A mild and fast continuous-flow trifluoromethylation of coumarins with the CF3 radical derived from CF3SO2Na and TBHP

Article abstract of DOI:10.1039/c5ob01516b

A mild and fast Cu(i)-catalyzed trifluoromethylation of coumarins with CF₃SO₂Na and TBHP in a continuous-flow reactor has been developed. This method is experimentally simple and carried out under mild conditions, affording the corresponding products in moderate to good yields, and showing wide substrate tolerance. The scale-up flow process results in an isolated yield of 68% and a productivity of 305 mg h^-1 of 3-trifluoromethyl-7-diethylamino-4-methyl coumarin when the concentration was increased five-fold. Given these features and the widespread applications of coumarins, this method may find use from laboratory to manufacturing.

Full text of DOI:10.1039/c5ob01516b

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DOI: 10.1039/C5OB01516B
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A mild and fast continuous-flow trifluoromethylation of
coumarins with CF3 radical derived from CF3SO2Na and TBHP
Received 00th January 20xx,
Accepted 00th January 20xx
Xiaodan Zhang, Ping Huang, Yaming Li† and Chunying Duan
A mild and fast Cu(I)-catalyzed trifluoromethylation of coumarins with CF3SO2Na and TBHP in continuous-flow reactor has
been developed. This method is experimentally simple and carried out at mild condition, affording corresponding products
in moderate to good yields, and showing wide substrate tolerance. The scale-up flow process results in an isolated yield of
68% and a productivity of 305 mg/h of 3-trifluoromethyl-7-diethylamino-4-methyl coumarin when concentration was
magnified five-fold. Given these features and the widespread applications of coumarin, this method may find use from
laboratory to manufacturing.
DOI: 10.1039/x0xx00000x
www.rsc.org/
straightforward method of Mn(OAc)3 mediate
Introduction
Coumarin derivates represent a vast family of compounds which are
mostly extracted and isolated from traditional Chinese herbs1. It has
arisen as promising and valuable natural products with significant
and high biological activities2, such as anti-inflammatory3, anti-
oxidant3b, 4, anti-coagulants5. Meanwhile, coumarin is also very
suitable to act as fluorescent chromospheres, and have been widely
utilized in photosensitive polymeric materials6, laser7, and
fluorescent probe for metal ion8.
The trifluoromethyl group is highly electron withdrawing, and its
introduction can remarkably improve molecular properties9.
Trifluoromethylation has recently been adopted as a tool for
improving
the
desired
molecular
characteristics.
The
trifluoromethyl group is becoming an increasingly versatile
component and common trait among molecules found in
pharmaceuticals, agrochemicals, dyes, polymers and organic
materials10. Trifluoromethyl radical generated from the inexpensive
Langlois reagent (CF3SO2Na) and its partner tert-butyl
hydroperoxide
(THBP)
is
a
popular
approach
for
Trifluoromethylation10c, 11
.
α, β-unsaturated carbonyls that contain an electron-deficient
carbon-carbon double bond are not only versatile synthetic
intermediates but also a structural motif in biologically active
molecules12. Recently Bi13 has developed the first general,
regioselective C-H α-trifluoromethylation of α, β-unsaturated
carbonyl compounds, and this reaction allowed diverse substrates
(Scheme 1). In 2013, Wang14 has developed a copper-catalytic
trifluoromethylation of quinone. Coumarin compounds contain
α, β-Unsaturated carbonyl subunit, Dmowski15 reported
preparation of 3-trifluoromethyl-coumarin with 3-carboxylic
acid coumarin and sulfur tetrafluoride. In 2013, Zou16 reported a
Scheme 1 Syntheses of unsaturated α-trifluoromethyl ketones and 3-
trifluoromethyl coumarins
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian
116024, China. Tel./fax: +86-411-84986295; E-mail: ymli@dlut.edu.cn (Y. Li)
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
trifluoromethylation by coumarins with CF3SO2Na.
Continuous flow reaction has attracted much attention of
industry and academia for safety and sustainability17. Recent
studies have demonstrated that economic savings can be realized
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for certain cases by transforming a batch reaction into a continuous
Journal Name
With optimized batch conditions in hand, a continuous-flow
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process. Herein, we report a mild and fast method for Cu(I)- microreactor was assembled as described iDnOsIc:h1e0m.10e392/(Ca5).OIBn0it1i5a1l6lyB,
catalyzed trifluoromethylation of coumarin by using CF3SO2Na-TBHP we investigated the amount of CF3SO2Na on the reaction in
partners in continuous-flow system.
continuous-flow system, keeping reaction time 60 min at a flow
rate of 66 μL/min (reactor volume 4 mL, reaction time 60 min).
With 2 equiv of CF3SO2Na, the yield of 2a achieved to 66%, further
with 4 equiv of CF3SO2Na, the yield of 2a increased slightly to 70%
(Scheme 2(b)). Therefore, 2 equiv of CF3SO2Na was applied in the
following experiments considering the cost of CF3SO2Na. However,
in batch it must take 4 equiv of CF3SO2Na and react 6 h to achieve
65% yield of 2a. Subsequently, exploration of amount of TBHP on
this reaction showed that 4 equiv of TBHP gave the highest yield of
trifluoromethylation (Scheme 2(c)).
Results and discussion
Initially, trifluoromethylation of coumarin (1a) with CF3SO2Na was
selected as the model to screen the reaction parameters in batch
(Table 1). Firstly, CuCl2 as catalyst gave 3-trifluoromethyl coumarin
(2a) in 30% GC yield (entry 1). Next, when CuI, CuSCN or CuCl was
used as catalyst, the yields of product rose to 38%, 45% and 65%
respectively (entries 2-4). Screening copper catalysts revealed that
CuCl could promote the yield in the case of DMSO as solvent, then
several solvents were investigated. For the better dissolution of
CF3SO2Na, a solvent mixture DMSO/H2O was examined. However,
the yields of 2a dropped from 45% to 35% as the proportion of
DMSO to water decreased from 2︰1 to 1︰1 (entries 5 and 6), the
DCM and H2O mixture also gave poor yield (13%, entry 7). Other
solvents MeOH, THF, DMF and acetone, failed to lead a better
conversion as well (entries 8-12). With CuCl catalyst and DMSO
solvent, the yield of 2a still kept 65% while shortening time to 6 h
(entry 13). If further shortening time to 2 h, the yield would
decrease to 52% (entry 14). When 2 equiv of CF3SO2Na was applied,
the trifluoromethylation reaction only gave 34% yield (entry 15).
Finally, when carrying this reaction at 120 °C, there is no benefit
effect on 2a (59%, entry 16).
a
b
c
Table 1 Optimization of the reaction conditions in batcha
Entry Catalysis
Solvent
Time (h) Yieldb(%)
Scheme
2
Optimization of the amounts of CF3SO2Na and TBHP in
1
2
CuCl2
CuI
DMSO
24
24
24
24
24
24
24
24
24
24
24
24
6
30
38
45
65
45
35
13
53
10
21
15
22
65
52
34
59
continuous-flow reactor. Reaction conditions: coumarin (0.1 mmol), CuCl
(0.02 mmol), flow rate (66 μL/min, 60 min), yields were determined by GC
analysis using n-dodecane as an internal standard. (a) Schematic diagram of
trifluoromethylation of coumarin in continuous-flow reactor. (b) The yields
of 2a vs 0.1, 0.2, 0.3 and 0.4 mmol of CF3SO2Na, TBHP 70% in water (0.6
mmol); (c) The yields of 2a vs 0.1, 0.2, 0.4 and 0.8 mmol of TBHP 70% in
water, CF3SO2Na (0.2 mmol).
DMSO
3
CuSCN
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
DMSO
4
DMSO
5
DMSO∶H2O（2∶1）
6
DMSO∶H2O（1∶1）
7
DCM∶H2O（2∶1）
CH3CN
8
9
MeOH
Due to the high surface-to-volume ratio of microreactor, heat
transfer and mass transfer take place rapidly18. Hence, we hope to
further optimize the flow rate (reaction time) and temperature in
continuous-flow reactor. The results showed that there are no big
differences of 2a yields (about 68%) when reaction carried out at
60 °C or at 80 °C. The yield decreased significantly while the
temperature went down to 40 °C (Scheme 3). On the other hand,
the yields of 2a increased from 48% to 68% as the flow rate
decreased from 400 to 100 μL/min (reaction time ranged from 10 to
40 min) under either 60 °C or 80 °C. Further decreasing the flow
rate to 80 even 66 μL/min，the yields of 2a kept around 68%
(extending reaction time to 50 or 60 min). Finally, we established
the optimal reaction conditions: using 2 equiv of CF3SO2Na, the
trifluoromethylation of coumarin was performed at flow rate 100
μL/min, and reacted at 60 °C for 40 min in continuous-flow reactor.
10
11
12
13
14
15c
16d
THF
DMF
acetone
DMSO
DMSO
2
DMSO
6
DMSO
6
a Reaction Conditions: coumarin (1a, 0.1 mmol), CF3SO2Na (0.4 mmol), Cu
salt (0.02 mmol), TBHP 70% in water (0.6 mmol) , Solvent (1.5 mL) at 80 °C
under air, Reaction time (24 h). b Yields are determined by GC analysis
using n-dodecane as an internal standard.c CF3SO2Na (0.2 mmol).
d
Temperature 120 °C.
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Having optimized the reaction conditions in hand, we next
investigated the substrate scope of series of substituted
coumarins with a continuous-flow reactor. As shown in Table 2,
both electron-rich and electron-deficient function group at
coumarins could be tolerated. Alkyl-substituted coumarins provided
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a
DOI: 10.1039/C5OB01516B
(39%, 2i). Since 4-phenyl-coumarins as the family members of
coumarin derivates are widely distributed in natural products and
biological studies19, the 3-trifluoromethyl-4-phenyl-coumarin 2j was
obtained in moderate yield of 50%. The 3-trifluoromethyl-7-
diethylamino-4-methyl coumarin derivate afforded to a higher yield
of 71% (2k).
80
70
60
40 °C
50
60 °C
80 °C
40
30
400/10 200/20 133/30 100/40 80/50
60/66
flow rate (μL/min) / time (min)
Scheme
3 Optimization of the flow rate (reaction time) and
temperature in continuous-flow reactor. Reaction conditions:
coumarin (0.1 mmol), CuCl (0.02 mmol), CF3SO2Na (0.2 mmol), TBHP
70% in water (0.4 mmol), yields were determined by GC analysis using
n-dodecane as an internal standard.
Scheme 4 Proposed mechanism for coumarin trifloromethylation
Based on our experiment and others work11, 13, 14, 20, a plausible
mechanism (Scheme 4) for synthesis of 3-trifluoromethyl-coumarin
was proposed. Firstly, CF3SO2Na was reduced by Cu(I) to generate a
CF3 radical via a single-electron-transfer process, with oxidation of
Cu(I) to Cu(II). Then the CF3 radical attacked the α-position of
coumarin (A) so that the more stable free radical intermediate (B)
was formed. Afterwards the electron at C4-position of the
carbocation intermediate (B) was oxidized by Cu(II), with reduction
of Cu(II) to Cu(I). After that, the carbocation intermediate (C) was
produced via another single-electron-transfer process. Finally 3-
target products in moderate yields (56-66%, 2b-2d), among these,
tert-butyl coumarin (2e) was better than methyl- coumarins. Good
yields could be also obtained with 7-methoxyl substituted
derivative, giving a relatively higher 63% yield (2f). In the case of a
weak electron-withdrawing groups acetoxyl or bromo- at the 6-
position, moderate yields of 59% and 55% were obtained
respectively (2g and 2h). However, the strongly electron-
withdrawing group nitro- at the 6-position afforded a poor yield
Table 2 Substrate scope of trifluoromethyl coumarina
trifluoromethyl-coumarin (D) was obtained in
deprotonation.
a process of
Scheme 5 Procedure for scale-up trifluoromethlation reaction of 7-
diethylamino-4-methyl coumarin
In order to investigate the applicability of this trifluoromethyl
reaction on an industrial scale beyond laboratory scale, the
developed gram-scale procedure was scaled–up (scheme 5). The 7-
diethylamino-4-methyl coumarin derivate is highly fluorescent,
which makes this fluorophore attractive for use in biological studies,
and 7-diethylamino-4-methyl coumarin derivative has aslo been
incorporated into ligands used for studies of γ-aminobutyric acid
type A (GABAA)21 receptors. The 7-diethylamino-4-methyl coumarin
(6 mmol，1.386 g) was carried out as scale-up experiment using
the optimized conditions at 100 μL/min flow rate in continuous-flow
aReaction Conditions: coumarin (0.4 mmol), CF3SO2Na, 0.8 mmol), CuCl (0.08
mmol) as the catalyst, TBHP 70% in water (1.6 mmol).
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sample loop 1. The other 1 mL sample loop 2 was loaded with a
system. The scale-up flow process was run continuously for 240 min
to obtain 1.22 g of 2k， 68 % yield when the concentration was
magnified five-fold (0.5 M) than the optimization condition (0.1 M) .
This corresponds to a product output of 305 mg/h.
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solution 2 of TBHP (70% in water) in 1 mL DMSO. The valves of the
DOI: 10.1039/C5OB01516B
both loops were set to load and the reagents pumped through the
system using DMSO as a system solvent at a given same flow rate.
The reagents were combined in a Y-tape mixer before entering a 4
mL convection flow coil (CFC) reactor (1/32 inner diameter), which
was maintained at given temperature. The product stream exiting
the reactor was collected into a test tube, diluted with deionized
water, and extracted with ethyl acetate, analyzed by GC using n-
dodecane as an internal standard.
Conclusion
In conclusion, we have developed a fast and mild conversion of
coumarin to 3-trifluoromethy-coumarin in the continuous flow
reactor, using less amount of trifluoromethylation reagent and
taking shorter reaction time than batch reaction. The reactions are
easy to set up at 60 °C under air, using CuCl as the catalyst and a
stable and inexpensive CF3SO2Na as the trifluoromethyl reagent.
This reaction proceeds well for a wide range of substituent
coumarins. The up-scale reaction resulted in a productivity of 305
mg/h of 3-trifluoromethyl-7-diethylamino-4-methyl coumarin with
an isolated yield of 68%. Given these features and the widespread
applications of coumarin, this method may find use from laboratory
to manufacturing.
General substituted-coumarins reaction procedure
A solution 1 of substituted coumarins (0.4 mmol), CF3SO2Na (0.8
mmol, 124.8mg), and CuCl (0.08 mmol, 8mg) in DMSO (4 mL) was
injected into one of the 1 mL PTFE-FEP sample loop 1. The other 1
mL sample loop 2 was loaded with a solution 2 of TBHP (70% in
water, 1.6 mmol, 218 μL) in 4 mL DMSO. The solution 1 and 2 in
both needles were separately injected into the sample loop 1 and 2
at four times, with 1 mL each time (When the previous 1 mL of
solution flew into the reactor, the following 1 mL of solution was
immediately injected into the sample loop.).The valves of the both
loops were then set to load and the reagents pumped through the
system using DMSO as a system solvent at the same flow rate of 50
μL/min (the residence time = 40 min). The reagents were combined
in a Y-tape before entering a 4 mL convection flow coil (CFC) reactor
(1/32 inner diameter), which was maintained at 60 °C (residence
time=40 min). The product stream exiting the reactor was collected
into a test tube, diluted with deionized water, and extracted with
ethyl acetate (3×5 mL). The combined organic layer was dried with
Na2SO4 and then concentrated under vacuum. After evaporation,
the residue was purified by column chromatography on silica gel
(200-300 mesh size) using petroleum ether/EtOAc as eluent to give
the product.
Experiment
General information
All reagents unless otherwise noted were obtained from
commercial sources and used without further purification. DMSO
(98.0%) and CF3SO2Na (>95.0%) were used without any purification.
All these reactions were monitored by TLC with silica gel GF254
precoated plates. The products were isolated by column
chromatography on silica gel (200–300 mesh size). 1H NMR, 13C
NMR and 19F NMR spectra were recorded on INOVA 400 or 500
instruments with operating frequency of 400 or 500, 100 or 126 and
377 or 470 MHz, respectively. Chemical shifts for 1H NMR were
reported in ppm relative to TMS. All 13C NMR spectra were reported
in ppm relative to deuterated chloroform (77.00 ppm). The
following abbreviations are used to set multiplicities: s=singlet,
d=doublet, t=triplet, dd=doublet of doublets, q=quartet,
m=multiplet. Coupling constants (J) were reported in Hertz (Hz). Gas
chromatography analyses were performed with an FID detector.
GC-MS data were also performed. High-resolution mass data were
recorded on a high-resolution mass spectrometer in the ESI mode.
Procedure for scale-up trifluoromethlation reaction of 7-
diethylamino-4-methyl coumarin
A test tube was filled with 12 mL of DMSO, in which 7-diethylamino-
4-methyl coumarin (6 mmol, 1.386 g), CF3SO2Na (12 mmol, 1.872 g),
CuCl (0.6 mmol, 60 mg) were dissolved. Another test tube was filled
12 mL of DMSO containing TBHP (24 mmol, 3.27 mL). The
concentrations of 7-diethylamino-4-methyl coumarin and reagent in
DMSO were both magnified five-fold (0.5 M) than the optimization
reaction (0.1 M). The reagent solutions were separately pumped
into PTFE-FEP tubes (1/32 inner diameter) by two pumps (Syrris Ltd)
at flow rate of 50 μL/min. The two solution streams flowed and
mixed into a Y-Tape mixture, and then immediately entered a 4 mL
convection flow coil (CFC) reactor (1/32 inner diameter) at a flow
rate of 100 μL/min., which was maintained at 60 °C (residence
time=40 min). The flow process was run continuously for 240 min.
The product stream exiting the reactor was collected into a test
tube, diluted with deionized water, and extracted with ethyl acetate
(3×50 mL). The combined organic layer was dried with Na2SO4 and
then concentrated under vacuum. After evaporation, the residue
was purified by column chromatography on silica gel (200-300 mesh
size) using petroleum ether/EtOAc as eluent to give the 1.22 g
product. This flow process gived the product output of 305 mg/h.
Procedure for the synthesis of 3-trifloromethyl-coumarin
in batch
A flame-dried reaction vessel with a magnetic stirring bar was
charged with coumarin (0.1 mmol, 14.6 mg), CF3SO2Na (0.4 mmol,
62.4 mg), CuCl (0.02 mmol, 2 mg), and DMSO (1.5 mL) in sequence.
An aqueous solution of TBHP (70% solution in water, 0.6 mmol, 82
μL) was slowly added dropwise into the reaction mixture with
stirring at room temperature. The mixture was stirred at 80 °C
under air for 24 h. The reaction mixture was cooled to ambient
temperature and poured into deionized water. The resulting
mixture was extracted with ethyl acetate, analyzed by GC using n-
dodecane as an internal standard for yields.
22
3-(trifluoromethyl)-2H-1-Benzopyran-2-one (2a)16,
.
White
Procedure for the synthesis of 3-trifloromethyl-coumarin
in continuous-flow reactor
powder (52.2 mg, 61%); mp 120-121 °C; 1H NMR (400 MHz, CDCl3) δ
8.17 (s, 1H), 7.69 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 7.7 Hz, 1H), 7.40 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 155.89 (s), 154.59 (s), 143.33 (q, J
= 4.6 Hz), 134.43 (s), 129.46 (s), 125.31 (s), 121.31 (q, J = 271.1 Hz),
117.67 (q, J = 33.0 Hz), 116.98 (s), 116.74 (s); 19F NMR (470 MHz,
General optimized reaction condition procedure
A solution 1 of coumarin (0.1 mmol), CF3SO2Na, and CuCl (0.02
mmol) in DMSO (1.0 mL) was injected into the 1 mL PTFE-FEP
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CDCl3) δ -66.19(s, 3F); GC-MS (EI, m/z): 214(M+, 100), 186(57), 66.34 (s, 3F); GC-MS (EI, m/z): 292(M+, 71), 294V(7ie0w)A, rt1ic5le7O(n8l9in)e,
136(52), 63(34).
87(100).
6-Nitro-3-(trifluoromethyl)-2H-1-Benzopyran-2-one
DOI: 10.1039/C5OB01516B
(2i)16.
6-Methyl-3-(trifluoromethyl)-2H-1-Benzopyran-2-one
(2b)16.
1
White powder (51.0mg, 56%); mp 122-123 °C; 1H NMR (500 MHz,
CDCl3) δ 8.11 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.28 (d, J =
8.3 Hz, 1H), 2.44 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 155.19 (s),
151.73 (s), 142.38 (q, J = 4.8 Hz), 134.56 (s), 134.24 (s), 128.14 (s),
120.42 (q, J = 271.9 Hz), 116.38 (q, J = 33.3 Hz), 115.65 (s), 115.48
(s), 19.67 (s); 19F NMR (470 MHz, CDCl3) δ -66.13 (s, 3F); GC–MS (EI,
m/z): 228(M+, 100), 200(48), 199(43), 131(43).
Yellow powder (41.6mg, 39%); mp 188-189 °C; H NMR (500 MHz,
CDCl3) δ 8.58 (d, J = 2.6 Hz, 1H), 8.54 (dd, J = 9.1, 2.6 Hz, 1H), 8.26 (s,
1H), 7.56 (d, J = 9.1 Hz, 1H); 13C NMR (126 MHz, CDCl3) δ 157.80 (s),
154.15 (s), 144.43 (s), 142.07 (q, J = 4.9 Hz), 128.85 (s), 125.24 (s),
120.66 (q, J = 272.9 Hz), 120.05 (q, J = 34.1 Hz), 118.40 (s), 116.77
(s); 19F NMR (470 MHz, CDCl3) δ -66.51 (s); GC-MS (EI, m/z): 256(M+,
59), 157(100), 87(83), 62(55).
22
4-Phenyl-3-(trifluoromethyl)-2H-1-Benzopyran-2-one (2J)16,
.
8-Methyl-3-(trifluoromethyl)-2H-1-Benzopyran-2-one
(2c)16.
1
1
White powder (57.5 mg, 50%); mp: 132-133°C; H NMR (500 MHz,
CDCl3) δ 7.66 -7.59 (m, 1H), 7.57 – 7.51 (m, 3H), 7.41 (d, J = 8.3 Hz,
1H), 7.28 - 7.24 (m, 2H), 7.21 (t, J = 7.7 Hz, 1H), 7.02 (d, J = 8.1 Hz,
1H); 13C NMR (126 MHz, CDCl3) δ 156.85 (d, J = 2.1 Hz), 156.37 (s),
153.38 (s), 134.09 (s), 132.79 (s), 129.26 (d, J = 5.5 Hz), 128.46 (s),
127.23 (d, J = 1.6 Hz), 124.76 (s), 121.82 (q, J = 275.3 Hz), 119.43 (s),
116.82 (s), 114.98 (q, J = 30.3 Hz); 19F NMR (470 MHz, CDCl3) δ -
57.46 (s); GC-MS (EI, m/z): 190(M+, 71), 262(63), 165(100), 82(38).
White powder (52.9 mg, 58%), mp 121-122 °C; H NMR (500 MHz,
CDCl3): δ 8.14 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H),
7.28 (t, J = 7.6 Hz, 1H), 2.48 (s, 3H); 13C NMR (126 MHz, CDCl3) δ
156.06 (s), 153.02 (s), 143.64 (q, J = 4.9 Hz), 135.68 (s), 127.12 (s),
126.70 (s), 124.81 (s), 121.44 (q, J = 271.9 Hz), 117.33 (q, J = 33.3
Hz), 116.55 (s), 15.36 (s); 19F NMR (470 MHz, CDCl3) δ -66.10 (s, 3F).
GC-MS (EI, m/z): 228(M+, 100), 200(54), 199(52), 131(95).
6,8-Dimethyl-3-(trifluoromethyl)-2H-1-Benzopyran-2-one (2d).
1
7-(Diethylamino)-4-methyl-3-(trifluoromethyl)-2H-1-Benzopy-
White powder (57.4mg, 60%); mp 126-127 °C; H NMR (500 MHz,
1
ran-2-one (2k)23. Yellow powder (86.2 mg, 71%); mp: 92-93 °C; H
CDCl3) δ 8.07 (s, 1H), 7.34 (s, 1H), 7.22 (s, 1H), 2.44 (s, 3H), 2.40 (s,
3H); 13C NMR (126 MHz, CDCl3) δ 156.26 (s), 151.24 (s), 143.56 (q, J
= 4.8 Hz), 136.90 (s), 134.60 (s), 126.77 (s), 126.30 (s), 121.55 (q, J =
271.8 Hz), 117.19 (q, J = 32.8 Hz), 116.37 (s), 20.59 (s), 15.23 (s); 19F
NMR (470 MHz, CDCl3) δ -66.20 (s, 3F); HRMS (ESI) m/z: [M+Na]+
Calcd. For C12H9F3O2Na 265.0452; found 265.0456.
NMR (500 MHz, CDCl3) δ 7.56 (d, J = 9.2 Hz, 1H), 6.64 (dd, J = 9.2,
2.1 Hz, 1H), 6.45 (d, J = 2.2 Hz, 1H), 3.44 (q, J = 7.1 Hz, 4H), 2.56 (d, J
= 2.0 Hz, 3H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ
157.39 (d, J = 0.7 Hz), 155.95 (s), 155.06 (d, J = 0.6 Hz), 151.98 (s),
127.22 (s), 123.84 (q, J = 274.0 Hz), 109.39 (s), 108.02 (s), 107.97 (q,
J = 30.2 Hz), 96.92 (s), 44.96 (s), 15.31 (s), 12.50 (s); 19F NMR (470
MHz, CDCl3) δ -55.47 (s); GC-MS (EI, m/z): 299(M+, 34), 284(100),
256(43).
6-tert-Butyl-3-(trifluoromethyl)-2H-1-Benzopyran-2-one (2e).
1
White powder (71.2 mg, 66%); mp 162-163 °C; H NMR (400 MHz,
CDCl3) δ 8.11 (s, 1H), 7.66 (dd, J = 8.8, 2.2 Hz, 1H), 7.51 (d, J = 2.2 Hz,
1H), 7.26 (d, J = 8.8 Hz, 1H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3)
δ 156.26 (s), 152.63 (s), 148.57 (s), 143.84 (q, J = 4.5 Hz), 132.25 (s),
125.67 (s), 121.53 (q, J =271.3 Hz), 117.25 (q, J = 32.9 Hz), 116.51
(s), 116.20 (s), 34.61 (s), 31.18 (s); 19F NMR (377 MHz, CDCl3) δ -
66.56 (s, 3F); HRMS (ESI) m/z: [M+Na]+ Calcd. For C14H13F3O2Na
293.0765; found 293.0759.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (NSFC) (ProJect Nos. 21176039 and 20923006).
7-Methoxyl-3-(trifluoromethyl)-2H-1-Benzopyran-2-one (2f)16.
White powder (60.5 mg, 63%); mp 124-125 °C; H NMR (500 MHz,
Notes and references
1
1. Z. P. Li, J. P. Hu, M. N. Sun, H. J. Ji, S. F. Chu, G. Liu and N. H.
Chen, Int. Immunopharm., 2012, 14, 145.
CDCl3) δ 8.08 (s, 1H), 7.51 (d, J = 8.7 Hz, 1H), 6.93 (dd, J = 8.7, 2.4 Hz,
1H), 6.85 (d, J = 2.3 Hz, 1H), 3.92 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 164.93 (s), 156.78 (s), 156.36 (s), 143.22 (q, J = 4.2 Hz), 130.53 (s),
121.67 (q, J = 277.7 Hz), 113.74 (s), 113.71 (q, J = 33.6 Hz), 110.31
(s), 100.67 (s), 56.00 (s); 19F NMR (470 MHz, CDCl3) δ -65.68 (s, 3F);
GC-MS (EI, m/z): 244(M+, 78), 216(73), 201 (100), 69(40).
2. (a) L. M. Kabeya, C. N. Fuzissaki, S. H. Taleb-Contini, C. F. A. M.
da, Z. Naal, E. O. Santos, A. S. Figueiredo-Rinhel, A. E. Azzolini,
R. B. Vermelho, A. Malvezzi, A. T. Amaral, J. L. Lopes and Y. M.
Lucisano-Valim, Chem. Biol. Interact., 2013, 206, 63; (b) K. N.
Venugopala, V. Rashmi and B. Odhav, Bio. Med. Res. Int., 2013,
963248.
3. (a) W. W. Yu, H. H. Wang, H. J. Ying, Y. Yu, D. D. Chen, W. H. Ge
and L. Y. Shi, Int. Immunopharm., 2014, 21, 1; (b) A. Witaicenis,
L. N. Seito, A. da Silveira Chagas, L. D. de Almeida, A. C. Luchini,
P. Rodrigues-Orsi, S. H. Cestari and L. C. Di Stasi, Phytomedicine,
2014, 21, 240; (c) Z. Gao, Q. P. Wen, Y. Xia, J. X Yang, P. Gao, N.
Zhang, H. Y. Li and S. F. Zou, J. Pharm. Sci., 2014, 124, 54.
4. (a) G. L. Xi and Z. Q. Liu, Eur. J. Med. Chem., 2013, 68, 385; (b) J.
M. Li, X. Zhang, X. Wang, Y. C. Xie and L. D. Kong, Eur. J. Pharm.,
2011, 666, 196.
7-Acetyloxy-3-(trifluoromethyl)-2H-1-Benzopyran-2-one (2g)16.
1
White powder (64.1 mg, 59%); mp 146-147 °C; H NMR (500 MHz,
CDCl3) δ 8.15 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H),
7.17 (dd, J = 8.5, 2.1 Hz, 1H), 2.37 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 168.32 (s), 155.55 (d, J = 0.6 Hz), 155.33 (s), 155.18 (s), 142.74 (q,
J = 4.8 Hz), 130.30 (s), 121.28 (q, J = 272.0 Hz), 119.34 (s), 116.98 (q,
J = 33.4 Hz), 114.44 (s), 110.48 (s), 21.08 (s); 19F NMR (470 MHz,
CDCl3) δ -66.13 (s, 3F); GC-MS (EI, m/z): 230(M+, 26), 202(27),
43(100), 32(38).
6-Bromo-3-(trifluoromethyl)-2H-1-Benzopyran-2-one
(2m).
1
5. T. I. Verhoef, W. K. Redekop, A. K. Daly, R. M. van Schie, A. de
Boer and A. H. Maitland-van der Zee, Br. J. Clin. Pharm., 2014,
77, 626.
White powder (66.1 mg, 55%); mp 162-163 °C; H NMR (500 MHz,
CDCl3) δ 8.08 (s, 1H), 7.76 (m, 2H), 7.30 (d, J = 9.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 155.29 (s), 153.65 (s), 142.16 (q, J = 3.9 Hz),
137.34 (s), 131.78 (s), 121.21 (q, J = 272.4 Hz), 118.96 (q, J = 34.2
Hz), 118.93 (s), 118.41 (s), 118.01 (s); 19F NMR (470 MHz, CDCl3) δ -
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Organic & Biomolecular Chemistry
Page 6 of 6
ARTICLE
Journal Name
6. (a) J. He, L. Tremblay, S. Lacelle and Y. Zhao, Soft Matter, 2011,
7, 2380; (b) Y. Zhang, K. H. Shen, F. Guo, Y. F. Wang, Y. S. Wang,
Y. R. Wang and Y. Li, RSC Advances, 2013, 3, 20345.
7. S. Nasu, A. Tsuchiya and K. J. Kuroda, Mater. Chem., 2010, 20,
6688.
View Article Online
DOI: 10.1039/C5OB01516B
8. (a) S. I. Klink, P. O. Alink, L. Grave, F. G. A. Peters, J. W.
Hofstraat, F. Geurts and F. C. van Veggel, J. Chem. Soc., Perkin
Trans. 2, 2001, 3, 363; (b) Z. J. Jiang, H. S. Lv, J. Zhu and B. X.
Zhao, Synthetic Metals, 2012, 162, 2112.
9. (a) A. Shokri, X. B. Wang and S. R. Kass, J. Am. Chem. Soc., 2013,
135, 9525; (b) D. A. Nagib and D. W. MacMillan, Nature, 2011,
480, 224.
10. (a) Y. T. He, L. H. Li, Y. F. Yang, Z. Z. Zhou, H. L. Hua, X. Y. Liu and
Y. M. Liang, Org. Lett., 2014, 16, 270; (b) F. Yang, P. Klumphu, Y.
M. Liang and B. H. Lipshutz, Chem. Commun., 2014, 50, 936; (c)
Y.D. Ye, S.A. Kunzi and M.S. Sanford, Org. Lett., 2012, 14, 4979;
(d) J. Yin, Y. M. Li, R. Zhang, K. Jin and C. Y. Duan, Synthesis,
2014, 46, 607; (e) L. J. Zhai, Y. M. Li, J. Yin, K. Jin, R. Zhang, X. M.
Fu and C. Y. Duan, Tetrahedron, 2013, 69, 10262.
11. (a) Y. Lu, Y. M. Li, R. Zhang, K. Jin and C. Y. Duan, J. Fluorine
Chem., 2014, 161, 128; (b) Y. Li, L. P. Wu, H. Neumann and M.
Beller, Chem. Commun., 2013, 49, 2628; (c) S. R. Dubbaka, S.
Nizalapur, A. R. Atthunuri, M. Salla and T. Mathew,
Tetrahedron, 2014, 70, 2118; (d) S. R. Dubbaka, M. Salla, R.
Bolisetti and S. Nizalapur, RSC Advances, 2014, 4, 6496; (e) X.Z.
Luo, H.Q. Luo, Z.P. Zhang and W. Dong, Synlett, 2014, 25, 1307;
(f) F. Yang, P. Klumphu, Y. M. Liang and B. H. Lipshutz, Chem
Commun, 2014, 50, 936.
12. T. Hayashi and K. Yamasaki, Chem. Rev., 2003, 103, 2829.
13. Z. X. Fang, Y. Q. Ning, P. B. Mi, P. Q. Liao and X. H. Bi, Org. Lett.,
2014, 16, 1522.
14. X. Wang, Y.X. Ye, G.J. Ji, Y. Xu, S.N. Zhang, J.J. Feng, Y. Zhang
and J.B. Wang, Org. Lett., 2013, 15, 3730.
15. W. Dmowski and K. Piasecka-MacieJewska, Org. Prep. Proc. Int.,
2002, 34, 514.
16. X.H. Cao, X. Pan, P.J. Zhou, J.P. Zou and O.T. Asekun, Chem.
Comm., 2014, 50, 3359.
17. (a) P. L. S. Mascia, H. Heider, R. Zhang, B. Lakerveld, P.
Benyahia, R. D. I. Barton, C. L. Braatz, J. M. B. Cooney, T. F.
Evans, K. F. Jamison, A. S. Jensen and B. L. Myerson, Angew.
Chem.; Int. Ed., 2013, 52, 12359; (b) P. Poechlauer, J. Manley,
R. Broxterman, B. Gregertsen and M. Ridemark, Org. Process
Res. Dev., 2012, 16, 1586.
18. (a) L. N. Protasova, M. Bulut, D. Ormerod, A. Buekenhoudt, J.
Berton and C. V. Stevens, Org. Process Res. Dev., 2013, 17, 760;
(b) N. T. Zuidhof, M. H. J. M. de Croon, J. C. Schouten and J. T.
Tinge, Chem. Eng. Technol., 2012, 35, 1257.
19. (a) M. M. Garazd, Y. L. Garazd and V. P. Khilya, Chem. Nat.
Compd., 2003, 39, 54; (b) Y. M. Li, Z. S. Qi, H. F. Wang, X. M. Fu
and C. Y. Duan, J. Org. Chem., 2012, 77, 2053.
20. C. Zhang, Advanced Synthesis & Catalysis, 2014, 356, 2895.
21. (a) T. H. Huynh, B. Abrahamsen, K. K. Madsen, A. Gonzalez-
Franquesa, A. A. Jensen and L. Bunch, Bioorg. Med. Chem.,
2012, 20, 6831; (b) X. Liu, J. M. Cole and K. S. Low, J. Phys.
Chem. C, 2013, 117, 14731.
22. Y. Li, Y. Lu, G. Qiu and Q. Ding, Org Lett, 2014, 16, 4240.
23. (a) M. Matsui, K. Shibata, H. Muramatsu, H. Sawada and M.
Nakayama, Synlett, 1991, 113; (b) M. Matsui, J. Fluorine Chem.,
1999, 96, 65.
6 | J. Name., 2012, 00, 1-3
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