Reactions of 2-(trifluoromethyl)-2-hydroxy-2H-chromenes with silyl enol ethers promoted by AlCl3

Article abstract of DOI:10.1016/j.tet.2013.07.004

An efficient and straightforward nucleophilic substitution reaction between 2-(trifluoromethyl)-2-hydroxy-2H-chromenes and various silyl enol ethers promoted by Lewis acid has been studied. A series of novel 4-functionalized-2- trifluoromethyl-3-ethoxycarbonyl-4H-chromenes were prepared in good yields under mild conditions.

Full text of DOI:10.1016/j.tet.2013.07.004

Tetrahedron 69 (2013) 7975e7980
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Reactions of 2-(trifluoromethyl)-2-hydroxy-2H-chromenes with
silyl enol ethers promoted by AlCl3
,
,
b
,
a
Liang Zhang a b, Xinjin Li b, Zhongwei Wang a , Jingwei Zhao , Jinjin Wang ,
*
*
Jianwei Han b, Shizheng Zhu b
,
*
a College of Material Science and Technology, Shandong University of Science and Technology, Shandong, Qingdao 266590, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and straightforward nucleophilic substitution reaction between 2-(trifluoromethyl)-2-
hydroxy-2H-chromenes and various silyl enol ethers promoted by Lewis acid has been studied. A se-
ries of novel 4-functionalized-2-trifluoromethyl-3-ethoxycarbonyl-4H-chromenes were prepared in
good yields under mild conditions.
Received 24 April 2013
Received in revised form 18 June 2013
Accepted 3 July 2013
Available online 8 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Chromene
Trifluoromethyl
Silyl enol ethers
Nucleophilic substitution
Lewis acid
1. Introduction
More recently, many substituted 2H-chromenes and isochromenes
have been synthesized through oxidative carbonehydrogen cleavage
Chromenes are considered to be one of the most imperative
heterocycle in nature because of their usefulness as biologically
active agents.1 In the last few years, much attention has been fo-
cused on the synthesis of chromene ring system,2 for their potential
application as antioxidant,3 antitubercular,4 anti-HIV,5 antitumor,6
cytotoxic agent,7 and antileishmanial.8 On the other hand, tri-
fluoromethylated compounds have been recognized as one of the
most potentially important and efficient probes in finding new
biologically compounds9 because of the unique role of the CF3
group in enhancing the bioactivity of organic molecules.10 Owing to
this, 2-(trifluoromethyl)-2-hydroxy-2H-chromenes have attracted
our attention to develop a new general and efficient method for the
preparation of a variety of 2H-chromene heterocycles with CF3
group.
by Floreancig group (Scheme 2).13
Scheme 1.
Laurent has reported the synthesis of substituted 2-
perfluoroalkyl-4H-chromenes with good yields in the presence of
SnCl4 (Scheme 1).11 Hiemstra synthesized 2-substituted chromenes
via ring-closing metathesis and stable 1-benzopyrylium ions.12
Scheme 2.
Our group has recently reported reactions of 2-(tri-
fluoromethyl)-2-hydroxy-2H-chromenes with indoles and thio-
phenols promoted by Lewis acid (Scheme 3-1).14,15 When indoles
were used as the nucleophile, only 2-substituted or 4-substituted
* Corresponding authors. E-mail address: zhusz@mail.sioc.ac.cn (S. Zhu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.004

7976
L. Zhang et al. / Tetrahedron 69 (2013) 7975e7980
products were obtained, while both 2-substituted and 4-
substituted products were isolated when the nucleophile was thi-
ophenols. Herein, we report the reaction of 2-(trifluoromethyl)-2-
hydroxy-2H-chromenes 1 with silyl enol ethers 2 affording a se-
ries of substituted 2-trifluoromethyl-4H-chromenes (Scheme 3-2).
According to Table 2, it was indicated that all these reactions
occurred exclusively at 4-position of the 2H-chromenes. It seems
that the C2 trifluoromethyl group due to its steric effect on the
chromenol ring hinders the nucleophile to attack silyl enol ethers 2.
The reaction occurred between 1d and 2a, which both contained
Previous work:
This work:
Scheme 3.
2. Results and discussion
In the previous studies, we have reported reactions of 2-(tri-
fluoromethyl)-2-hydroxy-2H-chromenes 1 with indoles and thio-
phenols, and found the nucleophilic substitution took place at 2-
position or 4-position of 1. In this regard, a model reaction be-
tween 1a (1 equiv) and silyl enol ether 2a (1.5 equiv) was examined
to optimize the reaction conditions (Table 1).
Table 1
Screening of the reaction conditions
It was found that no reaction took place without Lewis acids
(Table 1, entries 1 and 2). When the reaction was promoted by
SnCl4, only little product was detected by 19F NMR (Table 1, entries
3 and 4). After different Lewis acids were examined, AlCl3 was
found to act as a good promoter to give the product 3aa in 87% yield
(Table 1, entry 7). When the dosage of AlCl3 was changed, the yields
decreased (Table 1, entries 6 and 8). However, when the amount of
2a was decreased, a little lower yield of 3aa was found under the
same conditions (Table 1, entry 12). Other aprotic solvents, such as
CH3CN and THF were also examined (Table 1, entries 10 and 11).
Thus, the optimal reaction conditions for this reaction were
established: 1.5 equiv of 2a, 1.0 equiv of AlCl3, and performing the
reaction at room temperature in CH2Cl2.
Entry
Lewis acid
(equiv)
Solvent
Time (h)
Temp
Product
yielda
1
2
3
4
5
6
7
8
d
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
THF
48
48
10
30
5
10
3
3
rt
rt
d
d
d
SnCl4 (0.5)
SnCl4 (1.0)
BF3$OEt2 (1.0)
AlCl3 (0.5)
AlCl3 (1.0)
AlCl3 (1.5)
ZnCl2 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
AlCl3 (1.0)
ꢀ78 ꢁC to rt
Trace
10
Trace
47
87
80
23
54
7
78
ꢀ78 ꢁC to rt
0
ꢁC to rt
rt
rt
rt
rt
rt
rt
rt
9
5
To our surprise, the nucleophilic substitution only take place at
4-position of 1a. With the optimized reaction conditions on hand,
reactions of 2-(trifluoromethyl)-2-hydroxy-2H-chromenes with
other silyl enol ethers were further studied. The results were
summarized in Table 2.
10
11
12b
18
18
3
CH2Cl2
a
Isolated yields.
The mole ratio of 1a to 2a was 1:1.
b

L. Zhang et al. / Tetrahedron 69 (2013) 7975e7980
7977
Table 2
Reactions of 1 with 2 promoted by AlCl3 in CH2Cl2 at room temperature
Entry
1
2
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1b
1b
1b
1c
1c
1c
1d
1d
1d
1d
1e
1e
2a
2b
2c
2d
2a
2b
2c
2d
2a
2b
2d
2a
2b
2c
2d
2a
2b
3
3
5
3
3
3
5
3
3
3
3
3
3
5
3
10
10
3aa
3ab
3ac
3ad
3ba
3bb
3bc
3bd
3ca
3cb
3cd
3da
3db
3dc
3dd
3ea
3eb
87
85
63
83
83
57
34
62
38
29
33
89
82
77
81
n.r.
n.r.
9
10
11
12
13
14
15
16
17
n.r.¼no reaction.
a
Isolated yields.
electron-donating functional groups (X¼OCH3, R¼t-Bu), corre-
sponding 4-substituded chromene was obtained in a good yield
(Table 2, entry 12). However, when the electron-donating ability of
the group X was decreased, yield of the affording product was re-
duced accordingly (Table 2, entries 3, 7, and 14). What is more, once
a nitro group was introduced into the 2H-chromene, the reaction
could not proceed to produce the desired products (Table 2, entries
16 and 17). This is probably due to the strong electron-withdrawing
effect of the nitro group.
and followed by the attack of 2 to produce substituted 4H-chro-
menes 3. It is noted that the attack prefer to take place at 4-position
rather than at 2-position probably due to the combined action of
the steric hindrance of CF3 group and the effect of ester carbonyl
group in 2H-chromenes, which can explain why 4H-chromenes 3
are the exclusive products.
3. Conclusion
All new compounds were characterized by 1H, 13C, 19F NMR
spectroscopy and mass spectrometry. All of the data in the spectra
were in good accordance with the structures. The structure of
compound 3ca was also confirmed by X-ray crystallography (Fig. 1).
According to the related literature11 and previous research in
our group, the possible reaction mechanism is proposed in
Scheme 4. Initially, the hydroxy group of 1 is activated by AlCl3 to
form the intermediate A. Subsequently, an elimination of AlCl2Oꢀ
produces the oxonium intermediate B, which is attacked by silyl
enol ethers to form product 3. Because of the electron de-
localization of oxonium intermediate, the intermediate C is formed
In conclusion, we have developed an efficient and new nucle-
ophiles substitution reaction of 2-(trifluoromethyl)-2-hydroxy-2H-
chromenes 1 and the silyl enol ether 2 in heterocyclic systems
under mild conditions. It was found that the regioselective nucle-
ophilic attack occurred at 4-position of the 2H-chromenes pro-
moted by AlCl3. The possible mechanism of the reaction was also
discussed.
4. Experimental
4.1. General information
Commercial reagents were used without further purification. All
solvents used were dried and purified by distillation. Chromenes
1aed and silyl enol ethers 2aed were prepared according to the
literature of 2e and 16, accordingly. Melting points were measured
on a Temp-Melt apparatus and uncorrected. 1H NMR and 19F NMR
spectra were recorded on an Agilent AM-400 instrument with
Me4Si and CFCl3 as the internal standard, respectively. 13C NMR
spectra were recorded on an Agilent AM-400 instrument with
Me4Si and as the internal standard. FT-IR spectra were obtained
with a Nicolet AV-360 spectrophotometer. Mass spectra were ob-
tained on a Finnigan GCeMS 4021 or a Finnigan MAT8430 in-
strument. Single crystal X-ray structure analysis was performed on
a Bruker P4 instrument. All reactions were monitored by TLC or 19F
NMR.
Fig. 1. The structure of compound 3ca.

7978
L. Zhang et al. / Tetrahedron 69 (2013) 7975e7980
Scheme 4. The possible mechanism for the formation of 4-substituted products 3.
4.2. Typical procedure for the reaction of ethyl 2-hydroxy-2-
(trifluoromethyl)-2H-chromene-3-carboxylate (1a) with silyl
enol ether (2a) in the presence of AlCl3 in CH2Cl2
1587, 1490, 1459, 1377, 1299, 1227, 1198, 1161, 1112, 1088, 1039,
759 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
1.29 (t, J¼7.2 Hz, 3H), 2.08 (s,
3H), 2.75 (q, J¼7.6 Hz, 1H), 2.80 (q, J¼4.4 Hz, 1H), 4.23 (q, J¼7.2 Hz,
2H), 4.35e4.36 (m,1H), 7.04e7.12 (m, 2H), 7.22 (d, J¼6.4 Hz, 2H). 13C
To a stirred solution of chromene (1a, 288 mg, 1 mmol) and
anhydrous aluminum chloride (133 mg, 1 mmol) in anhydrous
dichloromethane (12 mL) under nitrogen was added silyl enol ether
(2a, 258 mg, 1.5 mmol) at room temperature. At the end of the
reaction as judged by 19F NMR spectroscopy or TLC, the mixture
was diluted with water (10 mL), quenched carefully with a solution
of sodium bicarbonate (15 mL), and then extracted with dichloro-
methane (3ꢂ20 mL). The organic layers were washed with brine
(2ꢂ20 mL). Then the organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo. The crude products were
chromatographed over silica gel using an eluent of ethyl acetate/
petroleum ether (1:20) to afford the desired chromene.
NMR (100 MHz, CDCl3): d 13.7, 30.4, 31.9, 51.6, 61.9, 113.4, 114.9 (q,
1JCeF¼273 Hz, CF3), 116.5, 123.0, 125.5, 128.4, 128.5, 141.8 (q,
2JCeF¼37 Hz, CF3), 149.8, 165.2, 205.2. 19F NMR (376 MHz, CDCl3):
d
ꢀ67.4 (s, 3F, CF3). MS (ESI): m/z¼351.1 (MþNa)þ. HRMS (ESI): m/z
calcd for (C16H15F3O4þNa)þ: 351.0820; found: 351.0814.
4.2.4. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxocyclohexyl)-
4H-chromene (3ad). Yield 83%, yellow oil. IR (KBr): 2938, 2866,
1731, 1712, 1585, 1487, 1459, 1379, 1299, 1235, 1197, 1149, 1112, 1085,
994, 760 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
1.31 (t, J¼7.2 Hz, 3H),
1.33e1.45 (m, 2H), 1.62e1.84 (m, 2H), 1.95e2.02 (m, 2H), 2.23e2.35
(m, 1H), 2.41e2.47 (m, 1H), 2.82e2.88 (m, 1H), 4.21 (q, J¼7.2 Hz,
2H), 4.72 (s, 1H), 6.34 (d, J¼10.8 Hz, 1H), 7.26 (q, J¼10.4 Hz, 1H), 7.23
(t, J¼10.0 Hz,1H), 7.41 (d, J¼11.2 Hz,1H). 13C NMR (100 MHz, CDCl3):
4.2.1. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(3,3-dimethyl-2-
oxobutyl)-4H-chromene (3aa). Yield 87%, yellow oil. IR (KBr): 2973,
1734, 1710, 1489, 1479, 1460, 1377, 1300, 1232, 1197, 1150, 1111, 1087,
d
13.7, 24.7, 26.3, 26.9, 34.9, 41.8, 56.0, 61.9, 113.1, 116.0, 119.1 (q,
1JCeF¼273 Hz, CF3), 120.8, 125.4, 128.3, 130.1, 143.5 (q, 2JCeF¼37 Hz,
1034, 759 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.99 (s, 9H), 1.29 (t,
CF3), 151.3, 165.4, 209.5. 19F NMR (376 MHz, CDCl3):
d
ꢀ67.5 (s, 3F,
J¼7.2 Hz, 3H), 2.85e3.00 (m, 2H), 4.23 (q, J¼7.2 Hz, 2H), 4.36e4.39
CF3). MS (ESI): m/z¼391.0 (MþNa)þ. HRMS (ESI): m/z calcd for
(C19H19F3O4þNa)þ: 391.1133; found: 391.1128.
(m, 1H), 7.05e7.10 (m, 2H), 7.17e7.26 (m, 2H). 13C NMR (100 MHz,
CDCl3):
d 13.8, 25.8, 32.2, 44.2, 45.2, 61.9, 114.0, 115.0 (q,
1JCeF¼271 Hz, CF3), 116.4, 123.4, 125.3, 128.2, 128.5, 142.0 (q,
4.2.5. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(3,3-dimethyl-2-
oxobutyl)-6-chloro-4H-chromene (3ba). Yield 83%, yellow oil. IR
(KBr): 2971, 1735, 1710, 1480, 1373, 1307, 1236, 1198, 1152, 1119,
2JCeF¼37 Hz, CF3), 150.0, 165.2, 212.4. 19F NMR (376 MHz, CDCl3):
d
ꢀ67.3 (s, 3F, CF3). MS (ESI): m/z¼393.2 (MþNa)þ. HRMS (ESI): m/z
calcd for (C19H21F3O4þNa)þ: 393.1290; found: 393.1284.
1080, 998, 819 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 1.23 (s, 9H), 1.29
(t, J¼7.2 Hz, 3H), 2.85e3.02 (m, 2H), 4.23 (q, J¼7.2 Hz, 2H),
4.2.2. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxo-2-
phenylethyl)-4H-chromene (3ab). Yield 85%, yellow oil. IR (KBr):
1732, 1686, 1586, 1489, 1449, 1377, 1292, 1226, 1197, 1163, 1111, 1085,
4.32e4.25 (m, 1H), 6.99e7.02 (m, 1H), 7.17e7.19 (m, 2H). 13C NMR
(100 MHz, CDCl3):
d 13.8, 25.9, 32.0, 44.1, 45.0, 62.0, 113.6, 114.8 (q,
1JCeF¼271 Hz, CF3), 117.8, 125.0, 128.2, 128.4, 130.3, 141.8 (q,
1002, 757, 689 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
1.27 (t, J¼7.2 Hz,
2JCeF¼37 Hz, CF3), 148.4, 164.9, 212.2. 19F NMR (376 MHz, CDCl3):
3H), 3.30e3.39 (m, 1H), 3.54e3.61 (m, 1H), 4.22 (q, J¼7.2 Hz, 2H),
4.58e4.61 (m, 1H), 7.06e7.11 (m, 2H), 7.20e7.30 (m, 2H), 7.44 (t,
J¼10.0 Hz, 2H), 7.53 (t, J¼10.0 Hz,1H), 7.91 (d, J¼10.0 Hz, 2H).13C NMR
d
ꢀ67.3 (s, 3F, CF3). MS (ESI): m/z¼427.2 (MþNa)þ. HRMS (ESI): m/z
calcd for (C19H20ClF3O4þNa)þ: 427.0900; found: 427.0894.
(100 MHz, CDCl3):
d
13.7, 32.4, 47.2, 62.0, 113.8, 116.5, 119.1 (q,
4.2.6. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxo-2-phenyleth-
yl)-6-chloro-4H-chromene (3bb). Yield 57%, yellow solid, mp
108e110 ꢁC. IR (KBr): 1740, 1690, 1487, 1377, 1277, 1244, 1229, 1198,
1JCeF¼271 Hz, CF3),123.2,125.5,128.1,128.4,128.6,128.7,133.4,136.6,
2
142.8 (q, JCeF¼37 Hz, CF3), 150.0, 165.3, 196.8. 19F NMR (376 MHz,
CDCl3):
d
ꢀ67.6 (s, 3F, CF3). MS (ESI): m/z¼413.1 (MþNa)þ. HRMS
1141,1079,1003, 830, 760 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 1.25 (t,
(ESI): m/z calcd for (C21H17F3O4þNa)þ: 413.0977; found: 413.0971.
J¼7.2 Hz, 3H), 3.32 (q, J¼7.2 Hz, 1H), 3.55 (q, J¼4.0 Hz, 1H), 4.22 (q,
J¼7.2 Hz, 2H), 4.55 (m, 1H), 7.00 (d, J¼8.8 Hz, 1H), 7.16 (q, J¼2.4 Hz,
1H), 7.30 (d, J¼2.4 Hz, 1H), 7.43 (t, J¼8.0 Hz, 2H), 7.54 (t, J¼7.6 Hz,
4.2.3. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxopropyl)-4H-
chromene (3ac). Yield 63%, yellow oil. IR (KBr): 2983, 2926, 1725,
1H), 7.90 (d, J¼7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d 13.7, 32.0,

L. Zhang et al. / Tetrahedron 69 (2013) 7975e7980
7979
1
46.8, 62.1, 113.4, 114.8 (q, JCeF¼273 Hz, CF3), 117.9, 124.8, 128.1,
J¼7.2 Hz, 2H), 4.68 (s, 1H), 7.30 (d, J¼2.4 Hz, 1H), 7.37 (d, 2.4 Hz, 1H).
2
128.5, 128.7, 130.4, 133.5, 136.3, 142.1 (q, JCeF¼37 Hz, CF3), 148.5,
13C NMR (100 MHz, CDCl3):
d
13.7, 24.7, 26.4, 27.0, 35.4, 41.8, 55.7,
164.9, 196.3. 19F NMR (376 MHz, CDCl3):
d
ꢀ67.2 (s, 3F, CF3). MS
62.2, 113.6, 114.7 (q, JCeF¼273 Hz, CF3), 122.7, 123.9, 128.4, 129.0,
1
(ESI): m/z¼447.0 (MþNa)þ. HRMS (ESI): m/z calcd for
(C21H16ClF3O4þNa)þ: 447.0587; found: 447.0581.
130.3, 142.9 (q, JCeF¼37 Hz, CF3), 146.0, 164.6, 209.0. 19F NMR
2
(376 MHz, CDCl3):
d
ꢀ66.9 (s, 3F, CF3). MS (ESI): m/z¼459.1
(MþNa)þ. HRMS (ESI): m/z calcd for (C19H17Cl2F3O4þNa)þ:
4.2.7. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxopropyl)-6-
chloro-4H-chromene (3bc). Yield 34%, yellow oil. IR (KBr): 2983,
2920, 1726, 1483, 1374, 1307, 1244, 1199, 1162, 1082, 1032, 814,
459.0354; found: 459.0348.
4.2.12. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(3,3-dimethyl-2-
oxobutyl)-6-methoxy-4H-chromene (3da). Yield 89%, yellow oil. IR
(KBr): 2967, 1710, 1499, 1466, 1397, 1375, 1307, 1265, 1213, 1151, 1088,
732 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
1.29 (t, J¼7.2 Hz, 3H), 2.11 (s,
3H), 2.77 (q, J¼7.2 Hz, 1H), 3.03 (q, J¼4.0 Hz, 1H), 4.23 (q, J¼7.2 Hz,
2H), 4.30e4.32 (m,1H), 6.99 (d, J¼8.4 Hz,1H), 7.17e7.24 (m, 2H). 13C
1036, 738 cmꢀ1 1H NMR (400 MHz, CDCl3):
. d 1.00 (s, 9H), 1.28 (t,
NMR (100 MHz, CDCl3):
d
13.7, 30.3, 31.6, 51.3, 62.1, 113.1, 114.8 (q,
J¼7.2 Hz, 3H), 2.85e2.99 (m, 2H), 3.72 (s, 3H), 4.21 (q, J¼7.2 Hz, 2H),
1JCeF¼273 Hz, CF3), 117.9, 124.7, 128.3, 128.5, 130.4, 142.1 (q,
4.34e4.36(m,1H), 6.66(d, J¼2.8 Hz,1H), 6.72 (d, J¼2.8 Hz,1H), 6.96(d,
2JCeF¼37 Hz, CF3), 148.4, 164.9, 204.8. 19F NMR (376 MHz, CDCl3):
J¼9.2 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d 13.8, 25.9, 32.5, 44.2, 55.7,
d
ꢀ67.4 (s, 3F, CF3). MS (ESI): m/z¼385.2 (MþNa)þ. HRMS (ESI): m/z
61.8, 112.1, 112.8, 114.5, 114.9 (q, 1JCeF¼271 Hz, CF3), 117.3, 124.2, 142.4
calcd for (C16H13ClF3O4þNa)þ: 385.0430; found: 385.0425.
(q, JCeF¼37 Hz, CF3), 143.8, 156.8, 165.3, 212.6. 19F NMR (376 MHz,
2
CDCl3):
d
ꢀ67.2 (s, 3F, CF3). MS (ESI): m/z¼423.1 (MþNa)þ. HRMS(ESI):
4.2.8. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxocyclohexyl)-6-
chloro-4H-chromene (3bd). Yield 62%, yellow oil. IR (KBr): 2938,
2858, 1712, 1480, 1450, 1374, 1351, 1307, 1238, 1199, 1151, 1083, 997,
m/z calcd for (C20H23F3O5þNa)þ: 423.1395; found: 423.1390.
4.2.13. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxo-2-pheny-
lethyl)-6-methoxy-4H-chromene (3db). Yield 82%, yellow solid, mp
53e55 ꢁC. IR (KBr): 2932, 1732, 1688, 1500, 1444, 1375, 1308, 1242,
818, 740 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d
0.91 (m, J¼3.6 Hz, 1H),
1.28 (t, J¼7.2 Hz, 3H), 1.46e1.53 (m, 1H), 1.60e1.66 (m, 1H),
1.82e1.85 (m, 1H), 1.92e2.00 (m, 2H), 2.24e2.33 (m, 1H), 2.44e2.47
(m, 1H), 2.82 (m, 1H), 4.24 (q, J¼7.2 Hz, 2H), 4.67 (s, 1H), 6.96 (d,
J¼8.8 Hz, 1H), 7.17 (q, J¼2.4 Hz, 1H), 7.43 (d, J¼2.4 Hz, 1H). 13C NMR
1217, 1151, 1087, 1032, 689 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 1.25
(t, J¼7.2 Hz, 3H), 3.31 (q, J¼8.0 Hz,1H), 3.54 (q, J¼4.0 Hz,1H), 3.72 (s,
3H), 4.22 (q, J¼7.2 Hz, 2H), 4.56e4.57 (m, 1H), 6.73 (m, 2H), 6.99 (d,
J¼8.8 Hz, 1H), 7.42 (t, J¼7.2 Hz, 2H), 7.53 (t, J¼7.2 Hz, 1H), 7.90 (d,
(100 MHz, CDCl3): d 13.7, 24.7, 26.4, 26.8, 34.9, 41.8, 55.8, 62.0, 112.7,
114.8 (q, 1JCeF¼273 Hz, CF3),117.4,122.5,128.4,129.8,130.4,142.9 (q,
J¼7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d 13.7, 32.6, 47.2, 55.6,
61.9, 112.5, 114.5, 115.0 (q, JCeF¼273 Hz, CF3), 117.4, 123.9, 128.1,
2JCeF¼37 Hz, CF3), 149.8, 165.1, 209.3. 19F NMR (376 MHz, CDCl3):
1
2
d
ꢀ67.2 (s, 3F, CF3). MS (ESI): m/z¼425.1 (MþNa)þ. HRMS (ESI): m/z
128.6, 133.4, 136.5, 142.7 (q, JCeF¼37 Hz, CF3), 156.9, 165.4, 196.9.
calcd for (C19H18ClF3O4þNa)þ: 425.0743; found: 425.0738.
19F NMR (376 MHz, CDCl3):
d
ꢀ67.1 (s, 3F, CF3). MS (ESI): m/z¼443.1
(MþNa)þ. HRMS (ESI): m/z calcd for (C22H19F3O5þNa)þ: 443.1082;
4.2.9. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(3,3-dimethyl-2-
oxobutyl)-6,8-dichloro-4H-chromene (3ca). Yield 38%, yellow solid,
mp 93e94 ꢁC. IR (KBr): 2978, 1723, 1703, 1574, 1458, 1375, 1309,
found: 443.1077.
4.2.14. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxopropyl)-6-
methoxy-4H-chromene (3dc). Yield 77%, yellow oil. IR (KBr): 2937,
1244, 1197, 1165, 1090, 1016, 872, 775 cmꢀ1 1H NMR (400 MHz,
.
CDCl3):
d
1.04 (s, 9H), 1.29 (t, J¼7.2 Hz, 3H), 2.84e3.03 (m, 2H), 4.24
1727, 1500, 1467, 1436, 1375, 1308, 1215, 1151, 1088, 1035, 817 cmꢀ1
.
(q, J¼7.2 Hz, 2H), 4.35e4.37 (m, 1H), 7.10 (d, J¼3.2 Hz, 1H), 7.28 (d,
1H NMR (400 MHz, CDCl3):
d
1.29 (t, J¼7.2 Hz, 3H), 2.09 (s, 3H), 2.76
J¼2.4 Hz, 1H). 13C NMR (100 MHz, CDCl3):
d
13.7, 25.9, 32.5, 44.1,
(q, J¼7.6 Hz, 1H), 3.02 (q, J¼4.0 Hz, 1H), 3.76 (s, 3H), 4.22 (q,
1
44.9, 62.2, 114.5, 114.5 (q, JCeF¼271 Hz, CF3), 122.9, 126.4, 126.7,
J¼7.2 Hz, 2H), 4.33 (m, 1H), 6.75 (d, J¼7.6 Hz, 2H), 6.98 (d, J¼8.4 Hz,
128.8, 130.2, 141.8 (q, 2JCeF¼37 Hz, CF3), 144.8, 164.4, 211.8. 19F NMR
1H). 13C NMR (100 MHz, CDCl3):
d 13.7, 30.4, 32.2, 51.6, 55.7, 61.9,
(376 MHz, CDCl3):
d
ꢀ67.1 (s, 3F, CF3). MS (ESI): m/z¼461.1
112.2, 112.3114.5, 115.0 (q, 1JCeF¼273 Hz, CF3), 117.4, 123.9, 142.3 (q,
(MþNa)þ. HRMS (ESI): m/z calcd for (C19H19Cl2F3O4þNa)þ:
2JCeF¼37 Hz, CF3), 143.7, 157.0, 165.3, 205.4. 19F NMR (376 MHz,
461.0510; found: 461.0505.
CDCl3):
d
ꢀ67.2 (s, 3F, CF3). MS (ESI): m/z¼381.1 (MþNa)þ. HRMS
(ESI): m/z calcd for (C17H17F3O5þNa)þ: 381.0926; found: 381.0920.
4.2.10. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxo-2-phenylet-
hyl)-6,8-dichloro-4H-chromene (3cb). Yield 29%, yellow solid, mp
74e75 ꢁC. IR (KBr): 1729, 1682, 1598, 1456, 1360, 1307, 1266, 1242,
4.2.15. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxocyclohexyl)-
6-methoxy-4H-chromene (3dd). Yield 81%, yellow solid, mp
79e81ꢁC. IR (KBr): 2940,1719,1705,1500,1317,1294,1244,1212,1191,
1202, 1168, 1086, 1011, 978, 862, 780, 756, 692 cmꢀ1 1H NMR
.
(400 MHz, CDCl3):
d
1.26 (t, J¼7.2 Hz, 3H), 3.32 (q, J¼7.2 Hz, 1H),
1153, 1136, 1088, 885, 820 cmꢀ1. 1H NMR (400 MHz, CDCl3):
d 0.90 (q,
3.54 (q, J¼4.0 Hz, 1H), 4.23 (q, J¼7.2 Hz, 2H), 4.57e4.58 (m, 1H), 7.25
J¼10.4 Hz, 1H), 1.28 (t, J¼7.2 Hz, 3H),1.43e1.46 (m, 1H), 1.63e1.67 (m,
2H), 1.79e1.82 (m, 1H), 1.91e1.99 (m, 2H), 2.24e2.32 (m, 1H),
2.41e2.45 (m, 1H), 2.81e2.86 (m, 1H), 3.76 (s, 3H), 4.22 (q, J¼7.2 Hz,
2H), 4.68 (s,1H), 6.74 (d, J¼8.8 Hz,1H), 6.94 (d, J¼6.4 Hz, 2H).13C NMR
(q, J¼2.0 Hz, 2H), 7.44 (t, J¼6.8 Hz, 2H), 7.56 (t, J¼6.8 Hz,1H), 7.89 (d,
J¼8.4 Hz, 2H). 13C NMR (100 MHz, CDCl3):
d 13.7, 32.6, 46.6, 62.3,
114.4, 114.7 (q, 1JCeF¼273 Hz, CF3), 116.5, 123.0, 125.9, 126.3, 127.0,
2
128.1, 128.8, 129.0, 130.3, 133.6, 136.3, 142.2 (q, JCeF¼37 Hz, CF3),
(100 MHz, CDCl3): d 13.7, 24.7, 26.4, 26.7, 35.2, 41.8, 55.7, 56.0, 61.8,
145.0, 164.5, 196.0. 19F NMR (376 MHz, CDCl3):
d
ꢀ67.0 (s, 3F, CF3).
111.7, 113.6, 114.6, 115.0 (q, 1JCeF¼273 Hz, CF3), 116.9, 121.5, 143.6 (q,
MS (ESI): m/z¼457.0 (MꢀH)ꢀ. HRMS (ESI): m/z calcd for
(C21H14Cl2F3O4þNa)þ: 457.0221; found: 457.0223.
2JCeF¼37 Hz, CF3), 145.3, 156.9, 165.5, 209.8. 19F NMR (376 MHz,
CDCl3):
d
ꢀ67.0(s, 3F, CF3). MS (ESI): m/z¼421.1 (MþNa)þ. HRMS(ESI):
m/z calcd for (C20H21F3O5þNa)þ: 421.1240; found: 421.1233.
4.2.11. 2-(Trifluoromethyl)-3-ethoxycarbonyl-4-(2-oxocyclohexyl)-
6,8-dichloro-4H-chromene (3cd). Yield 33%, yellow solid, mp
82e83 ꢁC. IR (KBr): 2932, 1724, 1705, 1575, 1461, 1373, 1309, 1256,
Acknowledgements
1240, 1198, 1166, 1091, 1004, 870, 787 cmꢀ1
.
1H NMR (400 MHz,
Financial support for this project was provided by The National
Natural Science Foundation of China (NNSFC, Nos. 21032006
and 21102163) and National Basic Research Program (No.
2007CB80800).
CDCl3):
d
0.95 (m, J¼3.6 Hz, 1H), 1.29 (t, J¼7.2 Hz, 3H), 1.47e1.54 (m,
1H), 1.60e1.67 (m, 1H), 1.85e1.88 (m, 1H), 1.93e2.03 (m, 2H),
2.25e2.34 (m, 1H), 2.45e2.48 (m, 1H), 2.82e2.87 (m, 1H), 4.25 (q,

7980
L. Zhang et al. / Tetrahedron 69 (2013) 7975e7980
5. (a) Bhavsar, D.; Trivedi, J.; Parekh, S.; Savant, M.; Thakrar, S.; Bavishi, A.; Radadiya,
Supplementary data
A.; Vala, H.; Lunagariya, J.; Parmar, M.; Paresh, L.; Loddo, R.; Shah, A. Bioorg. Med.
Chem. Lett. 2011, 3443e3446; (b) Park, J. H.; Lee, S. U.; Kim, S. H.; Shin, S. Y.; Lee, J.
Y.; Shin, C. G.; Yoo, K. H.; Lee, Y. S. Arch. Pharm. Res. 2008, 31, 1e5.
6. Huang, W.; Ding, Y.; Miao, Y.; Liu, M. Z.; Li, Y.; Yang, G. F. Eur. J. Med. Chem. 2009,
44, 3687e3696.
7. (a) Raj, T.; Bhatia, R. K.; Kapur, A.; Sharma, M.; Saxena, A. K.; Ishar, M. P. S. Eur. J.
Med. Chem. 2010, 45, 790e794; (b) Sabry, N. M.; Mohamed, H. M.; Shawky, E.;
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765e772.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.07.004.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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