Enantioselective synthesis of 2-amino-4H-pyrans via the organocatalytic cascade reaction of malononitrile and α-substituted chalcones

Article abstract of DOI:10.1016/j.tetasy.2012.03.018

An organocatalytic cascade reaction of malononitrile and α-substituted chalcones has been developed for the synthesis of chiral multisubstituted 2-amino-4H-pyran derivatives. A series of chiral primary/tertiary amines and cinchona alkaloids were examined as the catalysts. Quinine was found to be the most efficient catalyst in the absence of any additive. The α-substitutents of the chalcones had a siginificant effect on the yield and the enantioselectivity. A number of multisubstituted 2-amino-4H-pyrans were obtained in excellent yields and enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2012.03.018

Tetrahedron: Asymmetry 23 (2012) 461–467
Contents lists available at SciVerse ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of 2-amino-4H-pyrans via the organocatalytic
cascade reaction of malononitrile and
a-substituted chalcones
⇑
Zhi-Peng Hu, Wei-Juan Wang, Xiao-Gang Yin, Xue-Jing Zhang, Ming Yan
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 February 2012
Accepted 26 March 2012
An organocatalytic cascade reaction of malononitrile and a-substituted chalcones has been developed for
the synthesis of chiral multisubstituted 2-amino-4H-pyran derivatives. A series of chiral primary/tertiary
amines and cinchona alkaloids were examined as the catalysts. Quinine was found to be the most effi-
cient catalyst in the absence of any additive. The a-substitutents of the chalcones had a siginificant effect
on the yield and the enantioselectivity. A number of multisubstituted 2-amino-4H-pyrans were obtained
in excellent yields and enantioselectivities.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
quent intramolecular cyclization is an attractive strategy for their
synthesis. As a continuation of our study on organocatalytic cas-
Over the last decade, asymmetric organocatalysis has evolved
into an important tool for the synthesis of chiral compounds in
addition to classical organometallic catalysis and biocatalysis.1
The organocatalytic conjugate addition of carboanion nucleophiles
to electron-deficient olefins is extremely powerful for asymmetric
carbon–carbon bond formation.2 Furthermore, cascade reactions
triggered by organocatalytic conjugate additions provide highly
efficient and convenient methods with which to construct cyclic
chiral compounds.3 Malononitrile is an active nucleophile with a
cade reactions,11 we are interested in the cascade reaction of mal-
ononitrile and chalcones. Such a transformation can provide chiral
multisubstituted 2-amino-4H-pyrans for further biological evalua-
tion. Previous studies have reported that the conjugate addition of
malononitrile to chalcones provides normal adducts and the subse-
quent intramolecular cyclization does not occur.4a–e These results
demonstrate that the stabilization of the enolate anion generated
in the conjugate addition step is crucial for any subsequent intra-
molecular cyclization. We speculate that the introduction of appro-
very acidic
a
-proton (pKa = 11). Organocatalytic conjugate addi-
priate a-substitutents can improve the stabilization of the enolate
anion intermediate and allow a subsequent intramolecular cycliza-
tion. Herein we report the organocatalytic cascade reaction of
tions of malononitrile to enones have also been developed.4 Zhao
et al. reported that the organocatalytic reaction of malononitrile
and b,c-unsaturated ketoesters generated 2-amino-4H-pyrans in
malononitrile and a-substituted chalcones. Chiral multisubstituted
good yields and enantioselectivities.5 Wang et al. found that the
organocatalytic reaction of malononitrile with (E)-3-benzyliden-
echroman-4-ones gave 2-amino-4H-pyrans efficiently.6 Recently
we developed an organocatalytic double conjugate addition of
malononitrile to conformationally flexible dienones. Chiral cyclo-
hexanones were obtained in excellent yields and enantioselectivi-
ties.7 We also found that the reaction of malononitrile with
conformationally restricted dienones resulted in bicyclic 2-ami-
no-4H-pyrans via a cascade Michael/intramolecular cyclization se-
quence (Scheme 1, eq. 1).8
2-Amino-4H-pyran is an important scaffold of many natural
products and bioactive compounds.9 In addition, 2-amino-4H-pyr-
ans are also used as photoactive materials.10 New synthetic meth-
ods for making chiral 2-amino-4H-pyrans are highly desirable. The
organocatalytic conjugate addition of malononitrile and subse-
2-amino-4H-pyrans were obtained in excellent yields and enanti-
oselectivities (Scheme 1, eq. 2).
2. Results and discussion
The reaction of a-phenyl chalcone 1a and malononitrile 2a was
studied. Cinchona alkaloids 3a–3d and organocatalysts 3e–3m
(Scheme 2) were examined as catalysts and the results are
summarized in Table 1. Quinine 3a catalyzed the reaction effi-
ciently. 2-Amino-4H-pyran 4a was obtained in good yield and
enantioselectivity (Table 1, entry 1). Quinidine 3b, cinchonine 3c,
and cinchonidine 3d provided moderate to good yields and lower
enantioselectivities (Table 1, entries 2–4). 60-Demethyl quinine
3e gave a low yield and moderate enantioselectivity (Table 1, entry
5). 60-Demethyl-9-benzyloxy-quinine 3f was ineffective for this
reaction (Table 1, entry 6). Primary amines 3g–3h, which are gen-
erally used for the activation of enones, also afforded low yields
and enantioselectivities (Table 1, entries 7–8). Takemoto’s amine-
⇑
Corresponding author. Tel./fax: +86 20 39943049.
E-mail address: yanming@mail.sysu.edu.cn (M. Yan).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.018

462
Z.-P. Hu et al. / Tetrahedron: Asymmetry 23 (2012) 461–467
CF3
S
F3C
N
H
N
H
NH2
N
Previous work
R2
R1
O
O
(10 mol %)
toluene, rt
NC
R2
R1
R1
R1
(1)
R2 = CN, COOEt
conformationally
up to 99% yield
99% ee
restricted dienones
This work
(2)
R3
O
R2
quinine
(20 mol%)
toluene, rt
R2
R1
O
R3
NC
R4
H2N
R1
R4
α-substituted chalcones
Scheme 1. Organocatalytic cascade reaction of malononitrile and enones.
N
N
N
HO
N
HO
HO
HO
N
HO
H
H
H
H
H3CO
H
H3CO
HO
N
N
N
N
N
3a (quinine)
3b
(quinidine)
3c (cinchonine)
CF3
3e
3d
(cinchonidine)
CF3
OMe
H
N
BnO
S
N
S
H
HO
F3C
N
H
N
H
F3C
N
H
N
H
NH2
NH2
N
N
N
3g
3i
3h
3f
OMe
OMe
CF3
CF3
H
H
O
N
N
S
S
NH
NH
F3C
N
N
H
F3C
N
H
N
H
N
N
H
H
NH
S
N
N
N
CF3
O
CF3
F3C
F3C
3j
3m
3k
Scheme 2. Organocatalysts 3a–3m.
3l
thiourea 3i provided low yield and enantioselectivity (Table 1, en-
try 9). However, improved enantioselectivities were achieved by
using the more sterically demanding catalysts 3j and 3k (Table 1,
entries 10–11). In addition, quinine-derived thiourea 3l and
squaramide 3m gave inferior results (Table 1, entries 12–13).
The reaction solvents were screened using quinine as the cata-
lyst and the results are summarized in Table 2. Low yield and
enantioselectivity were obtained in hexane (Table 2, entry 1). The
reaction provided good yield and enantioselectivity in toluene (Ta-
ble 2, entry 2). Moderate yields and enantioselectivities were
achieved in dichloromethane and chloroform (Table 2, entries 3–
4). Low yields and enantioselectivities were observed in THF,
diethyl ether, and 1,4-dioxane (Table 2, entries 5–7). Polar solvents,
such as acetone and ethanol were incompatible with the reaction
(Table 2, entries 8–9).
The effects of other reaction conditions were also studied and
the results are summarized in Table 3. The reaction provided com-
parable yields and enantioselectivities in 2, 2.5, and 5 days (Table 3,
entries 1–3). From these results it could be seen that the reaction
actually stopped in almost 2 days. In order to improve the yield,

Z.-P. Hu et al. / Tetrahedron: Asymmetry 23 (2012) 461–467
463
Table 1
Table 3
Screening of catalysts 3a–3ma
Optimization of the reaction conditionsa
H2N
NC
O
Ph
Ph
H2N
NC
O
Ph
O
O
3a-3m
quinine (20 mol%)
toluene, rt
(20 mol%)
NC
CN
Ph
Ph
NC
CN
Ph
Ph
Ph
toluene, rt
Ph
Ph
Ph
Ph
1a
2a
4a
1a
4a
2a
Entry
Catalyst
Yieldb (%)
Eec (%)
83
Entry
1a (mmol)
2a (mmol)
Time (days)
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
3a
3b
3c
3d
3e
3f
3g
3h
3i
80
85
31
74
29
0
23
14
46
66
50
30
0
1
2
3
4
5
6
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.15
0.15
0.15
0.1
0.2
0.3
0.2
0.2
0.2
2
2.5
5
2
2
2
4
3
4
80
80
79
69
84
85
78
79
72
84
83
84
86
86
85
85
86
85
ꢀ72
ꢀ50
62
68
n.d.d
29
ꢀ48
49
62
82
7b
8c
9d
3j
3k
3l
a
The reactions were carried out with 1a (0.1 mmol), 2a and quinine (0.02 mmol)
in toluene (1.0 mL) at room temperature.
36
n.d.d
b
3m
The reaction was carried out at 0 °C.
Quinine (0.01 mmol, 10 mol %) was used.
Quinine (0.005 mmol, 5 mol %) was used.
c
a
The reactions were carried out with 1a (0.1 mmol), 2a (0.15 mmol) and 3a–3m
(0.02 mmol) in toluene (1.0 mL) at room temperature for 2.5 days.
d
b
Isolated yields after column chromatography.
Ee values of purified 4a were determined by chiral HPLC.
n.d. = not determined.
c
d
substituted enone 1h also gave moderate yield and good enanti-
oselectivity (Table 4, entry 8). Ethyl cyanoacetate was also tested
in the reaction, and while good enantioselectivity was obtained,
the yield was poor (Table 4, entry 9). Benzoylacetonitrile was
found to be unreactive for the transformation (Table 4, entry 10).
A number of 1,2-disubstituted enones 1i–1l were also examined
and the results are summarized in Table 5. 3,4-Diphenyl-but-3-en-
2-one 1i provided the product in good yield and enantioselectivity
(Table 5, entry 1). The effect of the 2-substitutuents proved to be
significant (Table 5, entries 2–4). Excellent enantioselectivity was
obtained for 2-methyl chalcone 1j, however the yield was rather
low (Table 5, entry 2). Poor yield and enantioselectivity were ob-
served for 2-ethyloxycarbonyl chalcone 1k (Table 5, entry 3). 2-Cy-
Table 2
Effect of reaction solventsa
H2N
O
Ph
Ph
O
quinine (20 mol%)
solvent, rt
+
NC
CN
Ph
Ph
NC
Ph
Ph
1a
2a
4a
Entry
Solvent
Yield (%)
Ee (%)
1
2
3
4
5
6
7
8
9
Hexane
Toluene
CH2Cl2
CHCl3
THF
11
80
47
54
24
52
15
<5
38
44
83
75
75
44
51
47
n.d.
6
Table 4
Conjugate addition of malononitrile to enones with various 3-substitutentsa
O
H2N
O
Ph
Ph
Et2O
quinine (20 mol%)
toluene, rt
1,4-Dioxane
Acetone
EtOH
R1
NC
R4
Ph
b
R4
Ph
1a-1h
R1
4a-4j
2a-2c
a
The reactions were carried out with 1a (0.1 mmol), 2a (0.15 mmol) and quinine
(0.02 mmol) in solvent (1.0 mL) at room temperature for 2.5 days.
b
n.d. = not determined.
Entry
R1
R4
Time (h)
Yieldb (%)
Eec (%)
1
2
3
4
5
6
7
Phenyl 1a
4-Cl-C6H4 1b
4-Br-C6H4 1c
4-NO2-C6H4 1d
4-Me-C6H4 1e
4-MeO-C6H4 1f
Thienyl 1g
2-Propyl 1h
Phenyl 1a
CN 2a
CN 2a
CN 2a
CN 2a
CN 2a
CN 2a
CN 2a
CN 2a
COOEt 2b
PhCO 2c
48
48
48
48
48
72
46
72
120
168
4a, 82
4b, 80
4c, 90
4d, 91
4e, 80
4f, 37
4g, 86
4h, 62
4i, 18
n.r.e
86
83
87
82
84
85
86
91
87
n.d.f
we checked the effect of the ratio of 2a/1a. The reaction gave a bet-
ter yield at a ratio of 2/1. Increasing the ratio further did not im-
prove the yield (Table 3, entries 4–6). When the reaction was
carried out at 0 °C, a similar enantioselectivity and lower yield
were obtained after 4 days (Table 3, entry 7). When the loadings
of quinine were decreased to 10 and 5 mol %, longer reaction times
were required. Product 4a was obtained with similar enantioselec-
tivities, but in lower yields (Table 3, entries 8–9).
8
9d
10
Phenyl 1a
The substrate scope of this reaction was examined and the re-
sults are summarized in Table 4. In general, electron-withdrawing
groups on the 3-phenyl group of the chalcone were tolerated very
well (Table 4, entries 2–4). The reaction of 4-methoxyphenyl
substituted enone 1f gave a low yield (Table 4, entry 6). 3-Thienyl
substituted enone 1g provided the corresponding adducts with
good yield and enantioselectivity (Table 4, entry 7). 3-iso-Propyl
a
The reactions were carried out with 1 (0.1 mmol), 2 (0.2 mmol) and quinine
(0.02 mmol) in toluene (1.0 mL) at room temperature.
b
Isolated yields after column chromatography.
Ee values of purified 4a–4i were determined by chiral HPLC.
Quinine (0.04 mmol) was used.
n.r. = no reaction.
c
d
e
f
n.d. = not determined.

464
Z.-P. Hu et al. / Tetrahedron: Asymmetry 23 (2012) 461–467
Table 5
Conjugate addition of malononitrile to enones with various 1,2-substituentsa
H2N
O
R3
O
quinine (20 mol%)
toluene, rt
H2N
NC
O
R3
Ph
NC
CN
NC
R2
R2
Ph
2a
4k-4n
1i-1l
S
4g
Entry
1
R2
R3
Time (h)
Yieldb (%)
Eec (%)
1
1i
1j
1k
1l
Phenyl
Me
COOEt
CN
CH3
48
80
24
4
4k, 78
4l, 18
4m, 12
4n, 97
82
95
5
2d
3
Phenyl
Phenyl
Phenyl
Figure 1. X-ray crystal structure of the product 4g.
4
12
a
The reactions were carried out with 1 (0.1 mmol), 2a (0.2 mmol) and quinine
(0.02 mmol) in toluene (1.0 mL) at room temperature.
O
b
Isolated yields after column chromatography.
Ee values of purified 4k–4n were determined by chiral HPLC.
Quinine (0.04 mmol) was used.
c
NH2
Ph
Ph
d
NC
H
CN
Ph
1a
quinine
O
Ph
4a
CN
Ph
ano chalcone 1l provided the product in excellent yield, but with
low enantioselectivity (Table 5, entry 4).
Ph
The reaction of 2-acetyl chalcone 1m gave the product 4o in
excellent yield, but with low enantioselectivity (Scheme 3, eq. 1).
In this case, enolization occurred at the acetyl group instead of
the benzoyl group. Cyclic enone 1n provided the expected 2-ami-
no-4H-pyran 4p in moderate yield and with good enantioselectiv-
ity (Scheme 3, eq. 2).
The absolute configuration of product 4g was assigned as (S) on
the basis of the X-ray diffraction analysis (Fig. 1).12 Other products
are suggested to have the same absolute configuration by analogy.
A bifunctional catalytic mechanism is proposed for this reaction
(Scheme 4).4e Malononitrile is deprotonated by quinine to provide
an anion. The H-bonding interaction between the hydroxy group of
the quinine and the carbonyl group helps to activate the enone. In
addition, an H-bonding interaction also occurs between the malon-
onitrile anion and the ammonium group. The attack of the malon-
onitrile anion from the si-face of enone gives the chiral enol anion
B. The intramolecular cyclization of intermediate B and subsequent
tautomerization of the imidic ester C provide the product 4a.
N
N
H
NC
H
NH
Ph
O
N
H
NC
H
H
O
O
OCH3
H
Ph
Ph
Ph
Ph
N
Ph
A
NC
C
H
O
Ph
Ph
Ph
B
Scheme 4. Proposed catalytic mechanism.
studies on the biological evaluation of the products are currently
under way in our laboratory.
3. Conclusions
4. Experimental
In conclusion, we have developed an enantioselective cascade
reaction of malononitrile and
a-substituted chalcones. Chiral
4.1. General information
multisubstituted 2-amino-4H-pyrans have been prepared in good
yields and enantioselectivities. Quinine was identified as the best
catalyst for the reaction. The properties of the a-substitutents have
a siginificant effect on the yield and the enantioselectivity. Further
All solvents were used as the commercial anhydrous grade
without further purification. Flash column chromatography was
carried out over silica gel (230–400 mesh). 1H and 13C NMR spectra
O
H2N
NC
O
Me
O
quinine (20 mol%)
toluene, rt
(1)
Ph
Ph
NC
CN
Ph
COMe
1m
Ph
94% yield, 29% ee
4o
2a
O
H2N
O
quinine (20 mol%)
toluene, rt
Ph
(2)
NC
CN
NC
50% yield, 88% ee
Ph
4p
2a
1n
Scheme 3. Cascade reactions of malononitrile with enones 1m–1n.

Z.-P. Hu et al. / Tetrahedron: Asymmetry 23 (2012) 461–467
465
were recorded on a 400 MHz spectrometer. Chemical shifts in 1H
NMR spectra are reported in parts per million (ppm, d) downfield
from the internal standard Me4Si (TMS, d = 0 ppm). Chemical shifts
in 13C NMR spectra are reported relative to the central line of the
chloroform signal (d = 77.0 ppm). Peaks are labeled as singlet (s),
doublet (d), triplet (t), quartet (q), and multiplet (m). High-resolu-
tion mass spectra were obtained with a LCMS-IT-TOF mass spec-
trometer. Infrared (IR) are represented as frequency of absorption
(cmꢀ1). Enantiomeric excesses of compounds were determined
2H), 7.20–7.08 (m, 8H), d 6.83 (d, J = 6.5, Hz, 2H), 4.69 (s, 2H),
4.55 (s, 1H); 13C NMR (100 MHz, CDCl3): d = 159.59, 150.18,
147.20, 145.36, 136.57, 132.53, 129.36, 129.03, 128.93, 128.80,
128.54, 128.00, 127.67, 124.06, 118.90, 115.49, 61.01, 44.93; IR
(KBr): 3469, 3338, 2957, 2925, 2854, 2191, 1672, 1637, 1594,
1519, 1458, 1405, 1345, 1265, 1232, 1132, 860, 768, 698 cmꢀ1
;
MS (ESI): m/z = 396.1 [M+H]+; HRMS (ESI) calcd for C24H17N3NaO3
+
[M + Na]+: 418.1162, found: 418.1186; Enantiomeric excess was
determined by HPLC with a CHIRALCEL OD-H column (i-PrOH/hex-
ane = 30:70, 254 nm, 0.8 mL/min), tR (major) = 15.1 min, tR (min-
or) = 11.3 min, 82% ee.
by HPLC using a Daicel Chiralcel OD-H column. a-Phenyl chalcones
1a–1h and their analogues 1i–1n were prepared according to the
reported procedures.13 Organocatalysts 3e,14 3f,14 3g,15 3h,16 3i,17
3j,18 3k,19 3l,20 and 3m21 were prepared according to the literature.
4.2.5. (S)-2-Amino-5,6-diphenyl-4-p-tolyl-4H-pyran-3-carbonitrile
4e22
4.2. General procedure for the organocatalytic cascade reaction
White solid, ½a 2D0
¼ ꢀ103:9 (c 0.102, CHCl3); mp 205.0–206.5 °C.
ꢁ
of malononitrile and
a-substituted chalcones
1H NMR (400 MHz, CDCl3): d = 7.26–7.04 (m, 12H), 6.86–6.84 (m,
2H), 4.49 (s, 2H), 4.28 (s, 1H), 2.30 (s, 3H); 13C NMR (100 MHz,
CDCl3): d = 159.14, 144.75, 140.16, 137.54, 136.81, 133.21,
129.56, 129.46, 129.03, 128.62, 128.15, 127.87, 127.72, 127.18,
119.53, 116.84, 61.97, 44.50, 21.08; MS (ESI): m/z = 365.2
[M+H]+; Enantiomeric excess was determined by HPLC with a CHI-
RALCEL OD-H column (i-PrOH/hexane = 10:90, 254 nm, 0.8 mL/
min), tR (major) = 11.2 min, tR (minor) = 16.4 min, 84% ee.
A mixture of (E)-1,2,3-triphenylprop-2-en-1-one 1a (28.4 mg,
0.1 mmol), malononitrile 2a (13.2 mg, 0.2 mmol), and quinine 3a
(6.6 mg, 0.02 mmol) in toluene (1.0 mL) was stirred for 48 h at
room temperature. After the solvent was evaporated in vacuo,
the residue was purified by column chromatography over silica
gel (ethyl acetate:petroleum ether = 1:5) to give the product 4a.
4.2.1. (S)-2-Amino-4,5,6-triphenyl-4H-pyran-3-carbonitrile 4a22
4.2.6. (S)-2-Amino-4-(4-methoxyphenyl)-5,6-diphenyl-4H-
White solid, ½a 2D0
ꢁ
¼ ꢀ99:0 (c 0.098, CHCl3); mp 225.2–226.4 °C.
pyran-3-carbonitrile 4f22
1H NMR (400 MHz, DMSO-d6): d = 7.30–7.17 (m, 10H), 7.08–7.07
(m, 3H), 6.90–6.88 (m, 2H), 6.85 (s, 2H), 4.38 (s, 1H); 13C NMR
(100 MHz, DMSO-d6): d = 159.94, 144.31, 144.10, 137.45, 133.16,
129.30, 128.91, 128.56, 128.53, 128.07, 127.86, 127.56, 126.98,
126.79, 120.26, 116.14, 57.23, 44.54; MS (ESI): m/z = 351.1
[M+H]+. Enantiomeric excess was determined by HPLC with a CHI-
RALCEL OD-H column (i-PrOH/hexane = 10:90, 254 nm, 0.8 mL/
min), tR (major) = 11.8 min, tR (minor) = 19.5 min, 86% ee.
White solid, ½a 2D0
¼ ꢀ137:0 (c 0.10, CHCl3); mp 186.0–187.6 °C.
ꢁ
1H NMR (400 MHz, CDCl3): d = 7.21–7.06 (m, 10H), 6.85–6.81 (m,
4H), 4.52 (s, 2H), 4.28 (s, 1H), 3.77 (s, 3H); 13C NMR (100 MHz,
CDCl3): d = 159.07, 158.80, 144.57, 137.54, 135.36, 133.20,
129.58, 129.00, 128.95, 128.61, 128.17, 127.86, 127.20, 119.53,
117.01, 114.16, 62.07, 55.22, 44.19; MS (ESI): m/z = 381.1
[M+H]+; Enantiomeric excess was determined by HPLC with a CHI-
RALCEL OD-H column (i-PrOH/hexane = 10:90, 254 nm, 0.8 mL/
min), tR (major) = 17.4 min, tR (minor) = 28.9 min, 85% ee.
4.2.2. (S)-2-Amino-4-(4-chlorophenyl)-5,6-diphenyl-4H-pyran-
3-carbonitrile 4b22
4.2.7. (S)-2-Amino-5,6-diphenyl-4-(thiophen-2-yl)-4H-pyran-3-
White solid, ½a 2D0
ꢁ
¼ ꢀ105:0 (c 0.10, CHCl3); mp 201.7–202.1 °C.
carbonitrile 4g
1H NMR (400 MHz, CDCl3): d = 7.26–7.07 (m, 12H), 6.84–6.82 (m,
2H), 4.56 (s, 2H), 4.35 (s, 1H); 13C NMR (100 MHz, CDCl3):
d = 159.28, 144.91, 141.59, 137.09, 133.07, 132.91, 129.49,
129.26, 128.97, 128.92, 128.80, 128.34, 127.92, 127.41, 119.22,
116.37, 61.25, 44.47; MS (ESI): m/z = 385.1 [M+H]+; Enantiomeric
excess was determined by HPLC with a CHIRALCEL OD-H column
(i-PrOH/hexane = 10:90, 254 nm, 0.8 mL/min), tR (major) = 16.0 -
min, tR (minor) = 20.1 min, 83% ee.
White solid, ½a 2D0
¼ ꢀ93:3 (c 0.108, CHCl3); mp 196.6–199.7 °C.
ꢁ
1H NMR (400 MHz, CDCl3): d = 7.25–7.10 (m, 9H), 6.95–6.93 (m,
2H), 6.87–6.85 (m, 1H), 6.79 (d, J = 2.8, Hz, 1H), 4.66 (s, 1H), 4.58
(s, 2H); 13C NMR (100 MHz, CDCl3): d = 159.46, 148.02, 144.76,
137.09, 133.02, 129.57, 129.05, 128.77, 128.25, 127.91, 127.42,
126.84, 125.01, 124.93, 119.26, 116.70, 61.79, 40.01; IR (KBr):
3449, 3326, 2193, 1671, 1638, 1596, 1406, 1258, 1228, 1133,
771, 695 cmꢀ1; MS (ESI): m/z = 357.1 [M+H]+; HRMS (ESI) calcd
for C22H16N2NaOS+ [M+Na]+: 379.0876, found: 379.0876; Enantio-
meric excess was determined by HPLC with a CHIRALCEL OD-H col-
4.2.3. (S)-2-Amino-4-(4-bromophenyl)-5,6-diphenyl-4H-pyran-
3-carbonitrile 4c
umn
(i-PrOH/hexane = 10:90,
254 nm,
0.8 mL/min),
tR
White solid, ½a 2D0
¼ ꢀ117:3 (c 0.104, CHCl3); mp 196.9–198.0 °C.
ꢁ
(major) = 14.3 min, tR (minor) = 19.6 min, 86% ee.
1H NMR (400 MHz, CDCl3): d = 7.40 (d, J = 8.4, 2H), 7.22–7.06 (m,
10 H), d 6.83 (dd, J = 7.6, 1.4 Hz, 2H), 4.58 (s, 2H), 4.34 (s, 1H);
13C NMR (100 MHz, CDCl3): d = 159.30, 144.93, 142.11, 137.07,
132.89, 131.86, 129.61, 129.48, 128.96, 128.80, 128.34, 127.92,
127.41, 121.20, 119.23, 116.26, 61.08, 44.53; IR (KBr): 3459,
3336, 2923, 2851, 2183, 1673, 1637, 1592, 1484, 1410, 1265,
1229, 1139, 845, 769, 696 cmꢀ1; MS (ESI): m/z = 429.0 [M+H]+;
HRMS (ESI) calcd for C24H18N2OBr+ [M+H]+: 429.0597, found:
429.0599; Enantiomeric excess was determined by HPLC with a
CHIRALCEL OD-H column (i-PrOH/hexane = 10:90, 254 nm,
0.8 mL/min), tR (major) = 17.1 min, tR (minor) = 19.6 min, 87% ee.
4.2.8. (S)-2-Amino-4-isopropyl-5,6-diphenyl-4H-pyran-3-carbo-
nitrile 4h
White solid, ½a 2D0
¼ þ69:6 (c 0.056, CHCl3); mp 145.0–147.0 °C.
ꢁ
1H NMR (400 MHz, CDCl3): d = 7.22–7.07 (m, 10H), 4.54 (s, 2H),
3.36 (d, J = 2.4 Hz, 1H), 1.81–1.75 (m, 1H), 1.03 (d, J = 6.8 Hz, 3H),
0.86 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d = 162.13,
145.46, 137.92, 133.45, 129.38, 128.72, 128.53, 128.32, 127.80,
127.24, 121.28, 118.27, 55.34, 44.92, 32.30, 20.19, 16.47; IR
(KBr): 3450, 3329, 2960, 2927, 2851, 2188, 1674, 1636, 1596,
1445, 1408, 1257, 1230, 1138, 862, 749, 699 cmꢀ1; MS (ESI): m/
z = 317.1 [M+H]+; HRMS (ESI) calcd for C21H20N2NaO [M+Na]+:
339.1468, found: 339.1466; Enantiomeric excess was determined
by HPLC with a CHIRALCEL OD-H column (i-PrOH/hexane = 10:90,
254 nm, 0.8 mL/min), tR (major) = 9.3 min, tR (minor) = 7.3 min,
91% ee.
4.2.4. (S)-2-Amino-4-(4-nitrophenyl)-5,6-diphenyl-4H-pyran-3-
carbonitrile 4d
White solid, ½a 2D0
¼ ꢀ121:0 (c 0.062, CHCl3); mp 124.4–138.0 °C.
ꢁ
1H NMR (400 MHz, CDCl3): d = 8.13 (d, J = 8.3, 2H), 7.37 (d, J = 8.3,

466
Z.-P. Hu et al. / Tetrahedron: Asymmetry 23 (2012) 461–467
4.2.9. (S)-Ethyl 2-amino-4,5,6-triphenyl-4H-pyran-3-carboxyl-
by HPLC with a CHIRALCEL AD-H column (i-PrOH/hexane = 10:90,
254 nm, 0.8 mL/min), tR (major) = 6.2 min, tR (minor) = 5.6 min,
12% ee.
ate 4i
Colorless oil. ½a D20
ꢁ
¼ þ22:1 (c 0.068, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 7.28–7.16 (m, 10H), 7.09–7.07 (m, 3H), 6.85 (d,
J = 7.4 Hz, 2H), 6.19 (br s, 2H), 4.53 (s, 1H), 4.07 (q, J = 6.8 Hz,
2H), 1.21 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d = 169.12, 160.07, 145.93, 144.27, 138.72, 133.63, 129.54,
128.99, 128.35, 128.29, 128.07, 128.04, 127.79, 126.86, 126.22,
119.69, 80.03, 59.38, 44.09, 14.33; IR (KBr): 3458, 3328, 2960,
2928, 2852, 1674, 1636, 1598, 1495, 1445, 1408, 1257, 1231,
1148, 862, 748, 698 cmꢀ1; MS (ESI): m/z = 398.2 [M+H]+; HRMS
4.2.14. (R)-2-Amino-5-benzoyl-6-methyl-4-phenyl-4H-pyran-3-
carbonitrile 4o25
White solid, ½a 2D0
¼ ꢀ54:0 (c 0.100, CHCl3); mp 143.2–145.9 °C.
ꢁ
1H NMR (400 MHz, CDCl3): d = 7.57 (d, J = 7.5 Hz, 2H), 7.53–7.41
(m, 2H), 7.41–7.29 (m, 2H), 7.29–7.19 (m, 2H), 7.15 (t, J = 7.8 Hz,
2H), 4.62 (s, 2H), 4.59 (s, 1H), 1.79 (s, 3H); 13C NMR (100 MHz,
CDCl3): d = 195.83, 158.44, 148.71, 141.91, 137.74, 133.09,
128.73, 128.70, 128.63, 127.76, 127.45, 115.18, 60.84, 40.71,
18.04; MS (ESI): m/z = 317.1 [M+H]+; Enantiomeric excess was
determined by HPLC with a CHIRALCEL AD-H column (i-PrOH/hex-
ane = 10:90, 254 nm, 0.8 mL/min), tR (major) = 14.2 min, tR (min-
or) = 19.2 min, 29% ee.
(ESI) calcd for C26H24NO3 [M+H]+: 398.1751, found: 398.1757;
+
Enantiomeric excess was determined by HPLC with a CHIRALCEL
OD-H column (i-PrOH/hexane = 4:96, 254 nm, 0.5 mL/min), tR (ma-
jor) = 20.5 min, tR (minor) = 18.7 min, 87% ee.
4.2.10. (S)-2-Amino-6-methyl-4,5-diphenyl-4H-pyran-3-carbo-
nitrile 4k
4.2.15. (S)-2-Amino-4-phenyl-5,6-dihydro-4H-benzo[h] chrom-
White solid, ½a 2D0
ꢁ
¼ ꢀ65:4 (c 0.130, CHCl3); mp 129.0–132.0 °C.
ene-3-carbonitrile 4p6
1H NMR (400 MHz, CDCl3): d = 7.23–7.13 (m, 6H), 7.09–7.07 (m,
2H), 6.90–6.87 (m, 2H), 4.49 (s, 2H), 4.18 (s, 1H), 1.80 (s, 3H); 13C
NMR (100 MHz, CDCl3): d = 159.14, 142.98, 142.91, 137.51,
129.05, 128.37, 128.13, 127.87, 127.11, 126.97, 119.79, 115.05,
60.97, 44.20, 16.58; IR (KBr): 3464, 3348, 2924, 2189, 1699,
1642, 1598, 1562, 1403, 1168, 1067, 861, 795 cmꢀ1; MS (ESI): m/
z = 289.1 [M+H]+; HRMS (ESI) calcd for C19H17N2O+ [M+H]+:
289.1355, found: 289.1345; Enantiomeric excess was determined
by HPLC with a CHIRALCEL OD-H column (i-PrOH/hexane = 10:90,
254 nm, 0.8 mL/min), tR (major) = 9.6 min, tR (minor) = 14.3 min,
82% ee.
Yellow solid, ½a D20
¼ ꢀ44:0 (c 0.092, CHCl3); mp 174.0–177.9 °C.
ꢁ
1H NMR (400 MHz, CDCl3): d = 7.46 (d, J = 6.9 Hz, 1H), 7.40–7.16
(m, 7H), 7.11 (d, J = 7.1 Hz, 1H), 4.55 (s, 2H), 4.08 (s, 1H), 2.86–
2.63 (m, 2H), 2.22–2.14 (m, 1H), 2.10–2.02 (m, 1H); MS (ESI): m/
z = 301.1 [M+H]+; Enantiomeric excess was determined by HPLC
with a CHIRALCEL OD-H column (i-PrOH/hexane = 10:90, 254 nm,
0.8 mL/min), tR (major) = 15.5 min, tR (minor) = 18.7 min, 88% ee.
Acknowledgements
Financial supports from the National Natural Science Founda-
tion of China (Nos. 20972195, 21172270) and the Guangdong Engi-
neering Research Center of Chiral Drugs are gratefully
acknowledged.
4.2.11. (S)-2-Amino-5-methyl-4,6-diphenyl-4H-pyran-3-carbo-
nitrile 4l
Colorless oil. ½a D20
ꢁ
¼ þ11:6 (c 0.086, CHCl3); 1H NMR (400 MHz,
CDCl3): d = 7.41–7.27 (m, 10H), 4.41 (s, 2H), 3.99 (s, 1H), 1.58 (s,
3H); 13C NMR (100 MHz, CDCl3): d = 159.38, 143.28, 142.77,
133.08, 128.80, 128.72, 128.13, 127.79, 127.31, 120.24, 110.33,
59.79, 44.38, 16.84; IR (KBr): 3462, 3344, 2928, 2196, 1698,
1646, 1596, 1459, 1405, 1168, 1068, 859, 796 cmꢀ1; MS (ESI): m/
z = 289.1 [M+H]+; HRMS (ESI) calcd for C19H16N3NaO+ [M+Na]+:
311.1155, found: 311.1147; Enantiomeric excess was determined
by HPLC with a CHIRALCEL OD-H column (i-PrOH/hexane = 10:90,
254 nm, 0.8 mL/min), tR (major) = 11.4 min, tR (minor) = 16.8 min,
95% ee.
References
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4.2.12. (R)-Ethyl 6-amino-5-cyano-2,4-diphenyl-4H-pyran-3-
carboxylate 4m23
White solid, ½a 2D0
¼ ꢀ7:5 (c 0.106, CHCl3); mp 169.3–172.5 °C.
ꢁ
1H NMR (400 MHz, CDCl3): d = 7.46–7.37 (m, 5H), 7.35–7.30 (m,
4H), 7.26–7.23 (m, 1H), 4.60 (s, 1H), 4.53 (s, 2H), 3.82 (q,
J = 7.1 Hz, 2H), 0.80 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3):
d = 165.81, 158.07, 154.41, 142.94, 133.17, 130.01, 128.73,
128.50, 128.07, 127.68, 127.45, 118.71, 109.79, 62.06, 60.72,
39.85, 13.36; MS (ESI): m/z = 347.1 [M+H]+; Enantiomeric excess
was determined by HPLC with a CHIRALCEL AD-H column (i-
PrOH/hexane = 10:90, 254 nm, 0.8 mL/min), tR (major) = 12.4 min,
tR (minor) = 19.9 min, 5% ee.
4.2.13. (S)-2-Amino-4,6-diphenyl-4H-pyran-3,5-dicarbonitrile
4n24
White solid, ½a 2D0
ꢁ
¼ þ1:8 (c 0.112, CHCl3); mp 60.0–63.3 °C. 1H
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