Chiral diphenylperhydroindolinol silyl ether catalyzed domino oxa-Michael-aldol condensations for the asymmetric synthesis of benzopyrans

Article abstract of DOI:10.1016/j.tetasy.2014.02.016

Asymmetric domino oxa-Michael-aldol reactions between trans-cinnamaldehydes and salicylic aldehyde derivatives have been developed. Using (2S,3aS,7aS)-diphenylperhydro indolinol silyl ether 4i as the catalyst, most corresponding chiral benzopyrans can be

Full text of DOI:10.1016/j.tetasy.2014.02.016

Tetrahedron: Asymmetry 25 (2014) 523–528
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral diphenylperhydroindolinol silyl ether catalyzed domino
oxa-Michael–aldol condensations for the asymmetric synthesis
of benzopyrans
Ya-Hui Feng a, Ren-Shi Luo a, Lin Nie a, Jiang Weng a, Gui Lu a,b,
⇑
a Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China
b Institute of Human Virology, Sun Yat-sen University, Guangzhou 510080, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Accepted 24 February 2014
Asymmetric domino oxa-Michael–aldol reactions between trans-cinnamaldehydes and salicylic aldehyde
derivatives have been developed. Using (2S,3aS,7aS)-diphenylperhydro indolinol silyl ether 4i as the
catalyst, most corresponding chiral benzopyrans can be obtained with excellent chemo- and enantiose-
lectivities.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Aridsson et al. reported on an organocatalyzed asymmetric synthe-
sis of chiral benzopyrans with (S)-diphenylpyrrolinol TMS ether in
The benzopyran, or the chromene skeleton, is a widespread ele-
ment in natural products.1 The synthesis of benzopyrans, espe-
cially chiral benzopyrans, has attracted the attention of many
chemists because of their biological activities.2 On the laboratory
scale, practical synthetic routes to benzopyrans include enzyme-
catalyzed kinetic resolutions,3 metal-catalyzed reactions,4,5 and
organocatalytic reactions.6,7 Organocatalytic enantioselective sys-
tems have rapidly grown to be a very exciting field in organic
chemistry, and chiral secondary amines are probably the most
commonly used organocatalysts, which activate substrates either
by raising the highest occupied molecular orbital energy level or
lowering the lowest unoccupied molecular orbital energy level.8
Domino reactions have been viewed as green processes because
they remove the need for purification, minimize the generation of
chemical waste, and save time. Brase, List, MacMillan, Jørgenson,
Hayashi, and Enders et al. have developed many elegant domino
reactions with various secondary amine catalysts.9 Domino con-
densations between trans-cinnamaldehyde and salicylaldehyde,
which function as Michael acceptors and Michael donors respec-
tively, have proven to be a versatile route for the synthesis of ben-
zopyrans. Brase et al. have prepared racemic benzopyrans using
1,4-diazabicyclo[2.2.2]octane (DABCO) as the base.10 Recently,
highly enantioselective domino oxa-Michael–aldol reactions have
been independently realized by several groups using chiral prolinol
derivatives as catalysts, organic acids as additives.11 For example,
moderate yields and ees.11a Córdova11b and Wang11c further opti-
mized this domino reaction independently; the addition of organic
acid and molecular sieves was found to increase the ees and yields
efficiently. Córdova has also extended the substrate scope from
a,b-unsaturated aldehydes to ethyl trans-4-oxo-2-butenoate. Later,
Xu et al. developed a chiral amine/chiral acid combinational sys-
tem, which showed a synergistic effect for the improvement of
the reaction performance.11d Xu et al. also demonstrated an
improved protocol for this domino reaction with a recyclable
tertiary amine-modified diarylprolinol silyl ether as the catalyst,
with good ees (up to 90%) being obtained.11e
Compared with a proline catalyst, perhydroindole derivatives
possess two more stereogenic centers in the backbone, and may
exert stronger influences on both the orientation of the iminium
intermediate and salicylaldehyde, hence improving the stereose-
lectivities for this domino oxa-Michael–aldol reaction. In previous
work, we explored the application of perhydroindole derivatives in
the asymmetric Michael reactions of aldehydes to nitroalkenes,
and obtained high yields (up to 99%) together with excellent levels
of enantioselectivities (up to 99%).12 Herein we report the asym-
metric synthesis of chiral benzopyrans via organocatalytic domino
oxa-Michael–aldol reactions using a diphenylperhydroindolinol
silyl ether as the catalyst.
2. Results and discussion
Preliminary studies were carried out on the model reaction of
trans-cinnamaldehyde with salicylaldehyde. Perhydroindole
⇑
Corresponding author. Tel./fax: +86 20 39943048.
E-mail address: lugui@mail.sysu.edu.cn (G. Lu).
http://dx.doi.org/10.1016/j.tetasy.2014.02.016
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

524
Y.-H. Feng et al. / Tetrahedron: Asymmetry 25 (2014) 523–528
derivatives have proven to be efficient catalysts for Michael
reactions in our previous work;12 herein we mainly chose chiral
indole and perhydroindole derivatives to catalyze the domino
oxa-Michael–aldol reaction. (S)-Indoline-2-carboxylic acid 4a,
(2S,3aS,7aS)-perhydroindoline-2-carboxylic acid 4b, (2S,3aS,7aS)-
(octahydroindol-2-yl)-diphenylmethanol 4c and 4e were poor cat-
alysts for this reaction, with less than 5% product being isolated
even with 20 mol % catalyst loading for 84 h (Table 1, entries 1–3
and 5). When the hydroxy group of 4c was protected by a siloxy
group as 4g, significant improvements in both the yield and ee
were observed (Table 1, entry 3 vs 7), although this effect was
not notable for a bulkier diarylperhydroindolinol silyl ether (Ta-
ble 1, entry 4 vs 8).11c We also screened a chiral perhydroindolinol
siloxyl ether with a different siloxy group. The best result was
achieved for catalyst 4i with a TES-protected group,11a which
exhibited a comparable yield with the TMS-protected catalyst 4g,
but a significantly higher ee in the presence of 2-nitrobenzoic acid
(86% ee, Table 1 entry 9). We also observed a slight decrease in
enantioselectivity along with a perceptible drop in the yield when
the reaction was performed at a lower temperature such as 0 °C.
After compound 4i was selected as the catalyst, we screened the
effects of different solvents on the domino oxa-Michael–aldol
Table 1
Effects of catalysts on the domino oxa-Michael–aldol reactiona
CHO
CHO
OH
CHO
cat (20 mol%), 4Å MS
+
O
3a
2-NO2-PhCOOH (20 mol%)
CH2Cl2, 10 o
C
2a
1a
H
H
H
H
H
H
Ar
Ar
OH
NHTf
Ar
Ar
OR
COOH
COOH
N
H
N
N
H
N
H
N
H
H
4b
H
4f
R
4g Ar = Ph, R = TMS
4a
4c
4d
4e
Ar = Ph, R = H
Ar = 3,5-diCF3-Ph, R = H
Ar = Ph, R = Me
4h
4i
Ar = 3,5-diCF3-Ph, R = TMS
Ar = Ph, R = TES
Entry
Catalyst
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
84
84
84
84
84
84
84
84
84
84
<5
<5
<5
35
<5
30
81
50
82
70
ND
ND
ND
21
ND
2
75
26
86
83
9
10d
4i
a
Unless otherwise specified, the reaction was carried out with 1a (0.25 mmol) and 2a (0.5 mmol) in the presence of catalyst
(0.05 mmol), 2-nitrobenzoic acid (0.05 mmol), 4 Å MS (0.1 g), and CH2Cl2 (1 mL).
b
Isolated yield.
Determined by chiral HPLC analysis.
Preformed at 0 °C.
c
d
Table 2
Effects of solvents on the domino oxa-Michael–aldol reactiona
CHO
CHO
OH
CHO
cat 4i (20 mol%), 4Å MS,
+
O
2-NO2-PhCOOH (20 mol%)
solvent, 10 o
C
1a
2a
3a
Entry
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
Hexane
Toluene
Xylene
THF
Et2O
CH3CN
DMF
CHCl3
CH2Cl2
ClCH2CH2Cl
68
93
71
49
68
NR
34
87
82
86
60
76
67
36
65
ND
16
81
86
81
a
Unless otherwise specified, the reaction was carried out with 1a (0.25 mmol) and 2a (0.5 mmol) in the presence of catalyst 4i
(0.05 mmol), 2-nitrobenzoic acid (0.05 mmol), 4 Å MS (0.1 g), and solvent (1 mL) at 10 °C.
b
Isolated yield.
Determined by chiral HPLC analysis.
c

Y.-H. Feng et al. / Tetrahedron: Asymmetry 25 (2014) 523–528
525
reaction. Highly polar solvents, such as DMF and CH3CN, gave low
yields and enantioselectivities (Table 2, entries 6 and 7), which was
in agreement with the literature.11a–e Less polar halohydrocarbon
solvents, such as CH2Cl2, ClCH2CH2Cl, and CHCl3 led to better yields
and ees (Table 2, entries 8–10). Although toluene was reported to
provide moderate yields in similar reactions,11b we did observe
excellent yields with moderate ee in our system (Table 2, entry
2); we attributed this to the high solubility of catalyst 4i in toluene.
Finally CH2Cl2 was chosen as the optimal solvent (Table 2, entry 9).
The influence of various additives on the organocatalytic
oxa-Michael–aldol reactions was investigated and the results are
summarized in Table 3. In the absence of any additives, no product
was observed (Table 3, entry 1); the organic acid additive may
enhance the formation of active iminium-ion species. A series of
benzoic acids and acetic acids were effective for this reaction
(Table 3, entries 3–8). Stronger acids, such as CF3COOH and D-(+)-
10-camphorsulfonic acid, showed poor yields and ees (Table 3,
entries 9 and 14). We also tried some chiral acids11d and found that
in most cases the reaction rates were improved significantly, with
good yields (80–85%) and enantioselectivities being obtained
(Table 3, entries 10–13). Although Xu et al. reported that (S)-organ-
ic acids gave better results than their (R)-analogues,11d we only
Table 3
Effects of additives on the domino oxa-Michael–aldol reactiona
CHO
CHO
OH
CHO
cat 4i (20 mol%), 4Å MS,
+
O
additive (20 mol%)
CH2Cl2, 10 o
C
1a
Additive
2a
3a
Entry
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
No additive
PhCOOH
72
60
84
79
84
80
87
84
88
80
80
80
80
80
<5
83
82
83
82
80
90
75
31
85
85
80
82
NR
ND
57
86
78
77
79
80
74
38
81
72
74
75
ND
2-NO2-PhCOOH
3-NO2-PhCOOH
4-NO2-PhCOOH
2-Br-PhCOOH
2-I-PhCOOH
ClCH2COOH
CF3COOH
(S)-N-Boc-indoline-2-carboxylic acid
(2S,3aS,7aS)-N-Boc-octahydro-indole-2-carboxylic acid
(S)-N-Boc-proline
(R)-N-Boc-proline
9
10
11
12
13
14
D-(+)-10-Camphorsulfonic acid
a
Unless otherwise specified, the reaction was carried out with 1a (0.25 mmol) and 2a (0.5 mmol) in the presence of catalyst 4i
(0.05 mmol), additive (0.05 mmol), 4 Å MS (0.1 g) and CH2Cl2 (1 mL) at 10 °C.
b
Isolated yield.
Determined by chiral HPLC analysis.
c
Table 4
Asymmetric domino oxa-Michael–aldol reaction of various
a
,b-unsaturated aldehydes and salicylaldehyde derivativesa
CHO
CHO
4i
cat (20 mol%), 4Å MS
R2
R2
CHO
+
R1
2-NO2-PhCOOH (20 mol%)
OH
O
R1
CH2Cl2, 10 o
C
1
2
3
Entry
R1
R2
H
4-OMe
H
5-Br
5-Cl
5-Br
5-Cl
H
5-Br
5-Cl
H
Product
t (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
84
80
80
60
84
60
84
84
60
84
60
80
84
84
84
84
82
60
89
95
90
90
92
81
86
90
91
75
80
70
51
63
86
71
99
83
86
95
93
93
83
78
94
71
78
78
75
67
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
2-NO2C6H4
2-NO2C6H4
4-FC6H4
9
4-FC6H4
4-FC6H4
10
11
12
13d
14
15
16
2,4,5-TrifluoroC6H2
2,4,5-TrifluoroC6H2
4-MeOC6H4
4-MeC6H4
Me
4-OMe
5-Br
H
H
Me
5-OMe
a
Unless otherwise specified, the reaction was carried out with a,b-unsaturated aldehyde 1 (0.25 mmol) and salicylaldehyde deriv-
ative 2 (0.5 mmol) in the presence of catalyst 4i (0.05 mmol), 2-nitrobenzoic acid (0.05 mmol), 4 Å MS (0.1 g) in CH2Cl2 (1 mL).
b
Isolated yield.
Determined by chiral HPLC analysis.
Performed at 20 °C.
c
d

526
Y.-H. Feng et al. / Tetrahedron: Asymmetry 25 (2014) 523–528
H
H
OH
H
N+
Ph
Ph
OTES
domino oxa-Michael-
aldol reaction
O
N+
Ph
H
R2
Ph
OTES
R2
O
R1
OH
R1
H2O
2
O
OH
O
O
H
-H2O
O
Ph
R2
R2
Ph
R1
O
R1
N
H
OTES
H
3
R1
1
4i
Scheme 1. Possible mechanism for the organocatalytic oxa-Michael–aldol reaction.
0
observed comparable results when using (S)- and (R)-N-Boc-pro-
line, respectively (Table 3, entries 12 and 13). Eventually, 2-nitro-
benzoic acid was identified as the optimal additive because it
gave the highest ee (86% ee, Table 3 entry 3).
to stabilize the iminium intermediate, while the 4 ÅA molecule
sieves removed water from the reaction system to accelerate the
aldol condensation.
3. Conclusion
Having established 4i as a suitable catalyst, CH2Cl2 as the sol-
vent, and 2-nitrobenzoic acid as an effective additive, we then
investigated the substrate scope of this enantioselective domino
oxa-Michael–aldol reaction. The system worked well for a variety
of substituted cinnamaldehydes and salicylaldehyde derivatives,
although the yields and enantioselectivities varied with the elec-
We have described a new organocatalytic system, which readily
facilitated the domino oxa-Michael–aldol reaction of a wide range
of trans-cinnamaldehydes and salicylicaldehyde derivatives,
affording the target products with good yields and excellent
enantioselectivities. Further applications of this organocatalytic
system to other enantioselective tandem reactions are currently
underway in our laboratory.
tronic and steric properties of the substrates.
a,b-Unsaturated
aldehydes bearing electron-withdrawing groups, such as a nitro
or fluoro group, were good Michael acceptors, generally affording
the desired products in high yields and with excellent enantiose-
lectivities (Table 4, entries 3, 8, and 11). However, the results were
not favorable for cinnamaldehydes with electron-donating substit-
uents (Table 4, entry 14). No product was observed when the
reaction was performed between 4-methoxycinnamaldehyde and
5-bromo-salicylaldehyde at 10 °C, and an elevated temperature
(20 °C) was needed to ensure good conversion (Table 4, entry
4. Experimental section
4.1. General procedures
All reactions were carried out under an atmosphere of nitrogen
in flame-dried glassware with magnetic stirring. The solvents were
distilled from standard drying agents. Unless otherwise stated,
commercial reagents were purchased from Alfa Aesar, Acros and
Aldrich chemical companies and used without further purification.
Purification of the reaction products was carried out by flash chro-
matography with silica gel (200–300 mesh) purchased from
Qingdao Haiyang Chemical Co. Ltd. 1H NMR spectra were recorded
on a Bruker AVANCE 400 spectrometer. Chemical shifts are re-
ported as parts per million (ppm) in the d scale downfield from tet-
ramethylsilane (TMS). Peaks are labeled as singlet (s), doublet (d),
triplet (t), quartet (q), and multiplet (m). 13C NMR spectra were re-
corded on a Bruker spectrometer with complete proton decou-
pling, and chemical shifts are reported in ppm from TMS with
the solvent as the internal reference (CDCl3, d = 77.0 ppm). HPLC
analyses were conducted on a Shimadzu 10 A instrument using
Daicel Chiralcel OD-H, Chiralpak AD-H, Chiralpak AS-H columns
(0.46 cm diameter ꢀ 25 cm length). Optical rotations were re-
corded on a Perkin–Elmer polarimeter (Model 341). HRMS spectra
were recorded on an ESI-ion trap mass spectrometer (Shimadzu
LCMS-IT-TOF) or an EI mass spectrometer (Thermo Trace DSQ).
Analytical TLC was performed using EM separations percolated
silica gel 0.2 mm layer UV254 fluorescent sheets.
13). This process also worked well for less reactive a,b-unsaturated
aliphatic aldehydes, albeit with lower yields and enantioselectivi-
ties (Table 4, entries 15 and 16).
The enantioselectivity was also affected by the electronic prop-
erties of the substituents of salicylaldehydes. For example, 5-chloro
and 5-bromo salicylaldehydes showed slightly lower ees than the
unsubstituted salicylic aldehyde (Table 4, entries 3–5 and 8–10),
while 4-methoxy salicylaldehyde underwent the asymmetric reac-
tion with significantly lower yields and ee values (Table 4, entry 1
vs 2 and entry 11 vs 12). We assumed that the electron-donating
properties of the 4-methoxy increased the charge density of the
salicylic aldehydes, hence lowering both the reactivities and
enantioselectivities. Furthermore, the results showed that proper
steric hindrance at
a,b-unsaturated aldehydes was beneficial for
high ees (Table 4, entries 6, 7, and 11).
Based on the literature11 and on our experimental results, we
have proposed a possible mechanism for this reaction (Scheme 1).
The domino oxa-Michael/aldol reaction started from the iminium
activation of a,b-unsaturated aldehyde 1 by chiral indolinol deriv-
ative 4i, whose bulky phenyl groups efficiently shielded the Re-face
of the chiral iminium intermediate (R1 = aryl; when R1 = alkyl,
Si-face was shielded) and resulted in a stereoselective Si-facial
nucleophilic conjugate attack on the b-carbon of 1. Then an intra-
molecular nucleophilic attack on the salicylaldehyde moiety took
place, and was followed by hydrolysis of the resulting iminium
intermediate and elimination of water. 2-Nitrobenzoic acid might
act as a Brønsted acid to activate the salicylaldehyde moiety and
4.2. Typical procedure for the oxa-Michael–aldol reaction of
unsaturated aldehydes with salicylic aldehyde derivatives
a,b-
To a stirred solution of (2S,3aS,7aS)-diphenylperhydroindolinol
silyl ether (0.05 mmol), ,b-unsaturated aldehyde (0.25 mmol)
a

Y.-H. Feng et al. / Tetrahedron: Asymmetry 25 (2014) 523–528
527
and 4 Å MS (0.1 g) in CH2Cl2 (1 mL) were added and stirred at room
temperature for ten minutes. Next, o-nitrobenzoic acid
(0.05 mmol) and the salicylic aldehyde derivative (0.5 mmol) were
added slowly over 10 min. The mixture was stirred for indicated
time at 10 °C. The corresponding benzopyran was separated and
purified by silica gel chromatography. The ee value of the product
was determined by chiral HPLC analysis.
26.8 min (minor). ½a D20
ꢁ
¼ ꢂ42:6 (c 0.2, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 6.30 (s, 1H), 6.86 (d, J = 12.0 Hz, 1H), 6.93–6.98 (m,
3H), 7.26–7.28 (m, 1H), 7.30–7.34 (m, 3H), 7.42 (s, 1H), 9.64 (s,
1H). 13C NMR (100 MHz, CDCl3): d = 73.6, 115.6, 117.2, 119.9,
121.9, 128.6, 128.7, 129.4, 133.6, 133.8, 140.9, 154.6, 161.6,
164.1, 189.9. HRMS (ESI): m/z calcd for C16H11FO2Na [M+Na]+:
277.0635, found: 277.0632.
Compound 3a:11a isolated yield 82%. HPLC (Daicel Chiralpak
AD-H, hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm): tR = 21.7 min
(major), 24.6 min (minor). 1H NMR (400 MHz, CDCl3): d = 6.34 (s,
1H), 6.87 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 8.0 Hz, 1H), 7.24–7.36 (m,
7H), 7.41 (s, 1H), 9.65 (s, 1H). 13C NMR (100 MHz, CDCl3):
d = 74.3, 117.2, 120.0, 121.8, 126.8, 128.6, 128.7, 129.4, 133.7,
139.1, 140.8, 154.9, 190.0. MS (ESI): m/z 237.1 [M+H]+.
Compound 3i: isolated yield 86%. HPLC (Daicel Chiralpak AD-H,
hexane/i-PrOH = 70:30, 0.5 mL/min, 254 nm): tR = 13.3 min
(major), 14.6 min (minor). ½a D20
ꢁ
¼ þ29:4 (c 0.3, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 6.29 (s, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.96 (t,
J = 10.0 Hz, 2H), 7.27–7.31 (m, 2H), 7.35–7.39 (m, 3H), 9.65 (s,
1H). 13C NMR (100 MHz, CDCl3): d = 73.8, 113.8, 115.5, 115.7,
119.0, 121.6, 128.7, 128.8, 131.4, 134.4, 136.1, 139.1, 153.5,
161.7, 164.2, 189.6. HRMS (ESI): m/z calcd for C16H9BrFO2 [MꢂH]ꢂ:
330.9775, found: 330.9777.
Compound 3b:11c isolated yield 60%. HPLC (Daicel Chiralcel OD-
H, hexane/i-PrOH = 90:10, 0.5 mL/min, 254 nm): tR = 20.3 min (ma-
jor), 22.0 min (minor). 1H NMR (400 MHz, CDCl3): d = 3.80 (s, 3H),
6.33 (s, 1H), 6.43 (d, J = 2.2 Hz, 1H), 6.49–6.56 (m, 1H), 7.17 (d,
J = 8.0 Hz, 1H), 7.28–7.32 (m, 3H), 7.35–7.39 (m, 3H), 9.59 (s, 1H).
13C NMR (100 MHz, CDCl3): d = 55.5, 74.5, 101.9, 108.9, 113.4,
126.7, 128.5, 130.6, 133.1, 139.3, 141.0, 156.7, 164.5, 189.7. MS
(ESI): m/z 267.1 [M+H]+.
Compound 3j: isolated yield 90%. HPLC (Daicel Chiralpak AD-H,
hexane/i-PrOH = 70:30, 0.5 mL/min, 254 nm): tR = 12.8 min (ma-
jor), 14.4 min (minor). ½a D20
ꢁ
¼ þ18:6 (c 0.4, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 6.29 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.97 (t,
J = 8.0 Hz, 2H), 7.23–7.25 (m, 2H), 7.28–7.31 (m, 2H), 7.36 (s, 1H),
9.65 (s, 1H). 13C NMR (100 MHz, CDCl3): d = 73.8, 115.5, 115.7,
118.6, 121.0, 126.7, 128.5, 128.7, 128.8, 133.3, 134.4, 139.3,
153.0, 161.7, 164.2, 189.7. HRMS (ESI): m/z calcd for C16H9ClFO2
[MꢂH]ꢂ: 287.0281, found: 287.0275.
Compound 3c:11a isolated yield 89%. HPLC (Daicel Chiralpak AD-
H, hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm): tR = 30.1 min (min-
or), 32.4 min (major). 1H NMR (400 MHz, CDCl3): d = 6.42 (s, 1H),
6.94 (d, J = 8.0 Hz, 1H), 7.01 (t, J = 4.0 Hz, 1H), 7.26–7.29 (m, 1H),
7.34–7.38 (m, 1H), 7.47 (s, 1H), 7.52–7.54 (m, 2H), 8.13 (d,
J = 8.0 Hz, 2H), 9.68 (s, 1H). 13C NMR (100 MHz, CDCl3): d = 73.0,
117.1, 119.6, 122.5, 123.8, 127.5, 129.7, 132.8, 134.3, 141.5,
146.2, 147.4, 154.4, 189.9. MS (ESI): m/z 282.0 [M+H]+.
Compound 3k: isolated yield 91%. HPLC (Daicel Chiralcel OD-H,
hexane/i-PrOH = 95:5, 0.5 mL/min, 246 nm): tR = 21.3 min (major),
24.4 min (minor). ½a D20
ꢁ
¼ þ42:0 (c 0.6, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 6.57 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.95–7.01 (m, 3H),
7.29–7.33 (m, 2H), 7.55 (s, 1H), 9.62 (s, 1H). 13C NMR (100 MHz,
CDCl3): d = 67.8, 106.2, 116.8, 117.2, 119.3, 122.3, 129.5, 131.5,
134.1, 141.7, 145.5, 149.3, 151.8, 154.0, 156.9, 189.2. HRMS
Compound 3d: isolated yield 95%. HPLC (Daicel Chiralpak AD-H,
hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm): tR = 27.1 min (minor),
30.7 min (major). ½a D20
ꢁ
¼ ꢂ41:4 (c 0.4, CHCl3). 1H NMR (400 MHz,
(ESI): m/z calcd for C
16H9F3O2Na [M+Na]+: 313.0447, found:
CDCl3): d = 6.41 (s, 1H), 6.82 (d, J = 8.0 Hz, 1H), 7.38–7.44 (m, 3H),
7.47–7.52 (m, 2H), 8.14 (d, J = 6.0 Hz, 2H), 9.68 (s, 1H). 13C NMR
(100 MHz, CDCl3): d = 73.2, 114.4, 118.9, 121.3, 123.9, 127.6,
131.8, 133.5, 136.5, 139.7, 145.5, 148.0, 153.3, 189.6. HRMS (ESI):
m/z calcd for C16H9BrNO4 [MꢂH]ꢂ: 357.9720, found: 357.9709.
Compound 3e:11c isolated yield 90%. HPLC (Daicel Chiralpak
AD-H, hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm): tR = 25.3 min
(minor), 28.6 min (major). 1H NMR (400 MHz, CDCl3): d = 6.42 (s,
1H), 6.89 (d, J = 8.6 Hz, 1H), 7.27–7.31 (m, 2H), 7.40 (s, 1H), 7.51
(d, J = 8.7 Hz, 2H), 8.12–8.18 (m, 2H), 9.70 (s, 1H). 13C NMR
(100 MHz, CDCl3): d = 73.2, 118.5, 120.7, 123.9, 127.3, 127.6,
128.8, 133.6, 133.7, 139.8, 145.5, 148.0, 152.8, 189.6. MS (ESI):
m/z 314.0 [MꢂH]ꢂ.
313.0440.
Compound 3l: isolated yield 75%. HPLC (Daicel Chiralcel OD-H,
hexane/i-PrOH = 95:5, 0.5 mL/min, 254 nm): tR = 26.6 min (major),
28.7 min (minor). ½a D20
ꢁ
¼ ꢂ30:5 (c 0.3, CHCl3). 1H NMR (400 MHz,
CDCl3): d = 3.78 (s, 3H), 6.35 (d, J = 4.0 Hz, 1H), 6.54–6.57 (m, 2H),
6.93–7.00 (m, 2H), 7.21 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 9.56 (s,
1H). 13C NMR (100 MHz, CDCl3): d = 55.6, 67.9, 102.0, 109.5,
112.6, 128.7, 130.7, 141.9, 155.9, 164.8, 188.9. HRMS (ESI): m/z
calcd for C17H11F3O3Na [M+Na]+: 343.0553, found: 343.0536.
Compound 3m: isolated yield 80%. HPLC (Daicel Chiralcel OD-H,
hexane/i-PrOH = 70:30, 0.7 mL/min, 254 nm): tR = 15.3 min (ma-
jor), 20.9 min (minor). ½a D20
ꢁ
¼ þ36:1 (c 0.4, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 3.75 (s, 3H), 6.26 (s, 1H), 6.72 (d, J = 8.0 Hz,
1H), 6.80 (d, J = 8.0 Hz, 2H), 7.23–7.25 (m, 2H), 7.34–7.36 (m,
2H), 7.38–7.39 (m, 1H), 9.63 (s, 1H). 13C NMR (100 MHz, CDCl3):
d = 55.2, 74.3, 113.5, 114.0, 119.1, 121.8, 128.3, 130.5, 131.3,
134.7, 135.9, 138.8, 153.7, 160.1, 189.7. HRMS (ESI): m/z calcd for
Compound 3f: isolated yield 90%. HPLC (Daicel Chiralpak AD-H,
hexane/i-PrOH = 70:30, 0.5 mL/min, 254 nm): tR = 23.5 min
(major), 26.5 min (minor). ½a D20
ꢁ
¼ þ273 (c 0.4, CHCl3). 1H NMR
(400 MHz, CDCl3): d = 6.68 (d, J = 8.7 Hz, 1H), 7.07 (s, 1H), 7.21–
7.24 (m, 1H), 7.33–7.36 (m, 1H), 7.38 (d, J = 4.0 Hz, 1H), 7.42–
7.46 (m, 2H), 7.48 (s, 1H), 7.84–7.88 (m, 1H), 9.68 (s, 1H). 13C
NMR (100 MHz, CDCl3): d = 69.4, 100.0, 114.3, 119.2, 121.4,
125.0, 128.6, 130.0, 131.4, 132.6, 132.9, 136.4, 140.5, 153.1,
189.1. HRMS (ESI): m/z calcd for C16H9BrNO4 [MꢂH]ꢂ: 357.9720,
found: 357.9700.
C
17H13BrO3Na [M+Na]+: 366.9940, found: 366.9957.
Compound 3n:11d isolated yield 70%. HPLC (Daicel Chiralcel
OD-H, hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm): tR = 19.9 min
(major), 23.7 min (minor). 1H NMR (400 MHz, CDCl3): d = 2.28
(s, 3H), 6.29 (s, 1H), 6.85 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 8.0 Hz,
1H), 7.07 (d, J = 8.0 Hz, 2H), 7.22–7.25 (m, 4H), 7.39 (s, 1H), 9.63
(s, 1H). 13C NMR (100 MHz, CDCl3): d = 21.1, 74.2, 117.2, 120.0,
121.7, 126.8, 129.2, 133.6, 133.9, 136.1, 138.5, 140.7, 154.9,
190.0. MS (ESI): m/z 251.2 [M+H]+.
Compound 3g:11c isolated yield 92%. HPLC (Daicel Chiralpak
AD-H, hexane/i-PrOH = 70:30, 0.5 mL/min, 254 nm): tR = 21.7 min
(major), 25.9 min (minor). 1H NMR (400 MHz, CDCl3): d = 6.74 (d,
J = 8.7 Hz, 1H), 7.07 (s, 1H), 7.18–7.25 (m, 3H), 7.44–7.47 (m, 2H),
7.49 (s, 1H), 7.84–7.89 (m, 1H), 9.69 (s, 1H). 13C NMR (100 MHz,
CDCl3): d = 69.5, 118.8, 120.8, 125.0, 127.2, 128.4, 128.6, 130.0,
131.4, 132.6, 132.9, 133.5, 140.6, 148.9, 152.6, 189.1. MS (ESI):
m/z: 316.1 [M+H]+.
Compound 3o:11c isolated yield 30%. HPLC (Daicel Chiralcel OD-
H, hexane/i-PrOH = 90:10, 0.5 mL/min, 280 nm): tR = 24.9 min
(minor), 26.7 min (major). 1H NMR (400 MHz, CDCl3): d = 1.36 (d,
J = 6.6 Hz, 3H), 5.42 (q, J = 6.6 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H),
6.98–6.91 (m, 1H), 7.23–7.18 (m, 2H), 7.35–7.27 (m, 1H), 9.55 (s,
1H). 13C NMR (100 MHz, CDCl3): d = 19.9, 69.8, 117.3, 119.9,
121.6, 129.2, 133.4, 136.2, 140.2, 154.4, 190.0.
Compound 3h: isolated yield 81%. HPLC (Daicel Chiralpak AD-H,
hexane/i-PrOH = 96:4, 0.5 mL/min, 254 nm): tR = 24.1 min (major),

528
Y.-H. Feng et al. / Tetrahedron: Asymmetry 25 (2014) 523–528
H.; Ye, K.-Y.; Wu, Q.-F.; Dai, L.-X.; You, S.-L. Adv. Synth. Catal. 2012, 354, 1084–
Compound 3p:11d isolated yield 50%. HPLC (Daicel Chiralpak AS-
1094; (d) Shen, H. C. Tetrahedron 2009, 65, 3931–3952.
H, hexane/i-PrOH = 70:30, 0.5 mL/min, 254 nm): tR = 13.3 min (ma-
jor), 15.3 min (minor). 1H NMR (400 MHz, CDCl3): d = 1.33 (d,
J = 6.6 Hz, 3H). 3.79 (s, 3H), 5.40–5.34 (m, 1H), 6.74 (d, J = 2.9 Hz,
1H), 6.84–6.80 (m, 1H), 6.92–6.87 (m, 1H), 7.16 (s, 1H), 9.55 (s,
1H). 13C NMR (100 MHz, CDCl3): d = 19.4, 55.8, 69.6, 112.9, 118.1,
119.6, 120.3, 136.9, 140.2, 148.3, 154.2, 190.0.
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Acknowledgments
This work was financially supported by the 7th Framework
Programme (FP7-201431 CATAFLU.OR), Guangdong Innovative
Research Team Program (No. 2009010058) and The National
High-tech R&D Program of China (863 Program, No.
2013AA092903).
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