1H), 2.23 (d, J= 16.2 Hz, 1H),
2.41 (s, 2H), 4.63 (s, 1H), 4.88 (septet, J= 6.0Hz, 1H), 6.20
(br. s, 2H), 7.13–7.20 (m, 4H) ppm; 13C NMR (75MHz,
CDCl3): δ= 22.1, 22.6, 27.8, 29.5, 32.6, 33.9, 41.0, 51.0,
67.3, 80.8, 116.46, 128.0, 130.0, 131.7, 144.7, 158.3, 161.6,
168.6, 196.6 ppm. υmax (neat, cmÀ1): 3411, 3316, 2965,
1675, 1656, 1517, 1335, 1238, 1191. Anal. calcd. for
C21H24ClNO4 : C, 64.69; H, 6.20; N, 3.59. Found: C,
64.62; H, 6.34; N, 3.63. HPLC conditions: ChiralCel OD-
H, hexanes/i-PrOH =80:20, flow rate=0.7mL/min, UV
detection at 254 nm.
(S)-Methyl
2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-
tetrahydro-4H-chromene-3-carboxylate (4b)[3b].
White
solid, yield 29.4 mg (90%), mp: 149–150°C, [α]2D5 = +23.5
1
(c=1.2, CH2Cl2, 69% ee). H NMR (300MHz, CDCl3):
δ=0.96 (s, 3H), 1.09 (s, 3H), 2.15 (d, J= 16.2 Hz, 1H),
2.23 (d, J= 16.2 Hz, 1H), 2.42 (s, 2H), 3.59 (s, 3H), 4.70 (s,
1H), 6.18 (br. s, 2H), 7.07–7.12 (m, 1H), 7.17–7.26 (m,
4H) ppm; 13C NMR (75MHz, CDCl3): δ=27.8, 29.5, 32.6,
34.0, 41.0, 51.0, 51.3, 80.9, 117.1, 126.3, 128.1, 128.2,
145.8, 158.7, 161.5, 169.6, 196.4ppm. υmax (neat, cmÀ1):
3389, 3296, 2952, 1688, 1651, 1530, 1437, 1364, 1244.
Anal. calcd. for C19H21NO4 : C, 69.71; H, 6.47; N,
4.28. Found: C, 69.59; H, 6.48; N, 4.22. HPLC
conditions: ChiralCel OD-H, hexanes/i-PrOH = 80:20,
flow rate = 0.7 mL/min, UV detection at 254 nm.
(S)-Isopropyl 2-amino-4-(4-bromophenyl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4f).
White
solid, yield 39.4mg (91%), mp: 162–163°C, [α]2D5 =+17.7
1
(c = 1.75, CH2Cl2, 75% ee). H NMR (500 MHz, CDCl3):
δ= 0.98 (d, J = 7.9 Hz, 6H), 1.10 (s, 3H), 1.22 (d,
J = 6.1 Hz, 3H), 2.16 (d, J = 16.2 Hz, 1H), 2.23 (d,
J = 16.2 Hz, 1H), 2.42 (s, 2H), 4.63 (s, 1H), 4.89 (septet,
J = 7.9 Hz, 1H), 6.21 (br. s, 2H), 7.14 (d, J = 8.2 Hz, 2H),
7.32 (d, J = 8.2 Hz, 2H) ppm; 13C NMR (125MHz,
CDCl3): δ= 21.9, 22.4, 27.6, 29.3, 32.5, 33.9, 40.9, 50.9,
67.3, 80.7, 116.4, 119.9, 130.4, 131.0, 145.3, 158.4, 161.7,
168.7, 196.7 ppm. υmax (neat, cmÀ1): 3399, 3291, 2930,
1686, 1657, 1613, 1519, 1363, 1248, 1191, 1161; Anal.
calcd. for C21H24BrNO4 : C, 58.07; H, 5.57; N, 3.22.
Found: C, 58.11; H, 5.64; N, 3.22. HPLC conditions:
ChiralCel OD-H, hexanes/i-PrOH =80:20, flow rate = 0.7 mL/
min, UV detection at 254nm.
(S)-Isopropyl 2-amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-
tetrahydro-4H-chromene-3-carboxylate (4c).
White solid,
yield 30.1 mg (85%), mp: 161–162°C, [α]2D5 = +37.9
(c = 1.45, CH2Cl2, 80% ee). 1H NMR (300 MHz,
CDCl3): δ= 1.00 (d, J = 6.2 Hz, 6H), 1.11 (s, 3H), 1.24
(d, J = 6.2 Hz, 3H), 2.17 (d, J1 = 16.3 Hz, 1H), 2.23(d,
J = 16.3 Hz, 1H), 2.44 (s, 2H), 4.68 (s, 1H), 4.89
(septet, J = 6.2 Hz, 1H), 6.16 (br. s, 2H), 7.19–7.22 (m,
3H), 7.26–7.27 (m, 2H) ppm; 13C NMR (75 MHz,
CDCl3): δ= 22.0, 22.6, 27.8, 29.4, 32.6, 34.3, 41.0,
51.1, 67.2, 81.4, 116.9, 126.2, 127.8, 128.6, 146.0,
158.3, 161.5, 168.8, 196.6 ppm. υmax (neat, cmÀ1):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Ramireddy, S. Abbaraju, D. Ding, H. Arman, and J. C.-G. Zhao
Vol 9999
(S)-Isopropyl
2-amino-4-(4-cyanophenyl)-7,7-dimethyl-5-
3H), 2.16 (d, J= 16.2 Hz, 1H), 2.23 (d, J=16.2Hz, 1H),
2.42 (s, 2H), 3.75 (s, 3H), 4.63 (s, 1H), 4.89 (septet,
J = 6.2 Hz, 1H), 6.16 (br. s, 2H), 6.74 (d, J = 8.5 Hz,
2H), 7.17 (d, J = 8.5 Hz, 2H) ppm; 13C NMR
(125 MHz, CDCl3): δ= 22.0, 22.5, 22.7, 29.3, 32.5,
33.3, 40.9, 51.0, 55.4, 67.1, 81.6, 113.3, 117.1, 129.5,
138.5, 158.0, 158.3, 161.4, 169.0, 196.9 ppm. υmax
(neat, cmÀ1): 3407, 3304, 2958, 1686, 1655, 1607,
1508, 1364, 1243, 1199, 1161; Anal. calcd. for
C22H27NO5 : C, 68.55; H, 7.06; N, 3.63. Found: C,
68.40; H, 7.03; N, 3.58. HPLC conditions: ChiralCel
OD-H, hexanes/i-PrOH = 80:20, flow rate = 0.7 mL/min,
UV detection at 254 nm.
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4g).
solid, yield 28.5mg (75%), mp: 153–154°C, [α]2D5 =-10.7
(c=0.65, CH2Cl2, 66% ee). H NMR (300 MHz, CDCl3):
White
1
δ=0.93 (t, J= 6.2 Hz, 6H), 1.09 (s, 3H), 1.21 (d, J=6.2Hz,
3H), 2.14 (d, J= 16.2 Hz, 1H), 2.23 (d, J= 16.2Hz, 1H),
2.43 (s, 2H), 4.69 (s, 1H), 4.86 (septet, J= 6.2Hz, 1H),
6.26 (br. s, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4Hz,
2H) ppm; 13C NMR (75 MHz, CDCl3): δ =22.0, 22.6, 27.7,
29.4, 32.6, 34.9, 41.0, 50.9, 67.4, 79.9, 109.9, 115.8, 119.4,
129.5, 131.8, 151.7, 158.4, 162.0, 168.3, 196.5ppm; υmax
(neat, cmÀ1): 3415, 3301, 2959, 2227, 1684, 1656, 1604,
1527, 1362, 1248, 1202. Anal. calcd. for C22H24N2O4 : C,
69.46; H, 6.36; N, 7.36. Found: C, 69.30; H, 6.60; N, 7.18.
HPLC conditions: ChiralPak AD-H, hexanes/i-PrOH= 80:20,
flow rate= 0.8mL/min, UV detection at 254 nm.
(S)-Isopropyl
2-amino-4-(3-bromophenyl)-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4k).
White
solid, yield 39 mg (90%), mp: 180–182°C, [α]2D5 = À1.9
(c = 1.63, CH2Cl2, 74% ee). 1H NMR (500 MHz,
CDCl3): δ= 1.00 (d, J = 6.3 Hz, 6H), 1.10 (s, 3H), 1.24
(d, J = 6.3 Hz, 3H), 2.18 (d, J = 16.2 Hz, 1H), 2.23 (d,
J = 16.2 Hz, 1H), 2.44 (s, 2H), 4.63 (s, 1H), 4.9 (septet,
J = 6.3 Hz, 1H), 6.23 (br. s, 2H), 7.07 (t, J = 7.8 Hz,
1H), 7.18–7.24 (m, 2H), 7.40 (s, 1H) ppm; 13C NMR
(125 MHz, CDCl3): δ= 21.9, 22.5, 27.7, 29.3, 32.5,
34.2, 40.9, 50.9, 67.3, 80.7, 116.2, 122.0, 127.3, 129.3,
129.5, 131.8, 148.5, 158.3, 161.9, 168.7, 195.6 ppm.
υmax (neat, cmÀ1): 3405, 3293, 2944, 1686, 1654,
1620, 1519, 1359, 1248, 1199, 1159; Anal. calcd. for
C21H24BrNO4 : C, 58.07; H, 5.57; N, 3.22. Found: C,
57.96; H, 5.59; N, 3.09. HPLC conditions: ChiralCel
OD-H, hexanes/i-PrOH = 80:20, flow rate = 0.7 mL/min,
UV detection at 254 nm.
(S)-Isopropyl 2-amino-4-(4-nitrophenyl)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4h).
solid, yield 28.8mg (72%), mp: 196–197°C, [α]2D5 =-1.8
(c=1.1, CH2Cl2, 65% ee). H NMR (300MHz, CDCl3):
White
1
δ=0.93 (t, J=6.2Hz, 6H), 1.10 (s, 3H), 1.22 (d, J=6.2Hz,
3H), 2.14 (d, J=16.3Hz, 1H), 2.24 (d, J= 16.3 Hz, 1H),
2.44 (s, 2H), 4.75 (s, 1H), 4.87 (septet, J=6.2Hz, 1H), 6.28
(br. s, 2H), 7.42 (d, J=8.8Hz, 2H), 8.06 (d, J=8.8Hz, 2H)
ppm; 13C NMR (75MHz, CDCl3): δ= 22.1, 22.6, 27.7,
29.4, 32.6, 34.7, 41.0, 50.9, 67.5, 79.8, 115.7, 123.3, 129.5,
146.4, 153.8, 158.4, 162.2, 168.2, 196.5 ppm. υmax (neat,
cmÀ1): 3462, 3331, 2959, 2187, 1686, 1659, 1625, 1508,
1371, 1250. Anal. calcd. for C21H24N2O6 : C, 62.90; H,
6.04; N, 7.00. Found: C, 62.73; H, 5.94; N, 6.92; HPLC
conditions: ChiralPak AD-H, hexanes/i-PrOH=80:20, flow
rate=0.8mL/min, UV detection at 254nm.
(S)-Isopropyl
2-amino-4-(2-bromophenyl)-7,7-dimethyl-5-
(S)-Isopropyl 2-amino-4-(4-methylphenyl)-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4l).
White
solid, yield 36.8mg (85%), mp: 172–174°C, [α]2D5 =+1.5
(c=1.7, CH2Cl2, 20% ee). 1H NMR (300MHz, CDCl3):
δ= 0.81 (d, J = 6.3 Hz, 3H), 0.92 (s, 3H), 1.01 (s, 3H),
1.17 (d, J = 6.3 Hz, 3H), 2.05 (d, J = 16.1 Hz, 1H), 2.13
(d, J = 16.1 Hz, 1H), 2.33 (s, 2H), 4.78–4.88 (m, 1H),
4.89 (s, 1H), 6.20 (br. s, 2H), 6.83–6.88 (m, 1H),
7.04–7.09 (m, 1H), 7.19–7.21 (m, 1H), 7.31–7.34 (m,
1H) ppm; 13C NMR (75 MHz, CDCl3): δ= 21.9, 22.5,
28.01, 29.3, 32.4, 35.5, 41.0, 51.1, 67.2, 79.9, 115.1,
123.9, 126.8, 127.7, 132.9, 133.3, 143.7, 158.6, 161.8,
168.9, 196.6 ppm. υmax (neat, cmÀ1): 3397, 3290, 2945,
1688, 1661, 1616, 1517, 1363, 1248, 1199, 1161. Anal.
calcd. for C21H24BrNO4 : C, 58.07; H, 5.57; N, 3.22.
Found: C, 58.28; H, 5.70; N, 3.26. HPLC conditions:
ChiralPak AD-H, hexanes/i-PrOH = 80:20, flow rate = 0.8 mL/
min, UV detection at 254nm.
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4i).
White
solid, yield 31.3mg (85%), mp: 146–147°C, [α]2D5 =+9.0
1
(c = 1.3, CH2Cl2, 82% ee). H NMR (300 MHz, CDCl3):
δ=0.98–1.03 (m, 6H), 1.09 (s, 3H), 1.24 (d, J=6.2Hz,
3H), 2.15 (d, J= 16.1 Hz, 1H), 2.22 (d, J=16.1Hz, 1H),
2.25 (s, 3H), 2.42 (s, 2H), 4.63 (s, 1H), 4.86 (septet, J=6.2Hz,
1H), 6.15 (br. s, 2H), 6.98 (d, J = 8.0 Hz, 2H), 7.12 (d,
J = 8.0 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3):
δ= 21.5, 22.1, 22.6, 27.9, 29.5, 32.6, 33.8, 41.0, 51.07,
67.2, 81.5, 117.0, 128.4, 128.6, 135.5, 143.1, 158.2,
161.5, 168.8, 196.7 ppm. υmax (neat, cmÀ1): 3407, 3302,
2958, 1686, 1657, 1613, 1511, 1364, 1283, 1199, 1161;
Anal. calcd. for C22H27NO4 : C, 71.52; H, 7.37; N, 3.79.
Found: C, 71.28; H, 7.23; N, 3.78. HPLC conditions:
ChiralPak AD-H, hexanes/i-PrOH= 80:20, flow rate=0.8mL/
min, UV detection at 254 nm.
(S)-Isopropyl 2-amino-4-(3-methoxyphenyl)-7,7-dimethyl-5-
(S)-Isopropyl 2-amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4j).
White
oxo-5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4m).
White
solid, yield 32.3 mg (84%), mp: 127–128°C, [α]2D5 = +9.0
solid, yield 33.1mg (86%), mp: 133–134°C, [α]2D5 =+10.3
(c=1.55, CH2Cl2, 74% ee). 1H NMR (300MHz, CDCl3):
δ=1.00 (d, J=6.2 Hz, 6H), 1.09 (s, 3H), 1.24 (d, J=6.2Hz,
1
(c = 1.0, CH2Cl2, 80% ee). H NMR (500 MHz, CDCl3):
δ=0.99 (t, J=6.2Hz, 6H), 1.10 (s, 3H), 1.22 (d, J=6.2Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Enantioselective Synthesis of 2-Amino-4H-chromene Derivatives
3H), 2.16 (d, J= 16.2Hz, 1H), 2.23 (d, J=16.2Hz, 1H), 2.41 (s,
2H), 3.76 (s, 3H), 4.65 (s, 1H), 4.88 (septet, J=6.2Hz, 1H),
6.18 (br. s, 2H), 6.61–6.65 (m, 1H), 6.81–6.85 (m,
2H), 7.09 (t, J = 7.7 Hz, 1H) ppm; 13C NMR (75 MHz,
CDCl3): δ= 22.1, 22.6, 27.9, 29.4, 32.6, 34.3, 41.0, 51.1,
55.4, 67.2, 81.2, 111.4, 114.6, 116.8, 121.1, 128.7, 147.7,
158.3, 159.2, 161.5, 168.8, 196.6 ppm. υmax (neat, cmÀ1):
3405, 3304, 2961, 1686, 1655, 1508, 1357, 1243, 1191,
1161. Anal. calcd. for C22H27NO5 : C, 68.55; H, 7.06; N,
3.63. Found: C, 68.29; H, 7.07; N, 3.59. HPLC conditions:
ChiralCel OD-H, hexanes/i-PrOH= 80:20, flow rate = 0.7mL/
min, UV detection at 254 nm.
δ=1.04 (s, 3H), 1.10 (d, J=6.3 Hz, 6H), 1.25 (d, J=6.2Hz,
3H), 2.26 (s, 2H), 2.41 (s, 2H), 4.98 (septet, J= 6.3Hz, 1H),
5.06 (s, 1H), 6.21 (br. s, 2H), 6.79–6.87 (m, 2H), 7.00–7.02
(m, 1H) ppm; 13C NMR (75MHz, CDCl3): δ= 22.1, 22.6,
27.9, 28.9, 29.5, 32.6, 41.0, 51.1, 67.4, 81.2, 116.6, 123.2,
124.3, 126.5, 150.7, 158.6, 162.0, 168.6, 196.5 ppm. υmax
(neat, cmÀ1): 3415, 3304, 2965, 1687, 1650, 1612, 1278,
1370, 1277, 1198, 1164. Anal. calcd for C19H23NO4S: C,
63.13; H, 6.41; N, 3.88. Found: C, 63.19; H, 6.32; N, 3.81.
HPLC conditions: ChiralPak AD-H, hexanes/i-PrOH=80:20,
flow rate= 0.8mL/min, UV detection at 254nm.
(S)-Isopropyl
2-amino-5-oxo-4-phenyl-5,6,7,8-tetrahydro-
4H-chromene-3-carboxylate (4q).
White solid, yield
(S)-Isopropyl 2-amino-4-(2-methoxy-phenyl)-7,7-dimethyl-5-
27.1 mg (83%), mp: 122–124°C, [α]2D5 = +10.0 (c= 0.6,
oxo--5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4n).
White
1
solid, yield 31.6 mg (82%), mp: 129–130°C, [α]2D5 = +9.0
(c = 1.55, CH2Cl2, 51% ee). 1H NMR (500 MHz,
CDCl3): δ = 0.97 (d, J = 6.2 Hz, 6H), 1.09 (s, 3H),
1.24 (d, J = 7.2 Hz, 3H), 2.13 (d, J = 16.2 Hz, 1H),
2.21 (d, J = 16.2 Hz, 1H), 2.35 (d, J = 17.5 Hz, 1H),
2.43 (d, J = 17.5 Hz, 1H), 3.76 (s, 3H), 4.77 (s, 1H),
4.87 (septet, J=6.2Hz, 1H), 6.16 (br. s, 2H), 6.76 (d,
J=8.1Hz, 1H), 6.82–6.85 (m, 1H), 7.08–7.12 (m, 1H),
7.33 (d, J = 7.5 Hz, 1H) ppm; 13C NMR (125 MHz,
CDCl3): δ= 22.0, 22.5, 27.2, 29.6, 32.4, 41.0, 51.0,
55.4, 66.8, 79.5, 110.8, 114.8, 119.9, 127.6, 132.4,
158.0, 159.1, 162.3, 169.3, 196.9 ppm. υmax (neat,
cmÀ1): 3407, 3317, 2965, 1686, 1655, 1617, 1505,
1364, 1244, 1199, 1161. Anal. calcd. for C22H27NO5
: C, 68.55; H, 7.06; N, 3.63. Found: C, 68.66; H,
7.03; N, 3.69. HPLC conditions: ChiralPak AD-H,
hexanes/i-PrOH = 80:20, flow rate = 0.8 mL/min, UV
detection at 254 nm.
CH2Cl2, 70% ee). H NMR (300MHz, CDCl3): δ= 0.95
(d, J =6.2 Hz, 3H), 1.22 (d, J =6.2 Hz, 3H), 1.95–2.02
(m, 2H), 2.30–2.35 (m, 2H), 2.52–2.59 (m, 2H), 4.69 (s,
1H), 4.87 (septet, J = 6.2 Hz, 1H), 6.16 (br. s, 2H),
7.16–7.21 (m, 3H), 7.24–7.27 (m, 2H) ppm; 13C NMR
(75 MHz, CDCl3): δ= 22.6, 22.0, 22.6, 27.4, 34.2, 37.2,
67.2, 81.4, 118.2, 126.2, 127.9, 128.6, 146.2, 158.2,
163.1, 168.8, 196.7 ppm. υmax (neat, cmÀ1): 3443, 3317,
2965, 1686, 1659, 1596, 1347, 1241. Anal. calcd. for
C19H21NO4 : C, 69.71; H, 6.47; N, 4.28. Found: C,
69.65; H, 6.63; N, 4.41. HPLC conditions: ChiralPak
AD-H, hexanes/i-PrOH = 80:20, flow rate = 0.8 mL/min,
UV detection at 254nm.
General procedure for the asymmetric synthesis of
compound 6. To a solution of 5,5-dimethylcyclohexane-
1,3-dione (2, 11.2 mg, 0.10 mmol) and catalyst 1k (0.60 mg,
0.0010mmol, 1mol %) in toluene (1.5mL) at room
temperature was added benzylidenemalononitrile (5,
0.12 mmol) in the present of. The mixture was further stirred
at room temperature until completion (TLC monitoring).
The solvent was then removed under reduced pressure,
and the residue was purified by silica gel chromatography
(60:40 hexane/EtOAc) to afford the product 6.
(S)-Isopropyl 2-amino-7,7-dimethyl-4-napthalen-1-yl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4o).
White
solid, yield 32.8 mg (81%), mp: 144–146°C, [α]2D5 = À2.3
1
(c = 1.3, CH2Cl2, 65% ee). H NMR (300 MHz, CDCl3):
δ= 0.30 (d, J = 6.2 Hz, 3H), 0.95 (s, 3H), 1.08 (d,
J=6.9Hz, 6H), 2.09 (d, J= 16.2 Hz, 1H), 2.19 (d,
J=16.2Hz, 1H), 2.46 (s, 2H), 4.74 (septet, J=6.2Hz, 1H),
5.51 (s, 1H), 6.21 (br. s, 2H), 7.23–7.35 (m, 2H), 7.39–7.44
(m, 1H), 7.53–7.61 (m, 2H), 7.73–7.76 (m, 1H), 8.70–8.73
(m, 1H) ppm; 13C NMR (75MHz, CDCl3): δ =21.4, 22.3,
27.9, 29.1, 29.4, 32.6, 41.1, 50.9, 66.9, 82.9, 117.8, 125.3,
125.4, 125,9, 126.5, 126.9, 128.2, 131.9, 133.4, 144.5,
158.2, 161.1, 169.0, 196.8 ppm. υmax (neat, cmÀ1): 3403,
3311, 2953, 1686, 1661, 1607, 1515, 1353, 1243. Anal.
calcd. for C25H27NO4 : C, 74.05; H, 6.71; N, 3.45. Found:
C, 74.06; H, 6.84; N, 3.39. HPLC conditions: ChiralPak
AD-H, hexanes/i-PrOH=80:20, flow rate=0.8mL/min,
UV detection at 254nm.
(R)-2-Amino-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (6a).
White solid, yield 28.8 mg
(98%), mp: 203–204°C, [α]2D5 =À10.8 (c= 0.5, THF, 62%
1
ee). H NMR (500MHz, DMSO-d6): δ 7.26 (t, J=7.5Hz,
2H), 7.20 – 7.09 (m, 3H), 6.97 (s, 2H), 4.15 (s, 1H), 2.54
(S, 2H), 2.23 (d, J=16.2Hz, 1H), 2.08 (d, J=16.2Hz, 2H),
1.02 (s, 3H), 0.93 (s, 3H); 13C NMR (125MHz,
DMSO-d6): δ 196.0, 162.9, 158.9, 145.1, 128.7, 127.5,
127.0, 120.1, 113.1, 58.7, 50.4, 36.0, 32.2, 31.1, 28.8,
27.2ppm. υmax (neat, cmÀ1): 3422, 2972, 2181, 1712,
1527, 1362. HRMS m/z calcd. for C18H19N2O2 [M+H]+
295.1447; found 295.1441. HPLC conditions: ChiralPak
IB, hexanes/i-PrOH=80:20, flow rate=1.0mL/min, UV
detection at 254nm.
(S)-Isopropyl 2-amino-7,7-dimethyl-5-oxo-4-thiophen-2-yl-
(R)-2-Amino-4-(4-fluorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (4p).
White
solid, yield 24.1mg (67%), mp: 156–157°C, [α]2D5 = +9.5
tetrahydro-4H-chromene-3-carbonitrile (6b).
White solid,
yield 30mg (96%), mp: 188–189°C, [α]2D5 =+6.2 (c=0.55,
1
(c =0.6, CH2Cl2, 76% ee). H NMR (300 MHz, CDCl3):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Ramireddy, S. Abbaraju, D. Ding, H. Arman, and J. C.-G. Zhao
Vol 9999
THF, 54% ee). 1H NMR (300MHz, DMSO-d6): δ
7.22–7.05 (m, 5H), 7.03 (s, 2H), 4.18 (s, 1H), 2.52 (S,
2H), 2.23 (d, J= 16.1Hz, 1H), 2.08 (d, J=16.1Hz, 1H),
1.01 (s, 3H), 0.93 (s, 3H); 13C NMR (125MHz,
DMSO-d6): δ 196.1, 162.9, 159.7, 158.8, 141.4, 141.3,
129.5, 129.4, 120.0, 115.6, 115.3, 113.01, 58.47, 50.3,
35.3, 32.2, 28.7, 27.2ppm. υmax (neat, cmÀ1): 3415, 2982,
2205, 1751, 1422, 1303. HRMS m/z calcd. for
C18H18FN2O2 [M+H]+ 313.1352; found 313.1364. HPLC
conditions: ChiralPak IB, hexanes/i-PrOH=80:20, flow
rate=1.0mL/min, UV detection at 254nm.
(R)-2-Amino-4-(4-nitrophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6f). White solid,
yield 31.8 mg (94%), mp: 182–183°C, [α]2D5 = +31.2 (c = 0.5,
1
THF, 36% ee). H NMR (500 MHz, DMSO-d6): δ 8.15 (d,
J=8.4 Hz, 2H), 7.42 (d, J= 8.4Hz, 2H), 7.15 (s, 2H), 4.34
(s, 1H), 2.52 (s, 2H), 2.24 (d, J= 16.1 Hz, 1H), 2.09 (d,
J=16.1Hz, 1H), 1.02 (s, 3H), 0.94 (s, 3H); 13C NMR
(75 MHz, DMSO-d6): δ 196.1, 163.5, 159.0, 152.7, 146.6,
129.0, 124.1, 119.8, 112.1, 57.3, 50.2, 36.0, 32.2, 28.7,
27.3 ppm. υmax (neat, cmÀ1): 3488, 2972, 2185, 1740,
1256, 1122. HRMS m/z calcd. for C18H18N3O4 [M+ H]+
340.1297; found 340.1304. HPLC conditions: ChiralPak
IB, hexanes/i-PrOH= 80:20, flow rate= 1.0 mL/min, UV
detection at 254 nm.
(R)-2-Amino-4-(4-chlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6c).
White solid,
yield 31.5 mg (96%), mp: 205–206°C, [α]2D5 = À9.8
(c = 0.8, THF, 53% ee). 1H NMR (300 MHz,
(R)-2-Amino-4-(4-methylphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6g).
White solid,
DMSO-d6):
δ 7.33 (d, J = 8.2 Hz, 2H), 7.15 (d,
yield 28.03mg (91%), mp: 215–216°C, [α]2D5 = +37.8
J = 8.3 Hz, 2H), 7.06 (s, 2H), 4.17 (s, 1H), 2.46 (s,
2H), 2.23 (d, J = 16.1 Hz, 1H), 2.08 (d, J = 16.1 Hz,
1H), 1.01 (s, 3H), 0.93 (s, 3H); 13C NMR (75 MHz,
DMSO-d6): δ 196.1, 163.0, 158.9, 144.2, 131.5, 129.5,
128.7, 120.0, 112.7, 58.1, 50.3, 35.5, 32.2, 28.7,
27.3 ppm. υmax (neat, cmÀ1): 3396, 2966, 2182, 1606,
1386. HRMS m/z calcd. for C18H18ClN2O2 [M + H]+
329.1057; found 329.1074. HPLC conditions: ChiralPak
IB, hexanes/i-PrOH=80:20, flow rate=1.0mL/min, UV
detection at 254nm.
1
(c = 1.0, THF, 64% ee). H NMR (500MHz, DMSO-d6):
δ 7.06 (d, J= 7.9 Hz, 2H), 6.99 (d, J = 7.9 Hz, 2H), 6.93
(s, 2H), 4.10 (s, 1H), 2.53 (s, 2H), 2.28–2.17 (m, 3H),
2.07 (d, J = 16.0Hz, 1H), 1.01 (s, 3H), 0.93 (s, 3H); 13C
NMR (125MHz, DMSO-d6): δ 196.0, 162.7, 158.8,
142.2, 136.0, 129.3, 127.5, 120.1, 113.3, 58.8, 50.4,
35.6, 32.2, 28.8, 27.2, 21.0ppm. υmax (neat, cmÀ1): 3502,
2956, 2189, 1705, 1192. HRMS m/z calcd. for
C19H21N2O2 [M+ H]+ 309.1603; found 309.1611. HPLC
conditions: ChiralPak IB, hexanes/i-PrOH = 80:20, flow
rate = 1.0 mL/min, UV detection at 254 nm.
(R)-2-Amino-4-(4-bromophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6d).
White solid,
yield 36.5 mg (98%), mp: 199–200°C, [α]2D5 = À14.1
(R)-2-Amino-4-(4-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
1
tetrahydro-4H-chromene-3-carbonitrile (6h).
White solid,
(c = 0.7, THF, 54% ee). H NMR (300 MHz, DMSO-d6):
yield 23.9mg (74%), mp: 206–207°C, [α]2D5 =À21.1
δ 7.45 (d, J = 8.3 Hz, 2H), 7.07–7.11 (m, 4H), 4.15 (s,
1H), 2.48 (s, 2H), 2.23 (d, J = 16.0 Hz, 1H), 2.07 (d,
J = 16.0 Hz, 1H), 1.01 (s, 3H), 0.92 (s, 3H); 13C NMR
(75 MHz, DMSO-d6): δ δ 196.1, 163.0, 158.9, 144.6,
131.6, 129.9, 120.0, 112.6, 58.0, 55.3, 50.3, 35.6, 32.2,
28.7, 27.3. υmax (neat, cmÀ1): 3423, 2968, 2180, 1723,
1414, 1201. HRMS m/z calcd. for C18H18BrN2O2
[M + H]+ 373.0552; found 373.0554. HPLC conditions:
ChiralPak IB, hexanes/i-PrOH = 80:20, flow rate = 1.0 mL/
min, UV detection at 254 nm.
1
(c=0.6, THF, 60% ee). H NMR (300MHz, DMSO-d6):
δ7.07–6.99 (m, 2H), 6.95 (s, 2H), 6.90–6.77 (m, 2H),
4.09 (s, 1H), 3.69 (s, 3H), 2.58 (s, 2H), 2.23 (d,
J=16.2Hz, 1H), 2.06 (d, J=16.2Hz, 1H), 1.01 (s, 3H),
0.92 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ 196.1,
162.5, 158.8, 158.3, 137.2, 128.6, 120.2, 114.0, 113.4,
58.9, 55.4, 55.3, 51.0, 50.4, 44.6, 35.1, 32.2, 28.8,
27.2ppm. υmax (neat, cmÀ1): 3463, 2988, 2192, 1755,
1282. HRMS m/z calcd. for C19H21N2O3 [M+H]+
325.1552; found 325.1563. HPLC conditions: ChiralPak
IB, hexanes/i-PrOH=80:20, flow rate=1.0mL/min, UV
detection at 254nm.
(R)-2-Amino-4-(4-cyanophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6e).
yield 29.3 mg (92%), mp: 186–187°C, [α]2D5 =+13.2
White solid,
1
(R)-2-Amino-4-(3-bromophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
(c =0.7, THF, 31% ee). H NMR (300 MHz, DMSO-d6):
tetrahydro-4H-chromene-3-carbonitrile (6i).
White solid,
δ 7.90–7.62 (m, 2H), 7.53–7.25 (m, 2H), 7.14 (s, 2H),
4.27 (s, 1H), 2.51 (s, 2H), 2.24 (d, J = 16.0Hz, 1H), 2.09
(d, J = 16.0Hz, 1H), 1.02 (s, 3H), 0.93 (s, 3H); 13C NMR
(75 MHz, DMSO-d6): δ196.1, 163.5, 158.9, 150.6, 132.8,
128.7, 119.8, 119.2, 112.1, 109.8, 57.5, 50.3, 36.2, 32.2,
28.6, 27.4 ppm. υmax (neat, cmÀ1): 3441, 2981, 2210,
1682, 1381, 1166. HRMS m/z calcd. for C18H18N3O2
[M + H]+ 320.1399; found 320.1390. HPLC conditions:
ChiralPak IB, hexanes/i-PrOH = 80:20, flow rate = 1.0 mL/
min, UV detection at 254nm.
yield 34.7 mg (93%), mp: 216–217°C, [α]2D5 = +13.2
1
(c = 0.9, THF, 19% ee). H NMR (300MHz, DMSO-d6):
δ 7.42 (d, J= 8.0 Hz, 1H), 7.36–7.24 (m, 2H), 7.18 (d,
J = 7.8 Hz, 1H), 7.14 (s, 2H), 4.22 (s, 1H), 2.55 (s, 2H),
2.28 (d, J= 16.1 Hz, 1H), 2.14 (d, J = 16.1Hz, 1H), 1.06
(s, 3H), 0.98 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ
196.2, 163.3, 158.9, 147.9, 131.1, 130.4, 130.0, 126.8,
122.0, 120.0, 112.5, 58.0, 50.3, 35.8, 32.3, 28.8,
27.2 ppm. υmax (neat, cmÀ1): 3425, 2898, 2202, 1652,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Enantioselective Synthesis of 2-Amino-4H-chromene Derivatives
1313. HRMS m/z calcd. for C18H18BrN2O2 [M+ H]+
373.0552; found 373.0559. HPLC conditions: ChiralPak
IB, hexanes/i-PrOH =80:20, flow rate= 1.0 mL/min, UV
detection at 254nm.
J=5.1, 3.5Hz, 1H), 6.84 (d, J=2.9Hz, 1H), 2.51 (t,
J=14.7Hz, 1H), 2.41 (d, J=17.7Hz, 1H), 2.28 (d,
J=16.2Hz, 1H), 2.13 (d, J=16.1Hz, 1H), 1.02 (s, 3H),
0.95 (s, 3H); 13C NMR (125MHz, DMSO-d6): δ 195.9,
162.9, 159.3, 149.7, 127.2, 124.8, 124.4, 120.0, 113.3,
58.5, 50.3, 32.1, 30.8, 29.0, 26.9ppm. υmax (neat, cmÀ1):
3505, 2992, 2188, 1724, 1363. HRMS m/z calcd. for
C16H14N2O2S [M+H]+ 301.1011; found 301.1013.
HPLC conditions: ChiralPak IB, hexanes/i-PrOH=80:20,
flow rate=1.0mL/min, UV detection at 254nm.
(R)-2-Amino-5,6,7,8-tetrahydro-5-oxo-4-phenyl-4H-chromene-
3-carbonitrile (6n). White solid, yield 19.4mg (73%), mp:
210–211°C, [α]2D5 =+23.8 (c=0.6, THF, 52% ee). 1H NMR
(300MHz, DMSO-d6): δ 7.26 (t, J=7.2 Hz, 2H), 7.12–7.18
(m, 3H), 6.97 (s, 2H), 4.17 (s, 1H), 2.61 (s, 2H), 2.25–2.27
(m, 2H), 2.05–1.74 (m, 2H); 13C NMR (75MHz,
DMSO-d6): δ 196.3, 165.2, 159.0, 144.4, 131.7, 129.7,
128.9, 120.2, 114.0, 58.4, 37.1, 35.8, 27.3, 20.6ppm. υmax
(neat, cmÀ1): 3485, 2964, 2186, 1702, 1322. HRMS m/z
calcd. for C16H15N2O2 [M + H]+ 267.1134; found
273.1140. HPLC conditions: ChiralPak AD-H, hexanes/i-
PrOH= 85:15, flow rate= 1.0mL/min, UV detection at
254nm.
(R)-2-Amino-4-(2-bromophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6j).
White solid,
yield 35.4 mg (95%), mp: 208–210°C, [α]2D5 =+17.2 (c= 1,
1
THF, 51% ee). H NMR (500 MHz, DMSO-d6): δ 7.50
(s, 1H), 7.29 (t, J =7.5 Hz, 1H), 7.10 (dd, J = 15.1,
7.5Hz, 2H), 7.00 (s, 2H), 4.69 (s, 1H), 2.50 (s, 2H),
2.22 (d, J = 16.0Hz, 1H), 2.05 (d, J = 16.0Hz, 1H), 1.02
(s, 3H), 0.97 (s, 3H); 13C NMR (75 MHz, DMSO-d6): δ
195.9, 163.4, 158.9, 143.8, 133.0, 130.2, 128.8, 128.5,
123.1, 119.5, 112.5, 57.4, 50.3, 35.4, 32.2, 28.8,
27.4ppm. υmax (neat, cmÀ1): 3499, 2878, 2184, 1702,
1265. HRMS m/z calcd. for C18H18BrN2O2 [M+ H]+
373.0552; found 373.0553. HPLC conditions: ChiralPak
IB, hexanes/i-PrOH =80:20, flow rate= 1.0 mL/min, UV
detection at 254 nm.
(R)-2-Amino-4-(3-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6k).
White solid,
yield 27.88mg (86%), mp: 194–195°C, [α]2D5 =À7.5
(c=0.65, THF, 45% ee). 1H NMR (300MHz,
DMSO-d6): δ 7.18 (t, J=7.8Hz, 1H), 6.99 (s, 2H), 6.72
(dd, J=16.6, 7.8Hz, 2H), 6.63 (s, 1H), 4.12 (s, 1H), 3.69
(s, 3H), 2.50 (s, 2H), 2.24 (d, J=16.0Hz, 1H), 2.09 (d,
J=16.0Hz, 1H), 1.02 (s, 3H), 0.95 (s, 3H) ; 13C NMR
(75 MHz, DMSO-d6): δ 196.0, 163.0, 159.6, 158.9, 146.7,
129.8, 120.1, 119.7, 113.6, 113.0, 111.8, 58.6, 55.35, 50.3,
35.8, 32.2, 28.8, 27.1ppm. υmax (neat, cmÀ1): 3515, 2902,
2190, 1764, 1293. HRMS m/z calcd. for C19H21N2O3
[M+H]+ 325.1552; found 325.1560. HPLC conditions:
ChiralPak IB, hexanes/i-PrOH=80:20, flow rate=1.0mL/
min, UV detection at 254nm.
General procedure for the asymmetric synthesis of
compound 9.
To a solution of cyclohexane-1,2-dione
(8, 35.3mg, 0.32mmol) and catalyst 1a (17.8mg,
0.030 mmol, 10mol %) in toluene (1.5 mL) at 0°C was
added benzylidenemalononitrile (5, 0.30mmol). The
mixture was stirred until the reaction was completed
(TLC monitoring). The solvent was then removed under
reduced pressure, and the residue was purified by silica
gel chromatography (5:1 hexane/EtOAc) to afford the
product 9.
(S)-2-Amino-8-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-
3-carbonitrile (9a).
Viscous oil, yield 51.1mg (64%),
(R)-2-Amino-4-(2-methoxyphenyl)-7,7-dimethyl-5-oxo-5,6,
7,8-tetrahydro-4H-chromene-3-carbonitrile (6l). White solid,
yield 26.5mg (82%), mp: 201–202°C, [α]2D5 =+14.2
(c=0.8, THF, 51% ee). 1H NMR (500MHz, DMSO-d6): δ
7.17–7.10 (m, 1H), 6.99–6.89 (m, 2H), 6.83 (d, J=7.4Hz,
1H), 6.80 (s, 2H), 4.45 (s, 1H), 3.72 (s, 3H), 2.52 – 2.46 (s,
2H), 2.22 (d, J= 16.1Hz, 1H), 2.04 (d, J=16.1Hz, 1H),
1.02 (s, 3H), 0.94 (s, 3H); 13C NMR (125MHz,
DMSO-d6): δ 196.0, 163.5, 159.4, 157.2, 132.5, 128.9,
128.2, 120.7, 120.2, 112.3, 111.9, 67.9, 57.8, 56.0, 55.3,
51.0, 50.4, 44.8, 32.2, 30.7, 29.0, 26.9ppm. υmax (neat,
cmÀ1): 3466, 2912, 2178, 1644, 1113. HRMS m/z calcd.
for C19H21N2O3 [M+H]+ 325.1552; found 325.1569.
HPLC conditions: ChiralPak IB, hexanes/i-PrOH=80:20,
flow rate=1.0mL/min, UV detection at 254nm.
[α]2D5 = +30.0 (c 0.395, CH2Cl2); 1H NMR (500 MHz,
CDCl3): δ 7.29–7.38 (m, 3H), 7.22–7.23 (m, 2H), 4.74 (s,
2H), 4.10 (s, 1H), 2.45–2.58 (m, 2H), 2.12–2.27 (m,
2H),1.86–2.05 (m, 2H); 13C NMR (125MHz, CDCl3): δ
190.6, 159.0, 141.5, 140.5, 134.8, 129.4, 128.3, 128.2, 119.3,
59.5, 44.0, 38.0, 27.7, 21.9; vmax (cmÀ1): 3322, 2923, 2190,
1596; Anal. calcd. for C16H14N2O2 : C, 72.16; H, 5.30; N,
10.52. Found: C, 72.22; H, 5.15; N, 10.51; HPLC conditions:
ChiralCel OD-H column, 15:85 i-PrOH/hexane, flow
rate 1.0 mL/min, UV detection at 254 nm.
(S)-2-Amino-4-(4-chlorophenyl)-8-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (9b).
Viscous oil, yield
54.1 mg (60%), [α]2D5 = À25.2 ( c = 0.72, CH2Cl2); 1H
NMR (500 MHz, CDCl3): δ 7.34 (d, J = 8.0 Hz, 2H),
7.17 (d, J = 8.0 Hz, 2H), 4.86 (s, 2H), 4.10 (s, 1H),
2.49–2.56 (m, 2H), 2.09–2.25 (m, 2H), 1.88–2.02 (m,
2H); 13C NMR (125 MHz, CDCl3): δ190.6, 159.2,
140.5, 140.0, 134.2, 134.1, 129.6, 129.6, 119.2, 58.9,
43.4, 38.0, 27.6, 21.9; vmax (cmÀ1): 3436, 3322, 2190,
(R)-2-Amino-7,7-dimethyl-5-oxo-4-(thiophen-2-yl)-5,6,7,8-
tetrahydro-4H-chromene-3-carbonitrile (6m). White solid,
yield 18.9 mg (63%), mp: 181–182°C, [α]2D5 = +37.6
(c=0.6, THF, 52% ee). 1H NMR (500MHz, DMSO-d6): δ
7.29 (dd, J=5.1, 1.1Hz, 1H), 7.09 (s, 2H), 6.88 (dd,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

N. Ramireddy, S. Abbaraju, D. Ding, H. Arman, and J. C.-G. Zhao
Vol 9999
1668; Anal. calcd. for C16H13ClN2O2 : C, 63.90; H,
4.36; N, 9.31. Found: C, 63.65; H, 4.36; N, 9.30;
HPLC conditions: ChiralCel OD-H column, 15:85
i-PrOH/hexane, flow rate 1.0 mL/min, UV detection at
254 nm.
(S)-2-Amino-4-(4-bromophenyl)-8-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (9c). Viscous oil, yield 56.9mg
(55%), [α]2D5 =À63.8 (c 0.515, CH2Cl2); 1H NMR (500 MHz,
CDCl3): δ 7.05 (d, J= 8.0Hz, 2H), 7.11 (d, J=8.0Hz, 2H),
4.76 (s, 2H), 4.09 (s, 1H), 2.49–2.56 (m, 2H), 2.20–2.25 (m,
1H),2.10–2.16 (m 1H), 1.88–2.01 (m, 2H); 13C NMR
(75MHz, CDCl3): δ 190.3, 159.0, 140.5, 140.4, 133.9, 132.5,
129.8, 122.4, 119.0, 59.1, 43.6, 38.1, 27.8, 22.0; vmax (cmÀ1):
2922, 2192, 1632; HRMS m/z calcd. for C16H14BrN2O2
[M+H]+ 345.0233; found 345.0218; HPLC conditions:
ChiralCel OD-H column, 15:85 i-PrOH/hexane, flow rate
1.0mL/min, UV detection at 254nm.
AD-H column, 30:70 i-PrOH/hexane, flow rate 1.0mL/min,
UV detection at 254nm.
(S)-2-Amino-4-(4-methylphenyl)-8-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (9g). Viscous liquid, yield
41.2 mg (49%), [α]2D5 = À72.9 (c 0.305, CH2Cl2); 1H
NMR (300MHz, CDCl3): δ 7.16 (d, J=7.8Hz, 2H), 7.09
(d, J=7.8Hz, 2H), 4.71 (s, 2H), 4.06 (s, 1H), 2.48–2.55
(m, 2H), 2.35 (s, 3H), 2.17–2.23 (m, 2H), 1.86–2.00 (m,
2H); 13C NMR (75 MHz, CDCl3): δ 190.6, 158.8, 140.4,
138.4, 138.0, 135.0, 130.0, 128.0, 59.7, 43.7, 38.2, 27.9,
22.1, 21.5; vmax (cmÀ1): 3353, 3189, 2203, 1601; HRMS
m/z calcd. for C17H17N2O2 [M+H]+ 281.1285; found
281.1292; HPLC conditions: ChiralCel OD-H column,
15:85 i-PrOH/hexane, flow rate 1.0mL/min, UV detection
at 254nm.
(S)-2-Amino-8-oxo-4-(thiophenyl-2-yl)-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (9h).
Viscous liquid, yield
30.1mg (37%), [α]D25 =À24.1 (c 0.02, CH2Cl2); H NMR
(500MHz, CDCl3): δ 7.27–7.29 (m, 1H), 6.96–6.98 (m,
2H), 4.80 (s, 2H), 4.44 (s, 1H), 2.48–2.55 (m, 2H),
2.27–2.38 (m, 2H), 1.94–2.05 (m, 2H); 13C NMR
(125MHz, CDCl3): δ 190.6, 159.0, 145.6, 140.1, 133.9,
127.3, 126.2, 126.2, 119.0, 59.6, 38.9, 38.0, 27.7, 22.0;
vmax (cmÀ1): 3403, 2963, 2203, 1601; HRMS m/z calcd.
for C14H13N2O2S [M+H]+ 273.0692; found 273.0690;
HPLC conditions: ChiralPak AS column, 65:35 i-PrOH/
hexane, flow rate 1.0mL/min, UV detection at 254nm.
(S)-2-Amino-4-hexyl-8-oxo-5,6,7,8-tetrahydro-4H-chromene-
1
(S)-2-Amino-4-(4-cyanophenyl)-8-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (9d).
Pale yellow solid,
yield 44.5 mg (51%), mp: 101–103°C, [α]2D5 = À40.7 (c
1
0.685, CH2Cl2); H NMR (500MHz, CDCl3): δ 7.68 (d,
J=8.0Hz, 2H), 7.36 (d, J=8.0Hz, 2H), 4.91 (s, 2H),
4.19 (s, 1H), 2.45–2.57 (m, 2H), 2.22–2.28 (m, 1H),
1.90–2.11 (m, 3H); 13C NMR (125MHz, CDCl3): δ
190.3, 159.3, 146.6, 140.9, 133.3, 132.8, 129.0, 118.8,
118.6, 112.4, 58.2, 44.1, 37.9, 27.7, 21.8; vmax (cmÀ1):
3517, 2231, 1766, 1609; HRMS m/z calcd. for
C17H14N3O2 [M+H]+ 292.1081; found 292.1077; HPLC
conditions: ChiralCel OD-H column, 30:70 i-PrOH/
hexane, flow rate 1.0 mL/min, UV detection at 254 nm.
(S)-2-Amino-4-(4-nitrophenyl)-8-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carbonitrile (9e). Pale yellow solid, yield 51.3 mg
(55%), mp: 203–205°C (decompose), [α]2D5 =À19.1 (c 0.87,
3-carbonitrile (9i).
Viscous liquid, yield 9.8mg (12%),
[α]2D5 =À6.5 (c 0.03, CH2Cl2); 1H NMR (500MHz,
CDCl3): δ 4.67 (s, 2H), 3.14–3.16 (m, 1H), 2.47–2.59 (m,
3H), 2.23–2.29 (m, 1H), 2.01–2.06 (m, 2H), 1.57–1.71 (m,
3H), 1.16–1.38 (m, 7H), 0.87–0.90 (m, 3H); 13C NMR
(125MHz, CDCl3): δ 190.3, 160.4, 141.8, 136.2, 119.8,
57.2, 38.0, 37.2, 33.5, 31.9, 29.5, 27.6, 24.8, 22.8, 22.1,
14.3; vmax (cmÀ1): 3331, 2186, 1664; Anal. calcd for
C16H13N3O4 : C, 70.04; H, 8.08; N, 10.21. Found: C,
70.12; H, 7.94; N, 10.22; HPLC conditions: ChiralPak
AD-H column, i-PrOH/hexane 20:80, flow rate 1.0 mL/min,
UV detection at 254nm.
1
CH2Cl2); H NMR (500 MHz, CDCl3): δ 8.25 (d, J=8.0Hz,
2H), 7.43 (d, J=8.0 Hz, 2H), 4.90 (s, 2H), 4.27 (s, 1H),
2.48–2.60 (m, 2H), 2.25–2.31(m, 1H), 1.91–2.12(m, 3H);
13C NMR (125MHz, CDCl3): δ190.2, 159.3, 148.5, 148.0,
140.9, 132.6, 132.6, 129.2, 124.7, 118.7, 58.2, 43.8, 37.9,
27.7, 21.8; vmax (cmÀ1): 3427, 2921, 2190; Anal. calcd for
C16H13N3O4 : C, 61.73; H, 4.21; N, 13.50. Found: C, 61.69;
H, 4.02; N, 13.25; HPLC conditions: ChiralCel OD-H
column, 40:60 i-PrOH/hexane, flow rate 1.0 mL/min, UV
detection at 254nm.
Acknowledgments. This research is financially supported by the
Welch Foundation (Grant No. AX-1593) and partly by the
National Institute of General Medical Sciences (Grant No.
1SC1GM082718), for which the authors are most grateful.
(S)-2-Amino-4-(3-bromophenyl)-8-oxo-5,6,7,8-tetrahydro-
4H-chromene-3-carbonitrile (9f).
Viscous oil, yield
65.1 mg (63%), [α]2D5 = À46.3 (c 0.885, CH2Cl2); 1H
NMR (300MHz, CDCl3): δ 7.43–7.46 (m, 1H), 7.21–7.26
(m, 2H), 7.15–7.18 (m, 1H), 4.82 (s, 2H), 4.08 (s, 1H),
2.50–2.57 (m, 2H), 2.09–2.28 (m, 2H), 1.89–2.05 (m, 2H);
13C NMR (75 MHz, CDCl3): δ 190.4, 159.1, 143.7,
140.5, 133.8, 131.6, 131.1, 130.9, 126.9, 123.5, 119.0,
58.9, 43.9, 38.1, 27.8, 22.0; vmax (cmÀ1): 3435, 2184,
1692; HRMS m/z calcd. for C16H14BrN2O2 [M+H]+
345.0233; found 345.0226; HPLC conditions: ChiralPak
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet