Enantioselective synthesis of naphthopyran derivatives catalyzed by bifunctional thiourea-tertiary amines

Article abstract of DOI:10.1016/j.tetasy.2008.02.018

An efficient bifunctional thiourea catalyzed addition-cyclization reaction of 2-naphthol with α,α-dicyanoolefins is realized under mild conditions to afford the corresponding naphthopyran derivatives in high yields and moderate enantioselectivities. Addit

Full text of DOI:10.1016/j.tetasy.2008.02.018

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 709–714
Enantioselective synthesis of naphthopyran derivatives
catalyzed by bifunctional thiourea-tertiary amines
Xiao-Sheng Wang,a Gao-Sheng Yanga,* and Gang Zhaob,*
aAnhui Key Laboratory of Functional Molecular Solids, Institute of Organic Chemistry,
School of Chemistry and Materials Science, Anhui Normal University, Wuhu, Anhui 241000, China
bLaboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 19 January 2008; accepted 15 February 2008
Abstract—An efficient bifunctional thiourea catalyzed addition–cyclization reaction of 2-naphthol with a,a-dicyanoolefins is
realized under mild conditions to afford the corresponding naphthopyran derivatives in high yields and moderate enantioselectivities.
Additionally, the development of an asymmetric three-component one-pot procedure for the synthesis of naphthopyran derivatives
is also reported.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
bearing in mind that a,a-dicyanoolefins6 and 2-naphthols7
are suitable for acid and base activation, respectively
(Fig. 1), we assumed that a chiral bifunctional catalyst
may lead to an asymmetric version of the synthesis of
naphthopyran derivatives. Herein, we report the first enan-
tioselective addition of 2-naphthol to a,a-dicyanoolefins
catalyzed by thiourea and tertiary amine-based bifunc-
tional catalysts.
Benzo- and naphthopyran derivatives are an important
class of heterocyclic compounds possessing biological and
pharmacological activities, such as anticoagulant, spasmo-
lytic, diuretic, anticancer and antianaphylactin activities.1
Some of these compounds can also be employed as cosmet-
ics and pigments and as potential biodegradable agrochem-
icals.2 Therefore, the synthesis of such compounds has
attracted strong interest.3 Several conventional syntheses
of these polyfunctionalized benzopyrans involving the con-
densation of malononitrile with an aldehyde and phenol or
naphthol using bases or amides as catalysts have been well-
developed.3 However, to the best of our knowledge, no
asymmetric synthesis of naphthopyran derivatives has yet
been reported.
OH
base activation
H
CN
CN
acid activation
acid activation
Ph
Figure 1.
2. Results and discussion
On the other hand, over the last decade, a broad range of
synthetically useful reactions employing the chiral N,N-
dialkyl (thio) urea derivatives as active organocatalysts
have been explored.4 In the domain of urea and thiourea
catalysts, remarkable advances were made by Jacobsen
and Takemoto in a series of asymmetric reactions pro-
moted by urea or thiourea containing a Schiff base or ter-
tiary amine moiety as catalysts.5 Based on these studies and
Using the reaction of 2-benzylidenemalononitrile with
2-naphthol as a model reaction, a series of thiourea and
tertiary amine-based bifunctional catalysts (Fig. 2) were
screened at room temperature in CH2Cl2, and the results
are summarized in Table 1 (entries 1–7). Both the cinchona
alkaloids and prolinol derived thiourea catalysts 1a, 1b and
1g provided poor results. Of all the catalysts examined, the
(R,R)-1,2-cyclohexyldiamine derived 1c bearing a 3,5-
bis(trifluoromethyl)phenyl substituent exhibited the highest
enantioselectivity and yield (entry 3, 67% ee, and 89%
*
Corresponding authors. Fax: +86 21 64166128 (G.Z.); e-mail addresses:
gshyang@mail.ahnu.edu.cn; zhaog@mail.sioc.ac.cn
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.018

710
X.-S. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 709–714
Table 1. Screening of the optimal reaction conditions for 2a and 3a in the
presence of 1a
examined with catalyst 1c in order to improve the enantio-
selectivity. Unfortunately, poor enantioselectivity was
obtained for all the other five solvents selected with lower
yields (entries 9–13). A slightly better result was obtained
when 4 A molecular sieves were added to the reaction
system (entry 14), however, no beneficial effect on the
CN
H
NH2
CN
˚
OH
catalyst 1
CN +
O
solvent
enantioselectivity was observed at 0 °C (entry 15, 61% ee).
2a
3a
4a
With the optimized reaction conditions in hand, the scope
of the reaction of a,a-dicyanoolefins with 2-naphthol was
probed and the results are summarized in Table 2. Gener-
ally, all the arylidenemalononitriles examined could pro-
ceed smoothly to give the desired products (Table 2,
entries 2–16). It was found that substrates with electron-
donating groups on the phenyl ring, such as 2g with a
4-methoxyphenyl group or 2m with a furyl group, provided
lower yields than the electron-withdrawing group substi-
tuted ones, although no significant decrease in ee values
was observed (Table 2, entries 9 and 15). Moreover, a
much lower yield (19%) was obtained for an alkyl substi-
tuted substrate 2n with a comparable enantioselectivity to
the aromatic ones. (Table 2, entry 16).8 In addition, a
substituted, naphthol 7-methoxy-2-naphthol, was also
examined in this reaction with a much lower enantioselec-
tivity achieved; what was more striking was that when 1-
naphthol was used, only the racemic product 4b was ob-
tained (Table 2, entries 6 and 2), which revealed that the
structures of the naphthols should have great influence
on the enantioselectivity of this reaction.9 The enantioselec-
tivity of these products could be improved upon simple
recrystallization. For example, the ee of 4c increased up
to 99% just through a single recrystallization in ethanol.
The absolute configuration of the product 4c was deter-
mined to be (S)- by X-ray crystallographic analysis
(Fig. 3).10
Entry
Catalyst
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
1a
1b
1c
1d
1e
1f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH3CN
THF
86
82
89
65
75
58
88
72
68
53
10
67
32
98
83
8
24
67
46
43
23
25
58
40
13
<5
17
22
68
61
6
7
1g
1c
1c
1c
1c
1c
1c
1c
1c
8d
9d
10d
11d
12d
13d
14e
15f
n-Hexane
Et2O
CH2Cl2
CH2Cl2
a Unless otherwise noted, the reaction was conducted with 0.2 mmol of 2a
and 0.2 mmol of 3a in the presence of 20 mol % of 1 in 1.0 mL of solvent
at room temperature.
b Isolated yield.
c Determined by chiral HPLC analysis on a chiral OD column.
d 10 mol % of 1 was used.
e
˚
30 mg of 4 A MS was added.
The reaction was conducted at 0 °C and 30 mg of 4 A MS was added.
f
˚
yield). Changing the trifluoromethyl phenyl substituent in
1c to phenyl 1d, 4-fluorophenyl 1e or cyclohexyl 1f all
led to inferior chemical yields and enantioselectivies.
Next, the solvent, temperature and catalyst loading were
Furthermore, since the one-pot three-component synthesis
of naphthopyran derivatives from aldehydes, malononitrile
OMe
N
N
CF3
CF3
NH
NH
N
N
S
N
CF3
S
1a
S
N
CF3
H
H
1b
S
CF3
CF3
S
NH
N
NH
N
F
NH
N
H
H
H
N
N
N
1c
CF3
1f
1e
S
S
CF3
N
N
NH
N
H
H
H
NH
N
1d
1g
Figure 2. Thiourea-tertiary amine catalysts used in the study.

X.-S. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 709–714
Table 2. Enantioselective synthesis of naphthopyran derivatives catalyzed by 1ca
711
CN
R1
NH2
1c (20 mol %)
R2
OH
H
R2
O
CN
CN
+
DCM, 4
r. t.
A MS
R1
2a-n
3a-b
4a-p
Entry
2
R1
R2
H (3a)
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2a
2a
2b
2c
2d
2d
2e
2f
C6H4
C6H4
4-BrC6H4
4-ClC6H4
4-FC6H4
4a
4b
4c
4d
4e
4f
98
86
87
93
75
91
83
98
38
99
98
94
94
94
52
19
68
—
1-Naphthol
H (3a)
H (3a)
H (3a)
CH3O (3b)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
71 (>99)d
67
90
66
79
65
62
56
70
76
84
65
61
57
4-FC6H4
4-CH3C6H4
4g
4h
4i
4-NO2C6H4
4-CH3OC6H4
2,4-Cl2C6H3
3-FC6H4
3-CH3OC6H4
2-ClC6H4
3-ClC6H4
2-Furyl
2g
2h
2i
4j
4k
4l
2j
2k
2l
4m
4n
4o
4p
2m
2n
n-Hexyl
a Unless otherwise noted, the reaction was conducted with 0.2 mmol of 2 and 0.2 mmol of 3 in the presence of 20 mol % of 1c in 1.0 mL of DCM at room
˚
temperature and 30 mg of 4 A MS was added.
b Isolated yield.
c Determined by chiral HPLC analysis on a chiral OD-H column. The absolute configuration of the product 4c was determined to be (S)- by X-ray
crystallographic analysis and the others 4a, 4d–4p were assigned by assuming that a similar catalytic mechanism was followed.
d After a single recrystallization from 95% ethanol.
bifunctional thiourea-tertiary amine compounds. Moder-
ate to excellent enantioselectivities (56–90% ee) have been
achieved with high isolated yields. Moreover, the enantio-
selective synthesis of naphthopyran derivatives via a one-
pot three-component condensation of malnonitrile with
Br
CN
H
NH2
aldehyde and 2-naphthol were also explored.
O
4c
4. Experimental
Figure 3. X-ray structure of compound 4c.
4.1. General
and 2-naphthol have been reported,3d we conceived that an
asymmetric version of this procedure may also be possible.
Unless otherwise indicated, chemicals and solvents were
Indeed, the reactions could proceed smoothly as expected
purchased from commercial suppliers or purified by stan-
to provide the desired products in good yields albeit with
dard techniques. Flash column chromatography was per-
lower enantioselectivities than the above stepwise proce-
formed using silica gel. For thin-layer chromatography
dure. Various substituted phenyl aldehydes were reacted
(TLC), silica gel plates (HSGF 254) were used and com-
with malononitrile and 2-naphthol to study the scope of
pounds were visualized by irradiation with UV light or
this one-pot procedure (Table 3). In general, electron-defi-
by treatment with a solution of phosphomolybdic acid in
cient aldehydes reacted well to give the corresponding
1
ethanol followed by heating. The H NMR spectra were
naphthopyran derivatives in good to excellent yields and
recorded on a DPX-300 or Varian EM-360 (300 MHz).
All chemical shifts (d) are given in ppm. Data are reported
as follows: chemical shift, integration, multiplicity (s = sin-
moderate enantioselectivities (Table 3, entries 2–4 and 6–8).
However, lower enantioselectivities were observed when
electron-rich aryl aldehydes were used (entries 1 and 5).
gle, d = doublet, t = triplet, q = quartet, br = broad, m =
multiplet) and coupling constants (Hz). 13C NMR spectra
3. Conclusions
were recorded on a DPX-300 (75 MHz). Analytical high
performance liquid chromatography (HPLC) was carried
out on WATERS equipment using a chiral column. Melt-
ing points were determined on a SGW X-4 apparatus
In conclusion, we have reported the first enantioselective
synthesis of naphthopyran derivatives catalyzed by chiral

712
X.-S. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 709–714
Table 3. Asymmetric one-pot synthesis of naphthopyran derivatives catalyzed by 1ca
CN
R
NH2
1c (20 mol %)
OH
CN
CN
O
CHO
+
+
DCM, 4
r. t.
A MS
R
5
4
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
H
4a
4c
72
81
90
71
67
91
75
93
33
65
55
62
37
55
56
52
4-Br
4-Cl
4-F
4-Me
4-NO2
2-Cl
4d
4e
4g
4h
4m
4n
3-Cl
a Unless otherwise noted, the reaction was conducted with 0.2 mmol of 5, 0.2 mmol of malononitrile and 0.2 mmol of 2-naphthol in the presence of
˚
20 mol % of 1c in 1.0 mL of DCM at room temperature and 30 mg of 4 A MS was added.
b Isolated yield.
c Determined by chiral HPLC analysis on a chiral OD-H column. The absolute configuration of product 4c was determined to be (S) by X-ray
crystallographic analysis and the others 4a, 4d–4n were assigned by assuming that a similar catalytic mechanism was followed.
and were/are uncorrected. Optical rotations were measured
on a JASCO P-1010 Polarimeter at k = 589 nm. IR spectra
were recorded on a Perkin–Elmer 983G instrument. Ele-
mentary analysis was taken on a Vario EL III elementary
analysis instrument. Mass spectra analysis was performed
on API 200 LC/MS system (Applied Biosystems Co. Ltd).
4.1.4. 3-Amino-1-(4-chlorophenyl)-1H-benzo[f]chromene-2-
24:8
carbonitrile 4d.12a White solid. Mp 210–211 °C; ½aꢀD
¼
1
ꢁ43:9 (c 0.70, DMSO); H NMR (300 MHz, CDCl3) d
7.83–7.80 (m, 2H), 7.63–7.59 (m, 1H), 7.42–7.40 (m, 2H);
7.27–7.21 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H), 5.23 (s, 1H),
4.62 (s, 1H); the enantiomeric ratio was determined by
HPLC analysis, using a Chiracel OD-H column (25 °C,
Catalysts 1a,11a 1b,11b 1c,5f 1d,5f 1e,6a 1f11b and 1g11c were
synthesized according to references.
254 nm, 3:2, hexane/2-propanol, 0.7 mL/min); tmajor
8.31 min, tminor = 11.34 min.
=
4.1.5. 3-Amino-1-(4-fluorophenyl)-1H-benzo[f]chromene-2-
4.1.1. General procedure for the asymmetric synthesis of
naphthopyran derivatives 4a–4o. To
27:1
carbonitrile 4e.12a White solid. Mp 237–238 °C; ½aꢀD
¼
a
solution of
ꢁ2:8 (c 0.64, DMSO); 1H NMR (300 MHz, CDCl3) d
7.83–7.80 (m, 2H), 7.65–7.63 (m, 1H), 7.40 (dd,
J = 2.8 Hz, 2H), 7.25 (d, J = 6.8 Hz, 1H), 7.17–7.12 (m,
2H), 6.94 (t, J = 8.6 Hz, 2H), 5.24 (s, 1H), 4.62 (s, 2H);
the enantiomeric ratio was determined by HPLC analy-
sis, using a Chiracel OD-H column (25 °C, 254 nm,
3:2, hexane/2-propanol, 0.7 mL/min); tmajor = 9.26 min,
tminor = 14.71 min.
0.2 mmol of 2-naphthol and 0.2 mmol of a,a-dicyanoole-
fins in the presence of 20 mol % of 1c in 1.0 mL of DCM
˚
at room temperature, 30 mg of 4 A MS was added. Stirring
at room temperature was continued for 6–48 h. The crude
mixture was purified by column chromatography on silica
gel to afford the corresponding products.
4.1.2.
3-Amino-1-phenyl-1H-benzo[f]chromene-2-carbo-
23:8
nitrile 4a.12a White solid. Mp 278–279 °C; ½aꢀD ¼ ꢁ5:2
(c 1.15, DMSO);12 1H NMR (300 MHz, DMSO-d6) d
7.96–7.90 (m, 2H), 7.85 (d, J = 4.5 Hz, 1H), 7.47–7.13
(m, 8H); 7.0 (s, 1H), 5.30 (s, 1H); the enantiomeric ratio
was determined by HPLC analysis, using a Chiracel OD
column (25 °C, 254 nm, 4:1, hexane/2-propanol, 0.6 mL/
min); tmajor = 18.24 min, tminor = 31.29 min.
4.1.6. 3-Amino-1-(4-fluorophenyl)-9-methoxy-1H-benzo[f]-
chromene-2-carbonitrile 4f. White solid. Mp 238–239 °C;
24:6
½aꢀD ¼ ꢁ51:35 (c 0.54, DMSO); IR (KBr) m = 3465,
3359, 2183, 1662, 1654, 1592, 1509, 1408, 1239, 1218,
827 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 7.70 (t,
J = 18.2 Hz, 2H), 7.19–7.02 (m, 4H), 6.96 (t, J = 8.2 Hz,
2H), 6.85 (s, 1H), 5.12 (s, 1H), 4.52 (s, 2H), 3.69 (s, 3H);
13C NMR (75 MHz, CDCl3) d 162.9, 160.1, 159.6, 158.5,
147.7, 142.5, 132.1, 130.5, 129.6, 129.5, 126.5, 121.0,
117.3, 116.0, 115.7, 115.1, 114.5, 103.6, 58.3, 55.5, 37.8;
LRMS (EI): m/e 346 (M+, 16), 252 (17), 251 (100), 208
(15), 84 (11), 55 (13), 42 (14), 41 (10); Anal. Calcd for
C21H15FN2O2: C, 72.82; H, 4.37; N, 8.09. Found: C,
72.82; H, 4.45; N, 8.08; the enantiomeric ratio was
determined by HPLC analysis, using a Chiracel OD-H
column (25 °C, 254 nm, 3:2, hexane/2-propanol, 0.7 mL/
min); tmajor = 17.64 min, tminor = 21.22 min.
4.1.3. 3-Amino-1-(4-bromophenyl)-1H-benzo[f]chromene-2-
carbonitrile 4c.12a White solid. Mp 221–222 °C;
27:7
½aꢀD ¼ ꢁ57:3 (c 0.93, DMSO); 1H NMR (300 MHz,
CDCl3) d 7.82–7.80 (m, 2H), 7.60–7.59 (m, 1H), 7.39–
7.36 (m, 3H), 7.26–7.22 (m, 2H), 7.07–7.04 (m, 2H), 5.20
(d, J = 4.5 Hz, 1H), 4.63 (s, 1H); the enantiomeric ratio
was determined by HPLC analysis, using a Chiracel
OD-H column (25 °C, 254 nm, 3:2, hexane/2-propanol,
0.7 mL/min); tmajor = 9.65 min, tminor = 14.87 min.

X.-S. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 709–714
713
4.1.7.
3-Amino-1-p-tolyl-1H-benzo[f]chromene-2-carbo-
4.1.13. 3-Amino-1-(2-chlorophenyl)-1H-benzo[f]chromene-2-
carbonitrile 4m.12a White solid. Mp 265–267 °C;
24:3
nitrile 4g.12a White solid. Mp 253–254 °C; ½aꢀD
¼
23:9
1
ꢁ20:3 (c 0.59, DMSO); H NMR (300 MHz, CDCl3) d
7.81–7.78 (m, 2H), 7.71–7.68 (m, 1H); 7.40–7.37 (m, 2H);
7.25 (d, J = 8.6 Hz, 1H), 7.12–7.02 (m, 4H), 5.21 (s, 1H),
4.57 (s, 2H); the enantiomeric ratio was determined by
HPLC analysis, using a Chiracel OD-H column (25 °C,
½aꢀD ¼ þ28:5 (c 0.48, DMSO); 1H NMR (300 MHz,
CDCl3) d 7.82–7.78 (m, 2H), 7.67 (d, J = 7.7 Hz, 1H);
7.45–7.37 (m, 3H); 7.26–7.24 (m, 1H), 7.12–7.02 (m, 2H),
6.91 (dd, J = 8.8 Hz, 1H), 5.89 (s, 1H), 4.54 (s, 2H); the
enantiomeric ratio was determined by HPLC analysis,
using a Chiracel OD-H column (25 °C, 254 nm, 3:2,
254 nm, 3:2, hexane/2-propanol, 0.7 mL/min); tmajor
8.42 min, tminor = 12.28 min.
=
hexane/2-propanol,
0.7 mL/min);
tmajor = 15.08 min,
tminor = 23.16 min.
4.1.8.
3-Amino-1-(4-nitrophenyl)-1H-benzo[f]chromene-2-
carbonitrile 4h.3c Pale yellow solid. Mp 185–186 °C;
4.1.14. 3-Amino-1-(3-chlorophenyl)-1H-benzo[f]chromene-2-
25:0
27:4
½aꢀD ¼ ꢁ115:9 (c 0.40, DMSO); 1H NMR (300 MHz,
carbonitrile 4n.12c White solid. Mp 240–241 °C; ½aꢀD
¼
1
CDCl3) d 8.13 (d, J = 9.7 Hz, 2H), 7.88–7.82 (m, 2H),
7.55–7.51 (m, 1H), 7.45–7.26 (m, 5H), 5.36 (s, 1H), 4.76
(s, 2H); the enantiomeric ratio was determined by HPLC
analysis, using a Chiracel OD-H column (25 °C, 254 nm,
3:2, hexane/2-propanol, 0.7 mL/min); tmajor = 14.75 min,
tminor = 20.71 min.
ꢁ18:4 (c 0.62, DMSO); H NMR (300 MHz, CDCl3) d
7.82 (d, J = 8.6 Hz, 2H), 7.65–7.62 (m, 1H), 7.43–7.40
(m, 2H), 7.23–7.08 (m, 5H), 5.22 (s, 1H), 4.64 (s, 2H); the
enantiomeric ratio was determined by HPLC analysis,
using a Chiracel OD-H column (25 °C, 254 nm, 3:2,
hexane/2-propanol,
0.7 mL/min);
tmajor = 14.90 min,
tminor = 19.62 min.
4.1.9. 3-Amino-1-(4-methoxyphenyl)-1H-benzo[f]chromene-
2-carbonitrile 4i.12a Pale white solid. Mp 194 °C;
4.1.15.
3-Amino-1-(furan-2-yl)-1H-benzo[f]chromene-2-
27:3
27:1
½aꢀD ¼ ꢁ19:5 (c 0.65, DMSO); 1H NMR (300 MHz,
carbonitrile 4o.3e White solid. Mp 225–226 °C; ½aꢀD
¼
1
CDCl3) d 7.78 (d, J = 8.6 Hz, 2H), 7.69–7.66 (m, 1H),
7.39–7.36 (m, 2H), 7.22 (d, J = 10 Hz, 1H), 7.09 (d,
J = 7.6 Hz, 2H), 6.78 (d, J = 7.5 Hz, 2H), 5.19 (s, 1H),
4.60 (s, 2H), 3.72 (s, 3H); the enantiomeric ratio was deter-
mined by HPLC analysis, using a Chiracel OD-H column
(25 °C, 254 nm, 3:2, hexane/2-propanol, 0.7 mL/min);
tmajor = 9.83 min, tminor = 16.12 min.
ꢁ45:5 (c 0.41, DMSO); H NMR (300 MHz, CDCl3) d
8.03 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.9 Hz, 2H), 7.54–
7.42 (m, 3H), 7.27 (d, J = 9.2 Hz, 1H), 7.08 (s, 2H), 6.30–
6.22 (m, 2H), 5.48 (s, 1H); the enantiomeric ratio was deter-
mined by HPLC analysis, using a Chiracel OD-H column
(25 °C, 254 nm, 3:2, hexane/2-propanol, 0.7 mL/min);
tmajor = 14.67 min, tminor = 7.71 min.
4.1.10.
3-Amino-1-(2,4-dichlorophenyl)-1H-benzo[f]chro-
4.1.16. 3-Amino-1-pentyl-1H-benzo[f]chromene-2-carboni-
27:8
mene-2-carbonitrile 4j.12a White solid. Mp 239–240 °C;
trile 4p.12d Colourless oil. ½aꢀD ¼ þ5:5 (c 0.64, CHCl3);
26:8
½aꢀD ¼ þ4:3 (c 0.73, DMSO); 1H NMR (300 MHz,
1H NMR (300 MHz, CDCl3) d 7.91–7.81 (m, 2H), 7.71 (d,
J = 8.6 Hz, 1H), 7.59–7.44 (m, 2H), 7.14 (d, J = 9.2 Hz,
1H), 4.68 (s, 2H), 4.25 (t, J = 8.7 Hz, 1H), 1.82–1.79 (m,
2H), 1.46–1.21 (m, 6H), 0.83–0.79 (t, J = 6.1 Hz, 3H); the
enantiomeric ratio was determined by HPLC analysis,
using a Chiracel OD-H column (25 °C, 254 nm, 19:1,
CDCl3) d 7.83–7.79 (m, 2H), 7.61–7.58 (m, 1H), 7.45–
7.36 (m, 3H), 7.26–7.24 (m, 1H), 7.03 (dd, J = 7.6 Hz,
1H), 6.84 (d, J = 9.5 Hz, 1H), 5.84 (s, 1H), 4.67 (s, 2H);
the enantiomeric ratio was determined by HPLC analysis,
using a Chiracel OD-H column (25 °C, 254 nm, 3:2,
hexane/2-propanol,
0.7 mL/min);
tmajor = 12.90 min,
hexane/2-propanol,
0.7 mL/min);
tmajor = 30.60 min,
tminor = 18.49 min.
tminor = 33.27 min.
4.1.11. 3-Amino-1-(3-fluorophenyl)-1H-benzo[f]chromene-2-
carbonitrile 4k.12b White solid. Mp 278–279 °C;
4.1.17. Ethyl 3-amino-1-(4-chlorophenyl)-1H-benzo[f]chro-
mene-2-carboxylate 4q.12a White solid. Mp 190–191 °C;
27:5
12:7
½aꢀD ¼ ꢁ21:7 (c 0.62, DMSO); 1H NMR (300 MHz,
½aꢀD ¼ þ2:5 (c 0.33, CDCl3); 1H NMR (300 MHz,
CDCl3), d 7.82 (d, J = 8.8 Hz, 2H), 7.66–7.63 (m, 1H),
7.43–7.40 (m, 2H), 7.28–7.25 (m, 2H), 7.06 (d,
J = 7.7 Hz, 1H), 6.91–6.84 (m, 1H), 6.79 (d, J = 9.8 Hz,
1H) 5.25 (s, 1H), 4.64 (s, 2H); the enantiomeric ratio was
determined by HPLC analysis, using a Chiracel OD-H col-
umn (25 °C, 254 nm, 3:2, hexane/2-propanol, 0.7 mL/min);
tmajor = 14.63 min, tminor = 20.19 min.
CDCl3) d 7.94 (d, J = 8.7 Hz, 1H), 7.76 (t, J = 8.4 Hz,
2H), 7.47–7.35 (m, 2H), 7.27–7.25 (m, 3H), 7.13 (d,
J = 7.1 Hz, 2H), 6.31 (s, 2H), 5.56 (s, 1H), 4.21(q,
J = 5.1 Hz, 2H), 1.36 (t, J = 5.9 Hz, 3H); the enantiomeric
ratio was determined by HPLC analysis, using a Chiracel
OJ column (25 °C, 254 nm, 9:1, hexane/2-propanol,
0.7 mL/min); tmajor = 29.05 min, tminor = 35.80 min.
4.1.12. 3-Amino-1-(3-methoxyphenyl)-1H-benzo[f]chromene-
2-carbonitrile 4l. White solid. Mp 262–263 °C;
4.1.18. General procedure for one-pot condensation of
malononitrile with an aldehyde and 2-naphthol. To a solu-
tion of 0.2 mmol of 2-naphthol, 0.2 mmol of malononitrile
and 0.2 mmol of an aldehyde in the presence of 20 mol %
of 1c in 1.0 mL of DCM at room temperature, 30 mg of
27:3
½aꢀD ¼ ꢁ6:6 (c 0.77, DMSO); 1H NMR (300 MHz,
DMSO-d6) d 7.98–7.85 (m, 3H), 7.45–7.42 (m, 2H), 7.33
(d, J = 9.0 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.0 (s, 2H),
6.78–6.68 (m, 3H), 5.28 (s, 1H), 3.58 (s, 3H); the enantio-
meric ratio was determined by HPLC analysis, using a
Chiracel OD-H column (25 °C, 254 nm, 3:2, hexane/2-pro-
panol, 0.7 mL/min); tmajor = 14.75 min, tminor = 21.04 min.
˚
4 A MS was added. Stirring at room temperature was
continued for 6–48 h. The crude mixture was purified by
column chromatography on silica gel to afford the corres-
ponding products.

714
X.-S. Wang et al. / Tetrahedron: Asymmetry 19 (2008) 709–714
6. (a) Jiang, L.; Zheng, H.-T.; Liu, T.-Y.; Yue, L.; Chen, Y.-C.
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