Enantioselective one-pot synthesis of 2-amino-4-(indol-3-yl)-4 H-chromenes

Article abstract of DOI:10.1021/ol2019949

An enantioselective one-pot synthesis of 2-amino-4-(indol-3-yl)-4H- chromenes via a Knoevenagel/Pinner/Friedel-Crafts reaction of salicylaldehyde, malononitrile, and indole is presented. Moderate to good yields (up to 89%) and high enantioselectivities (up to 90% ee) were obtained with an N,N′-dioxide-Zn(II) complex as the catalyst. This strategy provides an efficient and convenient method to access enantiomerically enriched 2-amino-4H-chromene derivatives.

Full text of DOI:10.1021/ol2019949

Enantioselective One-Pot Synthesis of
2-Amino-4-(indol-3-yl)-4H-Chromenes
Weiliang Chen, Yunfei Cai, Xuan Fu, Xiaohua Liu, Lili Lin, Xiaoming Feng*
Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of
Chemistry, Sichuan University, Chengdu 610064, China
Contents:
1. General remarks…………………………………………………….……….….S1
2. Extra information of the optimization of the reaction conditions………………S2
3. X-ray structure of 4a……………………………………………………………S2
4. Typical procedure for catalytic asymmetric Knoevenagel/Pinner/ Friedel–Crafts
Alkylation…………………………………………………………….…………S2
5. Characterization of the products…………………………………..…….………S3
6. References……………………………………………………………………....S11
7. Copy of 1H NMR and 13C NMR spectra for products……..………………. .…S12
1. General remarks
1H NMR spectra were recorded on commercial instruments (400 or 600 MHz). Chemical shifts were
reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3, δ =
7.26; DMSO, δ = 2.49). Spectra were reported as follows: chemical shift (δ ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration and
assignment. 13C NMR spectra were collected on commercial instruments (100 MHz) with complete
proton decoupling. Chemical shifts are reported in ppm from the tetramethylsilane with the solvent
resonance as internal standard (CDCl3, δ = 77.0; DMSO, δ = 39.6). Melting points (m.p.) were
measured on electrothermal digital melting point apparatus and were uncorrected. Enantiomeric
excesses (ee) were determined by HPLC analysis using the corresponding commercial chiral column as
o
stated in the experimental procedures at 23 C. Optical rotations were reported as follows: [α]T (c
D
g/100 mL, in ethyl acetate). HRMS was recorded on a commercial apparatus (ESI Source). All
catalytic reactions were run in dried glassware using standard techniques. CH2Cl2 was distilled over
CaH2. All salicyaldehydes, indoles and malononitrile were commercially available and used as
purchased without further purification.
1

2. Extra information of the optimization of the reaction conditions
Table 1. Details of the couter ion screening. a
entry
1
ligand
L1
metal
L/metal
2:1
yield (%)b
ee (%)c
0
ZnCl2
96
70
62
84
69
78
76
73
2
ZnSO4·7H2O
Zn(ClO4)2·6H2O
Zn(OTf)2
2:1
16
L1
3
2:1
60
L1
4
2:1
62
47
L1
5
Zn(BF4)2·6H2O
Zn(OTf)2
2:1
L1
6d
7 d
8e
2:1
82
84
L1
Zn(ClO4)2·6H2O
Zn(ClO4)2·6H2O
2:1
L1
2:1
6
L1
a Unless otherwise noted, reactions were carried out with 10 mol % of catalyst in CH2Cl2 (0.5 mL) at 35 °C for 26 h. b Isolated
yield. c Determined by HPLC using chiral IB column. d 20 mol % of NaBArF was added. e 20 mol % of sodium tetraphenylborate
was added.
The effect of the counter ion of the central metal was investigated. It is interesting that the addition
of NaBArF to the reaction increased the ee value, whereas the addition NaBPh4 dramatically decreased
the ee of the reaction (84% ee vs. 6% ee, entry 7 vs. entry 8). It indicated both the Lewis basicity and
the coordination capability of the counter ion have significant effect on the enantioselectivity of the
reaction.
Under the optimized condition, other electron-rich substrates were also employed as Michael donor.
When pyrrole was used instead of indole, the corresponding product was obtained in 5% ee with 92%
yield. Other substrates, such as 3,4-dimethoxyphenol, 3-benzylindolin-2-one, diethyl phosphonate,
were also tested, but only trace amounts of corresponding products were obtained.
3. X-ray structure of 4a
Single crystal of 4a [C18H13N3O] was obtained from the mixed solvents of petroleum ether and ethyl
acetate. The absolute configuration is S. CCDC833191 contains the supplementary crystallographic
data which can be obtained free of charge from The Cambrige Crystallographic Data Centere via
www.ccdc.cam.ac.uk/data_request/cif.
Crystal data. C18H13N3O, M = 287.31, orthorhombic, a = 9.896(2), b = 11.390(2), c = 12.460(3) Å,
U = 1404.5(5) Å3, T = 173.0 K, space group P212121, Z = 4.
4. Typical procedure for catalytic asymmetric Knoevenagel/Pinner/
Friedel–Crafts Alkylation
2

.
N,N'-dioxide L1 (12.4 mg, 0.02 mmol), Zn(ClO4)2 6H2O (3.7 mg, 0.01 mmol), NaBArF (18.0 mg, 0.02
mmol) and malononitrile 2 (6.6 mg, 0.1 mmol) were stirred in CH2Cl2 (0.5 mL) at 35 oC for 0.5 h, then
3a (10.2 μL, 0.1 mmol) was added. After 20 minutes, indole 1a (12.8, 0.11 mmol) and 3 Å MS (20 mg)
was added. The mixture was stirred at 35 °C for the time indicated. The reaction mixture was purified
by flash chromatography (petroleum ether: ethyl acetate = 2:1) on silica gel to afford the desired
product. [1]
5. Characterization of the products
2-amino-4-(1H-indol-3-yl)-4H-chromene-3-carbonitrile 4a: Yellow solid in
H2N
87% yield (petroleum ether : EtOAc = 2 : 1); [α]26D = +35.7 (c 0.2, EtOAc); the ee
O
NC
was determined by HPLC analysis using a chiral IB column (iPrOH/hexane =
20/80, 1.0 mL/min, 254 nm), tr (major) = 10.92 min, tr (minor) = 21.41 min, 87%
N
H
1
ee; H NMR (400 MHz, CDCl3) δ = 10.93 (1H, s), 7.34 (1H, d, J = 8.1 Hz), 7.30
(1H, d, J = 1.6 Hz), 7.25 – 7.17 (2H, m), 7.09 – 6.97 (4H, m), 6.87 (1H, t, J = 7.5 Hz), 6.82 (2H, s),
4.99 (1H, s) ppm; 13C NMR (100 MHz, DMSO) δ = 160.54, 148.90, 137.39, 129.75, 128.30, 125.69,
124.81, 124.19, 123.51, 121.49, 121.30, 119.20, 118.97, 118.91, 116.22, 112.20, 56.79, 32.93 ppm;
EI-HRMS: Calcd for C18H14N3O [M+H]+ 288.1137, Found 288.1131.
4r: 88% yield and 86% ee; [α]26D = -35.9 (c 0.4, EtOAc).
0
0
0
0
0
. 4
. 3
. 2
. 1
. 0
0
0
0
0
0
2
. 0
0
4
. 0
0
6
. 0
0
8
. 0
0
1
0
. 0
0
1
2
. 0
0
1
4
. 0
0
1
6
. 0
0
1
8
. 0
0
2 0 . 0 0
M
in u te s
0
0
0
.4
.2
.0
0
0
0
2
. 0 0
4 . 0
0
6
. 0 0
8 . 0
0
1
0 . 0
0
1 2 . 0 0
1
4 . 0
0
1 6 . 0 0
1
8 . 0
0
2 0 .0
0
2
2 . 0
0
2 4 .0
0
2 6 . 0 0
M
in u te s
2-amino-4-(5-fluoro-1H-indol-3-yl)-4H-chromene-3-carbonitrile
4b:
H2N
Yellow solid; M.P.: 44-46 oC; 81% yield (petroleum ether : EtOAc = 2 : 1);
[α]26D = +22.8 (c 0.5, EtOAc); the ee was determined by HPLC analysis using a
chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) =
O
NC
F
N
H
1
10.92 min, tr (minor) = 15.78 min, 83% ee; H NMR (600 MHz, DMSO) δ =
11.06 (1H, d, J = 1.6 Hz,), 7.38 (1H, d, J = 2.5 Hz,), 7.34 (1H, dd, J = 8.7, 4.6 Hz), 7.23 – 7.19 (1H, m),
7.08 (2H, t, J = 8.3 Hz), 7.01 (1H, t, J = 7.5 Hz), 6.92 – 6.88 (2H, m), 6.87 (2H, s), 4.99 (1H, s) ppm;
13C NMR (150 MHz, DMSO) δ = 160.60, 157.68, 156.15, 148.85, 133.98, 129.71, 128.43, 125.79,
125.73, 125.63, 124.93, 123.91, 121.19, 119.51, 119.48, 116.26, 113.25, 113.18, 109.72, 109.55,
103.46, 103.31, 56.40, 32.68 ppm; EI-HRMS: Calcd for C18H13FN3O [M+H]+ 306.1043, Found
306.1043.
3

0.40
0.20
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
Minutes
0.60
0.40
0.20
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
17.00
Minutes
2-amino-4-(5-chloro-1H-indol-3-yl)-4H-chromene-3-carbonitrile 4c:
H2N
Yellow solid in 85% yield (petroleum ether : EtOAc = 2 : 1); [α]26D = +11.9 (c
0.4, EtOAc); the ee was determined by HPLC analysis using a chiral IB
column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) = 10.78 min,
tr (minor) = 17.74 min, 88% ee; 1H NMR (400 MHz, DMSO) δ = 11.17 (1H, s),
O
NC
Cl
N
H
7.40 (1H, d, J = 2.2 Hz), 7.37 (1H, d, J = 8.6 Hz), 7.26 – 7.17 (2H, m), 7.11 – 6.97 (4H, m), 6.89 (2H,
s), 5.01 (1H, s) ppm; 13C NMR (100 MHz, DMSO) δ = 160.55, 148.84, 135.81, 129.72, 128.50, 126.73,
125.49, 124.96, 123.83, 123.58, 121.47, 121.14, 119.10, 117.99, 116.29, 113.80, 56.41, 32.62 ppm;
EI-HRMS: Calcd for C18H13ClN3O [M+H]+ 322.0747, Found 322.0741.
4s: 86% yield and 88% ee; [α]26D = -11.2 (c 0.5, EtOAc).
0
0
0
0
0
. 4
. 3
. 2
. 1
. 0
0
0
0
0
0
2
. 0
0
4
. 0
0
6
.
0
0
8
. 0
0
1
0
. 0
M
0
1
2
.
0
0
1
4
. 0
0
1
6
. 0
0
1
8
. 0
0
2 0 . 0 0
in
u t e s
0
0
0
0
0
.8
.6
.4
.2
.0
0
0
0
0
0
2
.0
0
4 . 0 0
6
.0
0
8
.0
0
1 0 .0
0
1
2 . 0 0
1 4 .0
0
1 6 .0
0
1
8 . 0 0
2 0 .0
0
2 2 . 0 0
M
in u t e s
2-amino-4-(5-bromo-1H-indol-3-yl)-4H-chromene-3-carbonitrile 4d:
H2N
Yellow solid in 75% yield (petroleum ether : EtOAc = 2 : 1); [α]26 = +8.7 (c
O
NC
D
Br
0.5, EtOAc); the ee was determined by HPLC analysis using a chiral IB
column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) = 10.90 min,
tr (minor) = 20.54 min, 90% ee; 1H NMR (400 MHz, CDCl3) δ = 8.30 (1H, s),
N
H
7.40 (1H, s), 7.25 – 7.15 (3H, m), 7.14 – 7.11 (1H, m), 7.06 – 6.96 (3H, m), 5.02 (1H, s), 4.68 (2H, s)
ppm; 13C NMR (100 MHz, DMSO) δ = 160.66, 148.95, 136.14, 129.83, 128.61, 127.59, 125.44,
125.07, 124.11, 123.93, 121.25, 121.17, 119.16, 116.40, 114.39, 111.76, 56.52, 32.73 ppm; EI-HRMS:
Calcd for C18H13BrN3O [M+H]+ 366.0242, Found 366.0240.
4t: 79% yield and 89% ee; [α]26D = -8.1 (c 0.5, EtOAc).
4

0.20
0.10
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
20.00
22.00
Minutes
0 .5 0
0 .4 0
0 .3 0
0 .2 0
0 .1 0
0 .0 0
2 .0 0
4 .0 0
6 .0 0
8 .0 0
1 0 .0 0
1 2 .0 0
1 4 .0 0
1 6 .0 0
1 8 .0 0
2 0 . 00
2 2 .0 0
M in u te s
2-amino-4-(6-chloro-1H-indol-3-yl)-4H-chromene-3-carbonitrile 4e:
Yellow solid; m.p. 76-78 oC ; 82% yield (petroleum ether : EtOAc = 2 : 1);
[α]26D = +22.2 (c 0.4, EtOAc); the ee was determined by HPLC analysis using
a chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) =
10.68 min, tr (minor) = 14.25 min, 85% ee; 1H NMR (400 MHz, DMSO): δ =
H2N
O
NC
Cl
N
H
11.09 (1H, s), 7.39 (1H, d, J = 1.4 Hz), 7.35 (1H, d, J = 2.2 Hz), 7.20 (2H, dd, J = 10.6, 4.8 Hz), 7.05
(2H, d, J = 7.9 Hz), 7.00 (1H, t, J = 7.4 Hz), 6.91 (1H, dd, J = 8.5, 1.7 Hz), 6.86 (2H, s), 5.00 (1H, s)
ppm. 13C NMR (100 MHz, DMSO) δ = 160.56, 148.87, 137.76, 129.66, 128.43, 126.37, 124.88, 124.79,
124.50, 123.91, 121.11, 120.13, 119.42, 119.33, 116.29, 111.82, 56.59, 32.70 ppm; EI-HRMS: Calcd
for C18H13ClN3O [M+H]+ 322.0747, Found 322.0741.
0.10
0.00
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
分钟
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
1.00
0.80
0.60
0.40
0.20
0.00
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
分钟
9.00
10.00
11.00
12.00
13.00
14.00
15.00
16.00
2-amino-4-(5-methyl-1H-indol-3-yl)-4H-chromene-3-carbonitrile 4f:
Yellow solid; M.P.: 74–76 oC; 83% yield (petroleum ether : EtOAc = 2 : 1);
[α]26D = +25.1 (c 0.4, EtOAc); the ee was determined by HPLC analysis using
a chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) =
H2N
O
NC
Me
N
H
1
10.24 min, tr (minor) = 18.74 min, 83% ee; H NMR (400 MHz, DMSO) δ =
10.78 (1H, s), 7.21 (3H, m), 7.08 – 7.01 (3H, m), 6.98 (1H, t, J = 7.4 Hz), 6.85 (1H, d, J = 8.3 Hz), 6.80
(2H, s), 4.95 (1H, s), 2.25 (3H, s) ppm; 13C NMR (100 MHz, DMSO) δ = 160.53, 148.87, 135.72,
129.70, 128.26, 127.17, 125.95, 124.79, 124.31, 123.64, 123.08, 121.30, 118.67, 118.54, 116.19,
111.88, 56.78, 32.84, 21.92 ppm; EI-HRMS: Calcd for C19H16N3O [M+H]+ 302.1293, Found 302.1299.
0 .3 0
0 .2 0
0 .1 0
0 .0 0
2 .0 0
4 .0 0
6 .0 0
8 .0 0
1 0 .0 0
M in u te s
1 2 .0 0
1 4 .0 0
1 6 .0 0
1 8 .0 0
2 0 .0 0
5

0 .6 0
0 .4 0
0 .2 0
0 .0 0
2 .0 0
4 .0 0
6
.0 0
8 .0 0
1 0 .0 0
M in u te s
1 2 .0 0
1 4 .0 0
1 6 .0 0
1 8 .0 0
2 0 .0 0
2-amino-4-(5-methoxy-1H-indol-3-yl)-4H-chromene-3-carbonitrile 4g:
H2N
Yellow solid in 89% yield (petroleum ether : EtOAc = 2 : 1); [α]26 = +11.0
O
NC
D
MeO
(c 0.5, EtOAc); the ee was determined by HPLC analysis using a chiral IB
column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) = 14.03 min,
tr (minor) = 34.99 min, 80% ee; 1H NMR (400 MHz, DMSO) δ = 10.75 (1H,
N
H
s), 7.21 (3H, dd, J = 18.5, 8.4 Hz), 7.10 (1H, d, J = 7.4 Hz), 7.05 (1H, d, J = 8.1 Hz), 7.00 (1H, t, J =
7.4 Hz), 6.82 (2H, s), 6.75 (1H, s), 6.70 (1H, dd, J = 8.8, 1.9 Hz), 4.96 (1H, s), 3.64 (3H, s) ; 13C NMR
(100 MHz, DMSO) δ = 160.68, 153.24, 148.97, 132.51, 129.75, 128.27, 126.09, 124.85, 124.27,
124.04, 121.35, 119.08, 116.14, 112.71, 110.98, 101.36, 55.70, 55.62, 32.86 ppm; EI-HRMS: Calcd for
C19H16N3O2 [M+H]+ 318.1243, Found 318.1236.
0 .1 0
0 .0 5
0 .0 0
0 .0 0
2 .0 0
4 .0 0
6 .0 0
8 .0 0
1 0 .0 0
1 2 .0 0
1 4 .0 0
1 6 .00
1 8 .0 0
2 0 .0 0
2 2 .0 0
2 4 .0 0
2 6 .0 0
2 8 .0 0
3 0 .0 0
3 2 .0 0
3 4 .0 0
3 6 .0 0
3 8 .0 0
M in u te s
0.40
0.20
0.00
0.00
2.00
4.00
6.00
8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00
Minutes
2-amino-4-(6-methoxy-1H-indol-3-yl)-4H-chromene-3-carbonitrile 4h:
H2N
Yellow solid; M.P.: 210–212 oC;78% yield (petroleum ether : EtOAc = 2 : 1);
O
NC
[α]26 = +23.2 (c 0.5, EtOAc); the ee was determined by HPLC analysis
D
using a chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr
MeO
N
H
1
(major) = 15.67 min, tr (minor) = 34.29 min, 80% ee; H NMR (400 MHz,
DMSO) δ = 10.70 (1H, s), 7.18 (1H, t, J = 7.6 Hz), 7.14 (1H, s), 7.09 – 7.01 (3H, m), 6.99 (1H, d, J =
7.4 Hz), 6.83 (1H, s), 6.79 (2H, s), 6.53 (1H, d, J = 8.7 Hz), 4.91 (1H, s), 3.70 (3H, s) ppm; 13C NMR
(100 MHz, DMSO): δ = 160.51, 155.95, 148.87, 138.13, 129.72, 128.27, 124.78, 124.23, 122.09,
121.28, 120.05, 119.42, 119.15, 116.20, 109.18, 95.31, 56.80, 55.63, 32.94 ppm; EI-HRMS: Calcd for
C19H16N3O2 [M+H]+ 318.1243, Found 318.1238.
0.20
0.15
0.10
0.05
0.00
0 .00
2 .00
4 .00
6 .00
8 .00
1 0.0 0
1 2.0 0
1 4.0 0
16 .0 0
18 .0 0
20 .0 0
22 .0 0
24 .0 0
26 .0 0
28 .0 0
30 .00
32 .00
34 .00
36 .00
38 .00
Minu te s
0.20
0.00
0.00
2.00
4.00
6.00
8.00
10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00 32.00 34.00 36.00 38.00
Minutes
6

2-amino-4-(4-methoxy-1H-indol-3-yl)-4H-chromene-3-carbonitrile 4i:
H2N
Yellow solid; M.P.: 102–104 oC; 81% yield (petroleum ether : EtOAc = 2 : 1);
O
NC
OMe
[α]26 = +100.9 (c 0.2, EtOAc); the ee was determined by HPLC analysis using a
D
chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) = 10.69
min, tr (minor) = 20.04 min, 80% ee; 1H NMR (600 MHz, DMSO) δ = 10.93 (1H,
N
H
s), 7.16 – 7.09 (2H, m), 7.03 (1H, s,), 7.00 – 6.91 (4H, m), 6.70 (2H, s), 6.41 (1H, d, J = 7.4 Hz), 5.18
(1H, s), 3.75 (3H, s) ppm; 13C NMR (150 MHz, DMSO) δ = 160.62, 154.12, 148.71, 138.75, 129.62,
127.72, 125.68, 124.43, 122.72, 122.43, 121.79, 120.31, 116.03, 115.98, 105.39, 99.61, 57.36, 55.21,
33.07 ppm; EI-HRMS: Calcd for C19H16N3O2 [M+H]+ 318.1243, Found 318.1242.
0 .3 0
0 .2 0
0 .1 0
0 .0 0
2 .0 0
4 .0 0
6 .0 0
8 .0 0
1 0 .0 0
1 2 .0 0
1 4 .0 0
1 6 .0 0
1 8 .0 0
2 0 .0 0
2 2 .0 0
2 4 .0 0
Min u te s
0.60
0.40
0.20
0.00
2.00
4.00
6.00
8.00
10.00
12 .00
14.00
16.00
18.00
20.00
22.00
Minutes
2-amino-4-(1H-indol-3-yl)-6-methoxy-4H-chromene-3-carbonitrile
4j:
H2N
Yellow solid; M.P.: 70–72 oC; 85% yield (petroleum ether : EtOAc = 2 : 1);
O
NC
[α]26 = -28.9 (c 0.2, EtOAc); the ee was determined by HPLC analysis using a
D
chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) =
N
H
OMe
1
13.20 min, tr (minor) = 24.37 min, 90% ee; H NMR (400 MHz, DMSO) δ =
10.93 (1H, s), 7.35 (1H, d, J = 8.1 Hz), 7.30 (1H, d, J = 2.0 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.03 (2H, m),
6.89 (1H, t, J = 7.5 Hz), 6.81 – 6.74 (3H, m), 6.61 (1H, d, J = 2.8 Hz), 4.96 (1H, s), 3.59 (3H, s) ppm;
13C NMR (100 MHz, DMSO): δ = 160.81, 156.02, 142.97, 137.37, 125.64, 125.19, 123.45, 121.49,
121.43, 119.09, 118.96, 118.91, 117.11, 114.09, 113.75, 112.20, 56.27, 55.75, 33.36 ppm; EI-HRMS:
Calcd for C19H16N3O2 [M+H]+ 318.1243, Found 318.1234.
4u: 82 % yield and 89% ee; [α]26D =+27.8 (c 0.5, EtOAc).
0.20
0.10
0.00
0.00
2.00
4.00
6.00
8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00
分钟
0.40
0.20
0.00
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
分钟
16.00
18.00
20.00
22.00
24.00
26.00
2-amino-4-(1H-indol-3-yl)-6-methyl-4H-chromene-3-carbonitrile 4k: Yellow
solid; M.P.: 72–74 oC; 81% yield (petroleum ether : EtOAc = 2 : 1); [α]26D = -21.0
(c 0.4, EtOAc); the ee was determined by HPLC analysis using a chiral IB column
H2N
O
NC
N
Me
H
7

(iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) = 10.20 min, tr (minor) = 19.49 min, 90% ee;
1H NMR (400 MHz, CDCl3) δ = 8.11 (1H, s), 7.32 (2H, m), 7.16 – 7.09 (2H, m), 7.03 – 6.93 (2H, m),
6.91 (1H, d, J = 8.3 Hz), 6.86 (1H, s), 4.99 (1H, s), 4.55 (2H, s), 2.14 (3H, s) ppm; 13C NMR (100 MHz,
CDCl3) δ = 159.32, 146.62, 136.95, 134.51, 129.70, 128.72, 125.68, 122.43, 122.37, 122.14, 120.49,
119.61, 119.27, 119.22, 115.83, 111.42, 60.72, 32.74, 20.72 ppm; EI-HRMS: Calcd for C19H16N3O
[M+H]+ 302.1293, Found 302.1283.
0.40
0.20
0.00
0.00
2.00
4.00
6.00
8.00
10.00
12.00
分钟
14.00
16.00
18.00
20.00
22.00
0.80
0.60
0.40
0.20
0.00
0.00
2.00
4.00
6.00
8.00
10.00
12.00
分钟
14.00
16.00
18.00
20.00
22.00
2-amino-4-(1H-indol-3-yl)-8-methyl-4H-chromene-3-carbonitrile
4l:
H2N
Yellow solid; M.P.: 58-62 oC; 78% yield (petroleum ether : EtOAc = 2 : 1);
O
NC
Me
[α]26 = +65.9 (0.4, EtOAc); the ee was determined by HPLC analysis using a
D
chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) =
9.92 min, tr (minor) = 17.85 min, 84% ee; 1H NMR (400 MHz, CDCl3) δ = 8.08
N
H
(1H, s), 7.33 (2H, t, J = 8.5 Hz), 7.16 – 7.08 (2H, m), 7.00 (2H, t, J = 7.4 Hz), 6.92 (1H, d, J = 7.1 Hz),
6.86 (1H, t, J = 7.5 Hz), 5.05 (1H, s), 4.60 (2H, s), 2.33 (3H, s) ppm; 13C NMR (100 MHz, CDCl3) δ =
159.23, 147.02, 136.91, 129.43, 127.04, 125.70, 125.23, 124.38, 122.57, 122.46, 122.15, 120.39,
119.63, 119.41, 119.20, 111.41, 60.88, 32.79, 15.88 ppm; EI-HRMS: Calcd for C19H16N3O [M+H]+
302.1293, Found 302.1303.
0
0
0
0
0
0
0
. 3
. 2
. 2
. 1
. 1
. 0
. 0
0
5
0
5
0
5
0
2
. 0
0
4
. 0
0
6
. 0
0
8
. 0
0
1
0
. 0
0
1
2
. 0
0
1
4
. 0
0
1
6
. 0
0
1
8
. 0
0
2
0
. 0
0
2 2 . 0 0
M
in u t e s
0
0
0
0
0
0
0
. 6
. 5
. 4
. 3
. 2
. 1
. 0
0
0
0
0
0
0
0
2
. 0
0
4
. 0
0
6
. 0
0
8
. 0
0
1
0
. 0
0
1
2
. 0
0
1
4
. 0
0
1
6
. 0
0
1
8
. 0
0
2
0
. 0
0
2 2 . 0 0
M
in u t e s
2-amino-4-(1H-indol-3-yl)-7-methoxy-4H-chromene-3-carbonitrile 4m:
H2N
Viscous oil; 37% yield (petroleum ether : EtOAc = 2 : 1); [α]26 = +13.9 (c
O
NC
D
0.2, EtOAc); the ee was determined by HPLC analysis using a chiral IC
column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) = 11.44
min, tr (minor) = 16.39 min, 81% ee; 1H NMR (400 MHz, DMSO) δ = 10.90
OMe
N
H
(1H, s), 7.34 (1H, d, J = 8.1 Hz), 7.29 (1H, s), 7.21 (1H, d, J = 7.5 Hz), 7.03 (1H, t, J = 7.6 Hz), 6.95
(1H, d, J = 8.4 Hz,), 6.85 (1H, d, J = 7.2 Hz,), 6.78 (2H, s), 6.62 – 6.55 (2H, m), 4.91 (1H, s), 3.71 (3H,
s) ppm; 13C NMR (100 MHz, DMSO) δ = 160.36, 159.12, 149.43, 137.41, 130.41, 125.67, 123.42,
8

121.44, 121.32, 119.31, 118.95, 118.89, 116.04, 112.16, 111.43, 101.07, 57.09, 55.78, 32.40 ppm;
EI-HRMS: Calcd for C19H16N3O2 [M+H]+ 318.1243, Found 318.1231.
0.08
0.06
0.04
0.02
0.00
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7.00
8.00
9.00
分钟
10.00 11.00 12.00 13.00 14.00 15.00 16.00 17.00 18.00
0.20
0.00
0.00
2.00
4.00
6.00
8.00
10.00
分钟
12.00
14.00
16.00
18.00
2-amino-6,8-di-tert-butyl-4-(1H-indol-3-yl)-4H-chromene-3-carbonitrile
H2N
4n: Yellow solid; M.P.: 52-54 oC; 41% yield (petroleum ether : EtOAc = 2 : 1);
[α]26D = +1.3 (c 0.2, EtOAc); the ee was determined by HPLC analysis using a
chiral IC column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) =
O
NC
tBu
N
H
tBu
1
5.63 min, tr (minor) = 9.06 min, 90% ee; H NMR (400 MHz, DMSO) δ =
10.87 (1H, s), 7.38 (1H, d, J = 7.9 Hz), 7.34 (1H, d, J = 8.1 Hz), 7.21 (1H, d, J = 2.1 Hz), 7.12 (1H, d, J
= 1.9 Hz), 7.07 – 7.01 (2H, m), 6.88 (1H, t, J = 7.5 Hz), 6.83 (2H, s), 4.91 (1H, s), 1.43 (9H, s), 1.14
(9H, s) ppm; 13C NMR (100 MHz, DMSO) δ = 160.87, 145.93, 145.88, 137.37, 136.37, 125.67, 124.43,
124.06, 122.93, 121.95, 121.52, 121.44, 120.01, 119.11, 118.87, 112.16, 56.56, 35.06, 34.54, 33.84,
31.61, 30.56 ppm; EI-HRMS: Calcd for C26H30N3O [M+H]+ 400.2389, Found 400.2385.
0.60
0.40
0.20
0.00
1.00
2.00
3.00
4.00
5.00
6.00
7 .00
8.00
9.00
10 .00
11.00
Minutes
0 .8 0
0 .6 0
0 .4 0
0 .2 0
0 .0 0
1 .0 0
2 . 0 0
3 .0 0
4 .0 0
5 .0 0
6 .0 0
7 .0 0
8 .0 0
9
.0 0
1 0 .0 0
M in u te s
2-amino-4-(6-chloro-1H-indol-3-yl)-6-methoxy-4H-chromene-3-
H2N
carbonitrile 4o: Yellow solid; M.P.: 144–146 oC; 68% yield (petroleum
ether : EtOAc = 2 : 1); [α]26D = -44.3 (c 0.4, EtOAc); the ee was determined
by HPLC analysis using a chiral IC column (iPrOH/hexane = 20/80, 1.0
mL/min, 254 nm), tr (major) = 11.88 min, tr (minor) = 15.69 min, 88% ee; 1H
O
NC
Cl
N
H
OMe
NMR (400 MHz, CDCl3) δ = 8.13 (1H, s), 7.31 (1H, s), 7.21 (1H, d, J = 8.5 Hz), 7.14 (1H, s), 6.99 –
6.94 (2H, m), 6.73 (1H, dd, J = 8.9, 2.7 Hz,), 6.53 (1H, d, J = 2.5 Hz,), 4.99 (1H, s), 4.57 (2H, s), 3.62
(3H, s) ppm.; 13C NMR (100 MHz, DMSO) δ = 160.85, 156.10, 142.95, 137.76, 126.39, 124.89,
124.74, 124.47, 121.27, 120.14, 119.34, 117.20, 114.01, 113.93, 111.84, 56.12, 55.78, 33.15 ppm;
EI-HRMS: Calcd for C19H15ClN3O2 [M+H]+ 352.0853, Found 352.0847.
9

0.20
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
Minut es
0.40
0.20
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
Minutes
H2N
O
2-amino-4-(5-bromo-1H-indol-3-yl)-6-methyl-4H-chromene-3-carbonitril
NC
e 4p: Yellow solid; M.P.: 76–78 oC; 68% yield (petroleum ether : EtOAc = 2 :
Br
1); [α]26 = -40.9 (c 0.5, EtOAc ); the ee was determined by HPLC analysis
D
N
H
Me
using a chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr
1
(major) = 10.25 min, tr (minor) = 18.26 min, 89% ee; H NMR (400 MHz, CDCl3) δ = 8.24 (1H, s),
7.40 (1H, s), 7.22 – 7.16 (2H, m), 7.15 – 7.12 (1H, m), 6.98 (1H, d, J = 8.4 Hz), 6.92 (1H, d, J = 8.3
Hz), 6.80 (1H, s), 4.95 (1H, s), 4.62 (2H, s), 2.15 (3H, s) ppm; 13C NMR (100 MHz, CDCl3) δ = 159.40,
146.49, 135.59, 134.66, 129.49, 128.98, 127.30, 125.08, 123.81, 121.83, 121.71, 120.47, 118.70,
116.00, 112.93, 112.91, 60.16, 32.55, 20.73 ppm; EI-HRMS: Calcd for C19H15BrN3O [M+H]+ 380.0398,
Found 380.0397.
0.40
0.20
0.00
2.00
4.00
6.00
8.00
10.00
Minutes
12.00
14.00
16.00
18.00
20.00
0.40
0.20
0.00
2.00
4.00
6.00
8.00
10.00
Minutes
12.00
14.00
16. 00
18.00
20.00
2-amino-4-(1H-indol-3-yl)-4H-benzo[g]chromene-3-carbonitrile
4q:
H2N
Yellow solid; M.P.: 267–269 oC; 70% yield (petroleum ether : EtOAc = 2 : 1);
O
NC
[α]26 = -2.4 (c 0.3, EtOAc); the ee was determined by HPLC analysis using a
D
chiral IB column (iPrOH/hexane = 20/80, 1.0 mL/min, 254 nm), tr (major) =
13.043 min, tr (minor) = 26.602 min, 87% ee; 1H NMR (400 MHz, DMSO) δ =
N
H
10.90 (1H, s), 8.12 (1H, d, J = 8.3 Hz), 7.88 (2H, t, J = 8.9 Hz), 7.45 – 7.34 (4H, m), 7.29 (1H, d, J =
8.1 Hz), 7.22 (1H, d, J = 8.0 Hz), 6.98 (1H, t, J = 7.5 Hz), 6.89 – 6.80 (3H, m), 5.58 (1H, s) ppm; 13C
NMR (100 MHz, DMSO) δ = 160.20, 146.91, 137.15, 131.25, 131.05, 129.59, 128.81, 127.21, 125.59,
125.20, 124.12, 123.49, 121.39, 121.36, 119.00, 118.97, 118.62, 117.13, 116.16, 112.18, 58.25,
30.89ppm; Calcd for C22H16N3O [M+H]+ 338.1293, Found 338.1285.
0.20
0.10
0.00
0.00
5.00
10.00
15.00
分钟
20.00
25.00
30.00
10

0.30
0.20
0.10
0.00
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00 22.00 24.00 26.00 28.00 30.00
分钟
6. References
[1]. Shanthi, G.; Perumal, P. T. Tetrahedron Lett. 2007, 48, 6785.
11

7．Copy of 1H NMR and 13C NMR spectra for products
12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30