Visible-light-driven, photoredox-catalyzed cascade of ortho-hydroxycinnamic esters to access 3-fluoroalkylated coumarins

Article abstract of DOI:10.1021/acs.joc.9b00715

A general and straightforward protocol for di-/perfluoroalkylation of ortho-hydroxycinnamic esters via a photoredox-catalyzed cascade was developed to access a variety of 3-fluoroalkylated coumarins. This method was characterized by all-in-one synthetic design, simplified operation, mild reaction conditions, and broad substrate scope. Moreover, a sequential one-pot procedure starting from commercially available salicylaldehyde was also successfully realized to synthesize 3-fluoroalkylated coumarins.

Full text of DOI:10.1021/acs.joc.9b00715

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Note
Visible-light-driven, Photoredox-catalyzed Cascade of Ortho-
hydroxycinnamic Esters to Access 3-Fluoroalkylated Coumarins
Dan Song, Chao-Ming Wang, Zhi-Peng Ye, Peng-Ju Xia, Zhi-
Xiong Deng, Jun-An Xiao, Hao-Yue Xiang, and Hua Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00715 • Publication Date (Web): 07 May 2019
Downloaded from http://pubs.acs.org on May 7, 2019
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Visible-light-driven, Photoredox-catalyzed Cascade of
Ortho-hydroxycinnamic Esters to Access 3-
Fluoroalkylated Coumarins
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Dan Song, † Chao-Ming Wang, † Zhi-Peng Ye, † Peng-Ju Xia, † Zhi-Xiong
Deng, † Jun-An Xiao, ‡ Hao-Yue Xiang,*,† Hua Yang*,†,§
†
College of Chemistry and Chemical Engineering, Central South University, Changsha 410083, P.
R. China
§
Key Laboratory of Hunan Province for Water Environment and Agriculture Product Safety,
Central South University, Changsha 410083, P. R. China
‡
Guangxi Key Laboratory of Natural Polymer Chemistry and Physics, Nanning Normal University,
Nanning, 530001, P. R. China
e-mail: hyangchem@csu.edu.cn, xianghaoyue@csu.edu.cn
RF
COOEt
R1
R1
RF
X
PC
+
O
O
OH
cascade process
broad scope
fluoroalkyl source
BrCF2R', ICF(CF3)2/ICnF2n+1
Togni's reagent (CF3)
mild conditions
simplified operation
33 examples
up to 83% yield
ABSTRACT: A general and straightforward protocol for di-/perfluoroalkylation of
ortho-hydroxycinnamic esters via a photoredox-catalyzed cascade was developed to
access a variety of 3-fluoroalkylated coumarins. This method was characterized by all-
in-one synthetic design, simplified operation, mild reaction conditions, and broad
substrate scope. Moreover, a sequential one-pot procedure starting from commercial
available salicylaldehyde was also successfully realized to synthesize 3-fluoroalkylated
coumarins.
As a privileged structural scaffold, coumarin, as well as its derivatives, frequently
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exist in many biologically active pharmaceuticals,1 natural products,2 and fluorescent
materials.3 The preparation of functionalized coumarins, especially C3-functionalized
analogues, has garnered extensive attention, aiming to enriching the library of
coumarins with the upgraded properties.4 It is commonly acknowledged that
incorporating fluorine-containing substituents into the organic skeletons has a
significantly beneficial impact on the physical properties including but not limited to
solubility, lipophilicity, metabolic stability, and bioavailability.5 Over the past few
decades, substantial efforts have been made toward the introduction of fluorinated
groups into coumarin framework.6 However, most of the conventional methods
involved multi-steps, excess oxidants, toxic or expensive fluoroalkylation reagents, and
expensive transition metals. Hence, it is persistently necessary and fundamental to
develop new straightforward protocols to prepare 3-fluoroalkylated coumarins under
mild conditions.
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Visible-light photoredox catalysis has witnessed rapid advancements in generating
an array of fluorinated radicals and constructing structurally complex scaffolds, owing
to its reaction condition mildness, operational simplicity, and environmental
friendliness.7 Following this line, several photocatalyzed syntheses of fluorinated
coumarins have been established (Scheme 1).8
Scheme 1. Representative Synthetic Profiles of 3-Fluoroalkyl Coumarins via
Photocatalysis
late-stage fluorination
step-by-step strategy
cyclization
H
O
previous work
X
fluorinated
RF
R
coumarin
conditions
intensively
studied
O
CO2Et
RF
O
PC
R
R
OH
O
ortho-hydroxycinnamic
ester
this work
X
RF
PC
privileged scaffold
all-in-one strategy
cyclization/fluorination cascade sequence
In general, the photocatalyzed strategies for accessing 3-fluoroalkylated
coumarins heavily rely on the late-stage fluoroalkylation of the preformed coumarin
core structure (Scheme 1).9 In 2016, Yuan and co-authors described a photochemical
difluoroalkylation of coumarins with BrCF2R under visible-light irradiation.9a
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Thereafter, an efficient method using a transition-metal-free photochemical strategy for
the direct Csp2-H radical difluoromethylation of coumarins with HCF2SO2Na was
established by Deng’s group.9b Meanwhile, a few important studies of visible-light-
induced tri/perfluoroalkylation of coumarins were also reported.9c-9g Despite all these
advancements, trimming down the synthetic steps to access 3-functionalized coumarins
in a more step-economic manner is still highly desirable.
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As known, the cyclizations of readily available ortho-hydroxycinnamic esters has
been intensively utilized to prepare various coumarins.10 However, harsh conditions are
usually requisite to overcome the inherent hurdle of the isomerization of Z-alkene in
ortho-hydroxycinnamic esters, thus facilitating the following cyclization. Noticing this
issue, we rationalized that photocatalytic radical addition of the double bond in ortho-
hydroxycinnamic esters could offer an alternative facile pathway for the isomerization
process. As a consequence, the incorporation of cyclization and fluorination would
offer a step-economic route for the synthesis of fluorine-containing coumarins under
mild conditions. As part of our continued interest in the photoredox catalysis11 and
fluorinated heterocycles12, we herein disclose a general photoredox-catalyzed protocol
for the construction of various fluoroalkylated coumarins from easy-to-prepare ortho-
hydroxycinnamic esters (Scheme 1).
We began our studies with a model reaction of ortho-hydroxycinnamic ester 1a
and commercially available BrCF2COOEt (2a) under irradiation of 30 W blue LEDs
(Table 1). Preliminary experiments were conducted in CH3CN with 2 equimolar
amount of 2a under the atmosphere of Ar at room temperature. Gratifyingly, catalyst
screening demonstrated that fac-Ir(ppy)3 successfully gave the desired product 3a in a
moderate yield, whereas other commonly used photocatalysts gave inferior results in
promoting this transformation (Table 1, entries 1-5). Subsequently, a series of bases
were tested, which can effectively consume HBr produced in the process of this
transformation (Table 1, entries 6-12). Satisfyingly, the yield for 3a was improved upon
using K2CO3, Et3N or DIPEA as the base. Effects of solvent were also
Table 1. Optimization of Reaction Conditionsa
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photocatalyst
CO2Et
+
CF2CO2Et
O
base
solvent, rt,
Ar, 12 h
BrCF2CO2Et
OH
1a
O
3a
2a
7
30 W blue LEDs
8
9
Entry
1
Photocatalyst
Ru(bpy)3(PF6)2
fac-Ir(ppy)3
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
DMF
Base
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
K2CO3
Cs2CO3
K2HPO4
K3PO4
Et3N
Yieldb (%)
trace
41
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2
3
Ir(ppy)2(dtbbpy)PF6
18
4
Ir[dF(CF3)(ppy)2](dtbbpy)PF6
Eosin Y
trace
NR
5
6
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
65
7
19
8
22
9
49
10
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13
14
15
16
17
18
19c
20d
21d, e
22d, f
65
DIPEA
---
62
trace
22
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
62
DMSO
THF
65
62
MeOH
dioxane
CH3CN
CH3CN
CH3CN
CH3CN
trace
37
28
69
69
69
aReaction conditions: 1a (0.2 mmol) and 2a (0.4 mmol), photocatalyst (2 mol %), and base
b
(2.0 equiv.) in solvent (1 mL), Ar, irradiation with 30 W blue LEDs, rt, 12 h. Isolated
yields. cIn air. d2 mL of solvent was used. e3 equiv. of 2a was used. f30 W white LEDs.
investigated, but without any improvement in efficiency. The yield of 3a was
consistently reduced in dioxane, CH2Cl2, or MeOH. And comparable yields were
obtained when DMF, DMSO or THF was used as the solvent (Table 1, entries 13-18).
To further improve the yield, other reaction parameters were also tested. The reaction
proceeded sluggishly and intricately in air (Table 1, entry 19). The yield of 3a was
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slightly increased when the reaction was performed at lower concentration (Table 1
entry 20), while increasing the amount of BrCF2CO2Et was unable to further improve
the yield (Table 1 entry 21). In addition, 3a was formed in a comparably yield under
white light irradiation (Table 1, entry 22).
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Having established the optimal conditions, the versatility of this approach was
subsequently explored and a range of ortho-hydroxycinnamic esters were prepared and
subjected to the optimized reaction conditions. The electronic feature of substituents at
ortho- or meta-position of the phenol moiety slightly affected the efficacy of this
reaction, and thus comparable chemical yields were secured (Scheme 2, 3a-3g and 3m-
3n). Specifically, with regard to the substituent at para-position of phenol group in the
substrate, the presence of methoxy group evidently undermined the yield, while other
substituents consistently provided moderate to good yields (Scheme 2, 3h-3l).
Disubstituted products 3o and 3p were also successfully prepared. To further
demonstrate the generality of this protocol, a range of bromodifluoroamides and 2-
(bromodifluoromethyl)benzoxazoles were also investigated, leading to the
corresponding products 3q-3t but with comparatively lower yields. The practicality and
scalability of this protocol was successfully demonstrated by performing the reaction
of 3a on a gram scale under standard reaction conditions to give a slightly reduced yield
(47%). Moreover, aiming to further simplifying the synthetic operation, a one-pot
process by starting from salicylaldehyde and 2-(triphenylphosphoranylidene)acetic
acid ethyl ester was developed, affording the desired product 3a in 49% yield.
Scheme 2. Substrate Scope for the Synthesis of 3-CF2-Containing Coumarinsa,b
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F
F
CO2Et
+
fac-Ir(ppy)3 (2 mol %)
K2CO3 (2 equiv.)
COR'
R
BrCF2COR'
R
OH
CH3CN (2 mL)
Ar, rt, 12 h
30W blue LEDs
O
3
O
2
1
9
CF2CO2Et
CF2CO2Et
R
CF2CO2Et
O
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O
O
R
O
O
O
R
3h
, R = OMe, 21%
, R = Me, 71%
F, 47%
, R = Cl, 45%
c
3a
3b
, R = H, 69%, 47%
3e
3f
3g
3i
3j
, R = OMe, 76%
, R = Me, 71%
, R = Cl, 58%
,
,
R
R
=
Me, 50%
F, 66%
,
R
=
3c
=
3k
3l
, R = Br,
F
52%
F
3d
, R = Cl, 83%
R
R
CF2CO2Et
N
CF2CO2Et
C
O
O
O
O
O
O
O
R
3o
3p
3m
3n
, R = Cl, 70%
, R = Br, 35%
, R = F, 61%
, R = Cl, 61%
3q
, 46%
F
F
F
F
F
F
H
H
CO2Me
N
N
N
Bn
C
C
O
O
O
O
O
O
O
O
O
3t
, 35%
3r
3s
, 51%
, 30%
One-Pot Processd
CF2CO2Et
O
CHO
OH
PPh3
CO2Et
i) MeCN, rt, 24 h
+
ii) fac-Ir(ppy)3 (2 mol %)
O
49% yield
2a
K2CO3 (2 eq.),
(2 eq.)
3a,
commercial available
30W blue LEDs, Ar,12 h
aReaction conditions: 1 (0.2 mmol, 1.0 equiv.), 2 (0.4 mmol, 2.0 equiv.), fac-Ir(ppy)3 (2 mol %), and K2CO3 (0.4
mmol, 2.0 equiv.) in CH3CN (2 mL); Ar, irradiation with 30 W blue LEDs, rt, 12 h. bIsolated yields. cPerformed
at 1.045 g scale for 1a, coumarin was concurrently isolated in 17% yield. dSalicylaldehyde (0.2 mmol, 1.0 equiv.),
2-(triphenylphosphoranylidene)acetic acid ethyl ester (0.24 mmol, 1.2 equiv.), in CH3CN (2 mL), rt, 12 h; then 2
(0.4 mmol, 2.0 equiv.), fac-Ir(ppy)3 (2 mol %), and K2CO3 (0.4 mmol, 2.0 equiv.) were added and stirred at rt
under Ar for an additional 12 h.
Encouraged by the above results, we extended this newly developed strategy to
install 3-perfluoroalkylated coumarins by simply replacing BrCF2COR′ with various
commercially available perfluoroalkylated radical resources. As shown in Scheme 3,
the substitution patterns and electronic characteristics of ortho-hydroxycinnamic esters
have slight effects on their reaction efficiency, with the desired products 5a-5m being
obtained in moderate to good yields. However, ortho-aminocinnamic esters only
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rendered a fairly complex reaction and the corresponding carbostyril derivatives 6 were
5
6
undetected.
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Scheme 3. Substrate Scope for the Synthesis of 3-Perfluoroalkyl Coumarinsa,b
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CO2Et
+
fac-Ir(ppy)3 (2 mol %)
K2CO3 (2 equiv.)
RF
O
R
RFX
R
CH3CN (2 mL)
Ar, rt, 12 h
30W blue LEDs
OH
O
5
1
4
C4F9
CF3
R
C6F13
O
R
R
O
O
O
O
O
5e
5f
,
R
=
H, 69%
5a
5b
5c
5d
,
R
=
H, 69%
, R = 6-Me, 60%
, R = 6-Cl, 80%
, R = 5-Cl, 70%
5j
, R = H, 48%
, R = Cl, 37%
5g
5h
, R = 6-Me, 60%
, R = 7 -OMe, 63%
5k
, R = 7-OMe, 72%
5i
, R = 8 - Cl,
50%
RF
F3C
F
C8F17
CF3
N
O
O
O
O
O
R'
5l,
44%
6
, not detected
5m
, 53%
aReaction conditions: 1 (0.2 mmol, 1.0 equiv.), 4 (Togni’s reagent II/ICnF2n+1/ICF(CF3)2, 1.0 mmol, 5.0 equiv.),
fac-Ir(ppy)3 (2 mol%), and K2CO3 (0.4 mmol, 2.0 equiv.) in CH3CN (2 mL); Ar, irradiation with 30 W blue
LEDs, rt, 12 h. bIsolated yields.
To gain mechanistic insights into the process, several control experiments were
subsequently conducted (Scheme 4). Radical trapping experiments were firstly
implemented by adding the radical scavenger 2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO, 5 equiv.) to the model reaction system. In this case, the formation of 3a was
almost completely suppressed along with the formation of coumarin 7a with 68% yield
(Scheme 4, eq a, see the Supporting Information for details). These results indicate that
a free-radical pathway was probably involved in the process of fluoroalkylation reaction.
As expected, the reaction was completely restrained in the absence of the catalyst or
light irradiation, which suggests that a photoredox catalysis process was involved in the
formation of 3a and 7a (Scheme 4, eq b). Importantly, the corresponding Stern–Volmer
studies reveal that the photoexcited fac-Ir(ppy)3 was quenched by ortho-
hydroxycinnamic ethyl ester (1a) as well as BrCF2COOEt (2a) with similar efficiency
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(see the Supporting Information for details). In addition, the reaction of coumarin with
BrCF2COOEt under the standard conditions also gave the target product in 47% yield
(Scheme 4, eq c).
9
Based on the above experimental results, two possible pathways for the
photocatalytic transformation are exemplified in Scheme 4. In path a, photocatalyst fac-
Ir(ppy)3 facilely generated the highly reducing excited *Ir(ppy)3 (E1/2(IrIV/*IrIII) = -1.73
V vs. SCE) under the irradiation of blue light. As shown in path b, the photoexcited
fac-Ir(ppy)3 was oxidatively quenched by RFX (E1/2 = -1.0 V to -1.6 V vs. SCE, see the
Supporting Information for details)13 with the generation of •RF radical via a single-
electron transfer (SET) process. Afterwards, the •RF radical regioselectively attacked
the most electron-rich position of the double bond in cinnamate 1 to give benzylic
radical A-1. This intermediate was further oxidized to carbocation A-2 by Ir(IV) species
(E1/2(IrIV/IrIII) = +0.77 V vs. SCE) via the second SET process, thus completing the
photocatalytic cycle and regenerating the ground state fac-Ir(ppy)3. In the presence of
base, the subsequent deprotonation of intermediate A-2 gave (Z)-fluoroalkylated
cinnamate A-3 as the key intermediate.6b Finally, an intramolecular lactonization of
intermediate A-3 directly generated fluoroalkylated coumarins 3/5. Alternatively,
*Ir(ppy)3 could be quenched through an energy transfer (EnT) pathway with the
formation of coumarins 7 and simultaneous recycling of the ground state fac-Ir(ppy)3
(path b). The subsequent radical addition and SET oxidation resulted in the formation
of B-1 and B-2 respectively, which ultimately delivered the desired product 3 or 5 in
the presence of base.9a, c
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Scheme 4. Control Experiments and Plausible Reaction Mechanism
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CO2Et
1a
standard
conditions
OH
+
3a
+
O
O
7a
2a
BrCF2CO2Et
trace
trace
68%
< 10%
a) adding TEMPO
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b) no light/photocatalyst
c)
H
CF2CO2Et
O
standard
conditions
2a
+
O
7a
O
O
3a
, 47%
proposed mechanism
RFX
RF
path b
7
1
path a
SET
*Ir3+
1
RF
RF
Ir4+
Photoredox
cycle
EnT
CO2Et
OH
A-1
O
B-1
O
Ir3+
SET
RF
CO2Et
7
RF
-H+
Base
CO2Et
OH
OH
A-2
A-3
lactonization
RF
Base
-H+
RF
O
O
O
O
B-2
3/5
In summary, we first developed a general and facile assembly of 3-
fluoroalkylated coumarins through a visible-light-induced cascade radical cyclization
process starting from readily prepared ortho-hydroxycinnamic esters. By using various
commercial fluoroalkylating reagents, a range of 3-di/tri/perfluoroalkylated coumarins
were successfully prepared under mild conditions. The notable features of these
reactions include mild reaction conditions, synthetic simplicity, and excellent
functional group compatibility. Moreover, a sequential one-pot protocol starting from
commercial available salicylaldehyde was also designed and successfully realized,
efficiently generating 3-fluoroalkylated coumarins. Further synthetic applications and
studies to unveil the biological activities of these privileged scaffolds are ongoing in
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our laboratory.
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EXPERIMENTAL SECTION
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General Experimental Methods. Unless otherwise noted, all the reagents were purchased from
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commercial suppliers and used without further purification. And the light source used for
illuminating the reaction vessel (commercial supplier: Synthware) consisted of blue LEDs (λmax
=
460 nm) purchased from Taobao (https://gpiled.taobao.com). 1H NMR spectra were recorded at 400
MHz. The chemical shifts were recorded in ppm relative to tetramethylsilane and with the solvent
resonance as the internal standard. Data were reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, p = quint, m = multiplet), coupling constants (Hz),
integration. 13C NMR data were collected at 100 MHz with complete proton decoupling. Chemical
shifts were reported in ppm from the tetramethylsilane with the solvent resonance as internal
standard. 19F NMR data were collected at 376 MHz with complete proton decoupling. UV–Vis
spectra were recorded using a shimadzu UV-2600. Infrared spectra (IR) were measured by FT-IR
apparatus. High resolution mass spectroscopy (HRMS) was recorded on TOF MS ES+ mass
spectrometer and acetonitrile was used to dissolve the sample. Cyclic Voltammetry (CV)
experiments were recorded on a CHI650D Electrochemical workstation. Emission intensities were
recorded using Perkin-Elemer LS 55 Fluorescence Spectrometer. Column chromatography was
carried out on silica gel (200-300 mesh).
General procedures for synthesis of 1a-1p.
The starting materials 1 were prepared according to the previously described method.14 The data of
known compounds are consistent with the previously reports6a, 10a, 15 and the copies of their 1HNMR
spectra were included in the Supporting Information. Characterization data of new compounds 1c,
1d, 1m and 1p were also provided herein.
Characterization data of compounds 1c, 1d, 1m and 1p
1
(E)-Ethyl 3-(2-hydroxy-3-fluorophenyl)acrylate (1c). White solid (504 mg, 80%): H NMR (400
MHz, CDCl3) δ 8.00 (d, J = 16.0 Hz, 1H), 7.25 (d, J = 9.6 Hz, 1H), 7.06-7.11 (m, 1H), 6.81-6.86
(m, 2H), 6.65 (d, J = 16.0 Hz, 1H), 4.30 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 6.4 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 168.0, 151.6 (d, J = 237.3 Hz), 143.6 (d, J = 15.4 Hz), 139.3 (d, J = 3.7 Hz),
124.2 (d, J = 3.3 Hz), 123.8 (d, J = 2.2 Hz), 119.84 (d, J = 7.2 Hz), 119.6, 116.6 (d, J = 18.5 Hz), 60.8,
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14.3; HRMS (ESI): C11H11FNaO3 [M+Na]+ calcd 233.0584, found 233.0597.
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(E)-Ethyl 3-(2-hydroxy-3-chlorophenyl)acrylate (1d). White solid (576 mg, 85%): H NMR (400
MHz, CDCl3) δ 7.93 (d, J = 16.0 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 7.6, 1.2 Hz, 1H),
6.89 (t, J = 8.0 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 6.15 (s, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.34 (t, J
= 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 167.3, 150.4, 139.0, 130.2, 127.8, 123.0, 121.0,
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120.9, 120.3, 60.6, 14.3; HRMS (ESI): C11H11ClNaO3 [M+Na]+ calcd 249.0289, found 249.0281.
1
(E)-Ethyl 3-(2-hydroxy-6-chlorophenyl)acrylate (1m). White solid (560 mg, 89%): H NMR (400
MHz, CDCl3) δ 8.21 (br s, 1H), 8.04 (d, J = 16.0 Hz, 1H), 7.16 (dd, J = 14.8, 8.0 Hz, 1H), 6.99 (d,
J = 16.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 6.64 (t, J = 8.8 Hz, 1H), 4.32 (q, J = 7.2 Hz, 2H), 1.37
(t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.6, 162.7 (d, J = 252.5 Hz), 157.6 (d, J
= 6.6 Hz), 134.6 (d, J = 3.2 Hz), 131.2 (d, J = 11.6 Hz), 121.3 (d, J = 8.9 Hz), 111.9 (d, J = 3.0 Hz),
110.9 (d, J = 13.7 Hz), 107.2 (d, J = 22.9 Hz), 61.0, 14.3; HRMS (ESI): C11H11FNaO3+ [M+Na]+
calcd 233.0584, found 233.0583.
1
(E)-Ethyl 3-(2-hydroxy-3,5-dibromophenyl)acrylate (1p). White solid (871 mg, 83%): H NMR
(400 MHz, CDCl3) δ 7.85 (d, J = 16.0 Hz, 1H), 7.55-7.60 (m, 2H), 6.54 (d, J = 16.0 Hz, 1H), 6.10
(s, 1H), 4.27 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
166.7, 150.3, 137.7, 135.1, 130.9, 124.4, 121.5, 112.8, 112.0, 60.8, 14.3; HRMS (ESI):
+
C11H10Br2NaO3 [M+Na]+ calcd 370.8889, found 370.8908.
General procedures for synthesis of 3a-3g and 5a-5m
To a mixture of ethyl 2-hydroxycinnamates 1 (0.20 mmol), K2CO3 (0.40 mmol, 2.0 equiv.), and F
sources for 2.0 equiv. BrCF2X or 5 equiv. Togni reagent II/CnF2n+1I in CH3CN (2 mL) was added
Ir(ppy)3 (2.00 mmol %) under Ar atmosphere. The reaction mixture was stirred at room temperature
under irradiation of 30 W blue LEDs (distance app. 3 cm) for 12 h. The solvent was removed in
vacuo and the resulting residue was then purified by flash chromatography using silica gel
(EtOAc/PE = 1/50).
Synthetic procedure for the preparation of 3a on gram scale
To a mixture of ethyl 2-hydroxycinnamates 1 (1.045 g, 5.5 mmol), K2CO3 (1.518 g, 11.0 mmol, 2.0
equiv.), and BrCF2CO2Et (1.410 mL, 11.0 mmol, 2.0 equiv.) was added Ir(ppy)3 (18 mg, 0.5 mmol
%) under Ar atmosphere. The reaction mixture was stirred at room temperature under irradiation of
30 W blue LEDs (distance app. 3 cm) for 12 h. The solvent was removed in vacuo and the resulting
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residue was then purified by flash chromatography using silica gel (EtOAc/PE = 1/50) to give 3a
(0.697 g, 47% yield).
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Characterization data of compounds 3a-3t and 5a-5m
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Ethyl 2,2-Difluoro-2-(2-oxo-2H-chromen-3-yl)acetate (3a).9a White solid (37 mg, 69%); 1H NMR
(400 MHz, CDCl3) δ 8.16 (s, 1H), 7.61-7.66 (m, 2H), 7.35-7.39 (m, 2H), 4.38 (q, J = 7.2 Hz, 2H),
1.34 (t, J = 7.2 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.1 (s, 2F).
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Ethyl 2,2-Difluoro-2-(8-methyl-2-oxo-2H-chromen-3-yl)acetate (3b). White solid (28 mg, 50%):
m.p. 64-65 ℃; IR (KBr) ν 2924, 1748, 1467, 1140, 970, 786, 460 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.15 (s, 1H), 7.47 (q, J = 7.6 Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 2.46 (s,
3H), 1.35 (t, J = 6.8 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.1 (s, 2F); 13C{1H} NMR
(100 MHz, CDCl3) δ 162.4 (t, JC-F = 32.8 Hz), 158.1 (t, JC-F = 4.5 Hz), 152.6, 142.3 (t, JC-F = 6.9
Hz), 135.0, 126.9, 126.6, 124.7, 120.8 (t, JC-F = 25.6 Hz), 117.3, 110.6 (t, JC-F = 250.7 Hz), 63.5,
+
15.4, 13.8; HRMS (ESI): C14H12F2NaO4 [M+Na]+ calcd 305.0596, found 305.0571.
Ethyl 2,2-Difluoro-2-(8-fluoro-2-oxo-2H-chromen-3-yl)acetate (3c). White solid (38 mg, 66%),
m.p. 116-118 ℃; IR (KBr) ν 2959, 1748, 1467, 1315, 1017, 744, 460 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.18 (s, 1H), 7.40-7.45 (m, 2H), 7.30-7.35 (m, 1H), 4.39 (q, J = 7.2 Hz, 2H), 1.35 (t, J =
7.1 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.3 (s, 2F), -132.2 (s, 1F); 13C{1H} NMR (100
MHz, CDCl3) δ 162.0 (t, JC-F = 32.6 Hz), 156.5 (t, JC-F = 4.4 Hz), 129.4 (d, JC-F = 253.8 Hz), 142.4
(d, JC-F = 11.8 Hz), 141.4 (td, JC-F = 7.1 Hz, 2.8 Hz), 125.2 (d, JC-F = 6.6 Hz), 124.4 (d, JC-F = 4.0
Hz), 122.2 (t, JC-F = 25.8 Hz), 120.0 (d, JC-F = 17.2 Hz), 119.3, 110.3 (t, JC-F = 251.5 Hz), 63.8, 13.8;
+
HRMS (ESI): C13H9F3NaO4 [M+Na]+ calcd 309.0345, found 309.0324.
Ethyl 2,2-Difluoro-2-(8-chloro-2-oxo-2H-chromen-3-yl)acetate (3d). White solid (50 mg, 83%),
1
m.p. 125-126 ℃; IR (KBr) ν 2959, 1728, 1447, 1201, 981, 780, 486 cm-1; H NMR (400 MHz,
CDCl3) δ 8.15 (s, 1H), 7.70 (dd, J = 8.0, 0.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.32 (t, J = 8.0 Hz,
1H), 4.39 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.2
(s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 162.0 (t, JC-F = 32.6 Hz), 156.8 (t, JC-F = 4.4 Hz), 149.9,
141.5 (t, JC-F = 7.0 Hz),134.0, 127.7, 125.4, 122.1, 122.0 (t, JC-F = 25.7 Hz ), 118.8, 110.3 (t, JC-F
=
+
251.5 Hz), 63.7, 13.8; HRMS (ESI): C13H9ClF2NaO4 [M+Na]+ calcd 325.0050, found 325.0054.
Ethyl 2,2-Difluoro-2-(7-methoxy-2-oxo-2H-chromen-3-yl)acetate (3e).9a White solid (43 mg, 76%);
1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.50 (d, J = 8.7 Hz, 1H), 6.92 (dd, J = 8.7, 2.3 Hz, 1H),
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6.86 (d, J = 2.1 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H); 19F{1H}
NMR (376 MHz, CDCl3) δ -105.5 (s, 2F).
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Ethyl 2,2-Difluoro-2-(7-methyl-2-oxo-2H-chromen-3-yl)acetate (3f).16 White solid (26 mg, 45%);
1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.17-7.19 (m, 2H), 4.39 (q, J
= 7.2 Hz, 2H), 2.49 (s, 3H), 1.34 (t, J = 6.8 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -105.9 (s,
2F).
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Ethyl 2,2-Difluoro-2-(7-chloro-2-oxo-2H-chromen-3-yl)acetate (3g). White solid (35 mg, 58%),
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m.p. 93-95 ℃; IR (KBr) ν 2924, 1748, 1468, 1316, 1017, 744, 460 cm-1; H NMR (400 MHz,
CDCl3) δ 8.13 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.38 (s, 1H), 7.35 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 4.39
19
(q, J = 7.2 Hz, 2H), 1.34 (t, J = 6.8 Hz, 3H); F{1H} NMR (376 MHz, CDCl3) δ -106.2 (s, 2F);
13C{1H} NMR (100 MHz, CDCl3) δ 162.1 (t, JC-F = 32.7 Hz), 157.3 (t, JC-F = 4.4 Hz), 154.4, 141.2
(t, JC-F = 7.0 Hz), 139.9, 130.0, 125.9, 121.2 (t, JC-F = 25.7 Hz), 117.4, 116.1, 110.3 (t, JC-F = 251.3
+
Hz), 63.7, 13.8; HRMS (ESI): C13H9ClF2NaO4 [M+Na]+ calcd 325.0050, found 325.0027.
Ethyl 2,2-Difluoro-2-(6-methoxy-2-oxo-2H-chromen-3-yl)acetate (3h). White solid (13 mg, 21%),
m.p. 166-167 ℃; IR (KBr) ν 2924, 1748, 1468, 1201, 1017, 744, 460 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.12 (s, 1H), 7.32 (d, J = 9.2 Hz, 1H), 7.21 (dd, J = 9.1, 2.6 Hz, 1H), 6.96 (d, J = 2.6 Hz,
1H), 4.38 (q, J = 7.1 Hz, 2H), 3.87 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 19F{1H} NMR (376 MHz,
CDCl3) δ -106.2 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3 (t, JC-F = 32.7 Hz), 158.1 (t, JC-F
= 4.5 Hz), 156.5, 148.7, 141.7 (t, JC-F = 7.0 Hz), 121.7, 121.5 (t, JC-F = 25.4 Hz), 118.1, 117.9, 110.8,
+
63.6, 56.0, 13.8; HRMS (ESI): C14H12F2NaO5 [M+Na]+ calcd 321.0545, found 321.0526.
Ethyl 2,2-Difluoro-2-(6-methyl-2-oxo-2H-chromen-3-yl)acetate (3i).9a Colorless oil (40 mg, 71%);
1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J = 3.2
Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H); 19F{1H} NMR (376 MHz,
CDCl3) δ -106.1 (s, 2F).
Ethyl 2,2-Difluoro-2-(6-fluoro-2-oxo-2H-chromen-3-yl)acetate (3j). White solid (27 mg, 47%), m.p.
135-136 ℃; IR (KBr) ν 2959, 1729, 1448, 1291, 982, 781, 558 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.11 (s, 1H), 7.36-7.38 (m, 2H), 7.30-7.33 (m, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.2 Hz,
3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.4 (s, 2F), -115.9 (s, 1F); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.0 (t, JC-F = 32.6 Hz), 159.0 (d, JC-F = 246.1 Hz), 157.5 (t, JC-F = 4.4 Hz), 150.4, 140.9
(td, JC-F = 7.0, 2.8 Hz), 122.5 (t, JC-F = 25.6 Hz), 121.2 (d, JC-F = 24.5 Hz), 118.7 (d, JC-F = 8.3 Hz),
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118.2 (d, JC-F = 9.1 Hz), 114.4 (d, JC-F = 24.1 Hz), 110.3 (t, JC-F = 251.5 Hz), 63.7, 13.8; HRMS
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+
(ESI): C13H9F3NaO4 [M+Na]+ calcd 309.0345, found 309.0366.
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Ethyl 2,2-Difluoro-2-(6-chloro-2-oxo-2H-chromen-3-yl)acetate (3k). White solid (27 mg, 45%),
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m.p. 102-104 ℃; IR (KBr) ν 2959, 1729, 1448, 1291, 982, 781, 487 cm-1; H NMR (400 MHz,
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CDCl3) δ 8.09 (s, 1H), 7.57-7.61 (m, 2H), 7.34 (d, J = 8.6 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.35
(t, J = 7.2 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.4 (s, 2F); 13C{1H} NMR (100 MHz,
CDCl3) δ 162.0 (t, JC-F = 32.6 Hz), 157.3 (t, JC-F = 4.4 Hz), 152.6, 140.8 (t, JC-F = 7.0 Hz), 133.6,
130.6, 128.4, 122.4 (t, JC-F = 25.8 Hz), 118.5, 110.3 (t, JC-F = 251.6 Hz), 63.7, 13.8; HRMS (ESI):
+
C13H9ClF2NaO4 [M+Na]+ calcd 325.0050, found 325.0076.
Ethyl 2,2-Difluoro-2-(6-bromo-2-oxo-2H-chromen-3-yl)acetate (3l). White solid (36 mg, 52%),
1
m.p. 108-109 ℃; IR (KBr) ν 2959, 1729, 1448, 1291, 982, 781, 487 cm-1; H NMR (400 MHz,
CDCl3) δ 8.08 (s, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.72 (dd, J = 8.8, 2.0 Hz, 1H), 7.26 (d, J = 8.8 Hz,
1H), 4.38 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.4
(s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 162.0 (t, JC-F = 32.7 Hz), 157.2, 153.1, 140.6 (t, JC-F
=
7.0 Hz), 136.4, 131.4, 122.4 (t, JC-F = 25.8 Hz), 119.0, 118.7, 117.8, 110.4 (t, JC-F = 251.6 Hz), 63.7,
+
13.8; HRMS (ESI): C13H9BrF2NaO4 [M+Na]+ calcd 368.9544, found 368.9564.
Ethyl 2,2-Difluoro-2-(5-fluoro-2-oxo-2H-chromen-3-yl)acetate (3m). White solid (27 mg, 47%),
m.p. 77-79 ℃; IR (KBr) ν 2959, 1729, 1448, 1291, 982, 781, 558 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.39 (s, 1H), 7.61 (dd, J = 14.4, 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 8.4 Hz, 1H),
4.39 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.2 (s,
2F), -117.1 (s, 1F); 13C{1H} NMR (100 MHz, CDCl3) δ 162.0 (t, JC-F = 32.6 Hz), 159.1 (d, JC-F
=
258.0 Hz), 157.1 (t, JC-F = 4.4 Hz), 154.6 (d, JC-F = 4.4 Hz), 135.1 (td, JC-F = 7.3, 4.4 Hz), 134.2 (d,
JC-F = 9.8 Hz), 121.4 (td, JC-F = 25.9, 1.6 Hz), 112.9 (d, JC-F = 3.9 Hz), 111.1 (d, JC-F = 19.6 Hz),
+
109.1 (t, JC-F = 251.6 Hz), 108.0 (d, JC-F = 19.1 Hz), 63.7, 13.8; HRMS (ESI): C13H9F3NaO4
[M+Na]+ calcd 309.0345, found 309.0356.
Ethyl 2,2-Difluoro-2-(5-chloro-2-oxo-2H-chromen-3-yl)acetate (3n). White solid (43 mg, 71%),
m.p. 95-97 ℃; IR (KBr) ν 2959, 1729, 1448, 1291, 982, 781, 558 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.54 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (dd, J = 8.0, 0.8 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 4.41
19
(q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H); F{1H} NMR (376 MHz, CDCl3) δ -106.1 (s, 2F);
13C{1H} NMR (100 MHz, CDCl3) δ 162.1 (t, JC-F = 32.6 Hz), 157.1 (t, JC-F = 4.4 Hz), 155.0, 138.3
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(t, JC-F = 7.3 Hz), 133.8, 133.7, 125.8, 122.0 (t, JC-F = 25.6 Hz), 116.3, 115.8, 110.3 (t, JC-F = 251.7
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+
Hz), 63.7, 13.8; HRMS (ESI): C13H9ClF2NaO4 [M+Na]+ calcd 325.0050, found 325.0054.
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Ethyl 2,2-Difluoro-2-(6,8-dichloro-2-oxo-2H-chromen-3-yl)acetate (3o). Colorless oil (47 mg,
70%); IR (KBr) ν 2959, 1729, 1448, 1080, 982, 781, 487 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.08
(s, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.53 (s, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H);
19F{1H} NMR (376 MHz, CDCl3) δ -106.4 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 161.8 (t,
JC-F = 32.6 Hz), 156.2 (t, JC-F = 4.4 Hz), 148.6, 140.5 (t, JC-F = 7.1 Hz), 133.5, 130.4, 126.9, 123.2
(t, JC-F = 25.6 Hz), 123.1, 119.3, 110.1 (t, JC-F = 252.1 Hz), 63.8, 13.8; HRMS (ESI):
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C13H8Cl2F2NaO4 [M+Na]+ calcd 358.9660, found 358.9661.
Ethyl 2,2-Difluoro-2-(6,8-dibromo-2-oxo-2H-chromen-3-yl)acetate (3p). Colorless oil (30 mg,
35%); IR (KBr) ν 2959, 1729, 1448, 1081, 982, 781, 487 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.06
(s, 1H), 7.97 (d, J = 1.6 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 4.38 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2
Hz, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -106.3 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ
161.8 (t, JC-F = 32.4 Hz), 156.3 (t, JC-F = 4.2 Hz), 150.1, 140.4 (t, JC-F = 7.1 Hz), 139.1, 130.6, 123.1
(t, JC-F = 25.9 Hz), 119.8, 117.7, 111.6, 110.0 (t, JC-F = 250.6 Hz), 63.8, 13.8; HRMS (ESI):
+
C13H8Br2F2NaO4 [M+Na]+ calcd 446.8650, found 446.8651.
3-(1,1-Difluoro-2-oxo-2-(pyrrolidin-1-yl)ethyl)-2H-chromen-2-one (3q). White solid (27 mg, 46%),
1
m.p. 170-171 ℃; IR (KBr) ν 2959, 1729, 1448, 1291, 982, 781, 487 cm-1; H NMR (400 MHz,
CDCl3) δ 8.10 (s, 1H), 7.57-7.62 (m, 2H), 7.33-7.37 (m, 2H), 3.89 (t, J = 6.8 Hz, 2H), 3.59 (t, J =
6.8 Hz, 2H), 2.02 (p, J = 6.7 Hz, 2H), 1.89 (p, J = 6.7 Hz, 2H); 19F{1H} NMR (376 MHz, CDCl3)
δ −103.5 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 160.7 (t, JC-F = 29.4 Hz), 157.8 (t, JC-F = 3.8
Hz), 154.3, 141.3 (t, JC-F = 7.5 Hz), 133.2, 129.0, 124.9, 122.5 (t, JC-F = 25.7 Hz), 117.8, 116.8,
+
114.0 (t, JC-F = 256.1 Hz), 48.0, 46.8 (t, JC-F = 6.5 Hz), 26.6, 23.3; HRMS (ESI): C15H13NF2NaO3
[M+Na]+ calcd 316.0756, found 316.0757.
N-benzyl 2,2-Difluoro-2-(2-oxo-2H-chromen-3-yl)acetamide (3r). White solid (20 mg, 30%), m.p.
142-144 ℃; IR (KBr) ν 2959, 1729, 1448, 1376, 1081, 781, 487 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.12 (s, 1H), 7.53-7.58 (m, 2H), 7.22-7.30 (m, 7H), 7.05 (s, 1H), 4.50 (d, J = 5.6 Hz, 2H); 19F{1H}
NMR (376 MHz, CDCl3) δ -107.2 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3) δ 162.6 (t, JC-F = 28.9
Hz), 157.9 (t, JC-F = 4.0 Hz), 154.3, 143.2 (t, JC-F = 7.4 Hz), 136.7, 133.7, 129.3, 128.9, 127.87,
127.85, 125.2, 120.7 (t, JC-F = 25.9 Hz), 117.6, 116.9, 112.4 (t, JC-F = 254.4 Hz), 43.9; HRMS (ESI):
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C18H13NF2NaO3 [M+Na]+ calcd 352.0756, found 352.0739.
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Methyl (2,2-difluoro-2-(2-oxo-2H-chromen-3-yl)acetyl)glycinate (3s). White solid (30 mg, 51%),
m.p. 146-147 ℃; IR (KBr) ν 22924, 1748, 1468, 1201, 1017, 970, 460 cm-1; 1H NMR (400 MHz,
CDCl3) δ 8.21 (s, 1H), 7.60-7.65 (m, 2H), 7.36-7.38 (m, 2H), 5.30 (s, 1H), 4.17 (d, J = 5.2 Hz, 2H),
3.80 (s, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -107.2 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3)
δ 169.0, 162.8 (t, JC-F = 29.6 Hz), 157.9 (t, JC-F = 3.9 Hz), 154.3, 143.3 (t, JC-F = 7.3 Hz), 133.8,
129.3, 125.2, 120.4 (t, JC-F = 25.8 Hz), 117.6, 116.9, 112.2 (t, JC-F =254.3 Hz), 52.7, 41.5; HRMS
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(ESI): C14H11NF2KO5 [M+K]+ calcd 350.0237, found 350.0265.
3-(Benzo[d]oxazol-2-yldifluoromethyl)-2H-chromen-2-one (3t). White solid (22 mg, 35%), m.p.
142-143 ℃; IR (KBr) ν 2959, 1729, 1448, 1376, 1081, 725, 487 cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.35 (s, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.63-7.68 (m, 3H), 7.46 (t, J = 7.7 Hz, 1H), 7.37-7.42 (m,
3H); 19F{1H} NMR (376 MHz, CDCl3) δ -98.8 (s, 2F); 13C{1H} NMR (100 MHz, CDCl3, C-CF2
lost in the background noise) δ 155.5–156.4 (m, 2C, C=O, C=N), 153.5, 149.6, 141.6 (t, JC-F = 6.8
Hz), 139.1, 132.9, 128.4, 125.9, 124.3, 124.1, 120.3, 116.5, 115.9, 110.5; HRMS (ESI):
+
C17H9NF2NaO3 [M+Na]+ calcd 336.0443, found 336.0450.
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3-Trifluoromethyl-2H-chromen-2-one (5a).9c White solid (30 mg, 69%); H NMR (400 MHz,
CDCl3) δ 8.16 (s, 1H), 7.66-7.01 (m, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.36-7.42 (m, 2H); 19F{1H}
NMR (376 MHz, CDCl3) δ -66.2 (s, 3F).
1
6-Methyl-3-trifluoromethyl-2H-chromen-2-one (5b).9c White solid (27 mg, 50%); H NMR (400
MHz, CDCl3) δ 8.10 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.40 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 2.45
(s, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -66.1 (s, 3F).
1
6-Chloro-3-trifluoromethyl-2H-chromen-2-one (5c).9d White solid (44 mg, 88%); H NMR (400
MHz, CDCl3) δ 8.10 (s, 1H), 7.62-7.64 (m, 2H), 7.36 (d, J = 8.4 Hz, 1H); 19F{1H} NMR (376 MHz,
CDCl3) δ -66.3 (s, 3F).
7-Methoxy-3-trifluoromethyl-2H-chromen-2-one (5d).6c White solid (35 mg, 72%); 1H NMR (400
MHz, CDCl3) δ 8.08 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 6.92 (dd, J = 8.8, 1.6 Hz, 1H), 6.84 (d, J =
2.0 Hz, 1H), 3.91 (s, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -65.7 (s, 3F).
1
3-(Perfluorobutyl)-2H-chromen-2-one (5e).17 White solid (50 mg, 69%); H NMR (400 MHz,
CDCl3) δ 8.14 (s, 1H), 7.70 (t, J = 7.9 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.37-7.41 (m, 2H); 19F{1H}
NMR (376 MHz, CDCl3) δ -80.9 (t, J = 9.3 Hz, 3F), -111.2 (t, J = 13.7 Hz, 2F), -121.4 – -121.7 (m,
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2F), -125.5 – -126.0 (m, 2F).
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5-Chloro-3-(perfluorobutyl)-2H-chromen-2-one (5f). White solid (33 mg, 53%), m.p. 65-67 ℃; IR
(KBr) ν 3325, 3066, 1731, 1350, 1063, 973, 695, 458 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.50 (s,
1H), 7.62 (t, J = 8.0 Hz,1H), 7.43 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H); 19F{1H} NMR (376
MHz, CDCl3) δ -80.8 – -80.9 (m, 3F), -111.2 (t, J = 12.7 Hz, 2F), -121.4 – -121.5 (m, 2F), -125.8 –
-125.9 (m, 2F); 13C{1H} NMR (100 MHz, CDCl3, C4F9-carbons lost in the background noise) δ
155.7, 154.6, 142.8 (t, JC-F = 8.6 Hz), 134.7, 134.1, 125.8, 117.4 (t, JC-F = 24.4 Hz), 115.8, 115.7,
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+
114.1 (t, JC-F = 33.7 Hz); HRMS (ESI): C13H4ClF9NaO2 [M+Na]+ calcd 420.9648, found 420.9616.
6-Methyl-3-(perfluorobutyl)-2H-chromen-2-one (5g). White solid (33 mg, 53%), m.p. 80-82 ℃; IR
(KBr) ν 3325, 3025, 1732, 1447, 1194, 973, 730, 421 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.01 (s,
1H), 7.42 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H), 7.21 (d, J = 8.4 Hz, 1H), 2.36 (s, 3H); 19F{1H} NMR
(376 MHz, CDCl3) δ -80.9 (t, J = 9.8 Hz, 3F), -111.2 (t, J = 13.6 Hz, 2F), -121.6 – -121.7 (m, 2F),
-125.8 – -126.0 (m, 2F); 13C{1H} NMR (100 MHz, CDCl3, C4F9-carbons lost in the background
noise) δ 155.6, 153.1, 146.4 (t, JC-F = 8.1 Hz), 135.8, 135.1, 129.2, 116.8, 116.6, 116.3, 20.6; HRMS
+
(ESI): C14H7F9KO2 [M+K]+ calcd 416.9934, found 416.9975.
7-Methoxy-3-(perfluorobutyl)-2H-chromen-2-one (5h).18 White solid (50 mg, 69%); 1H NMR (400
MHz, CDCl3) δ 8.05 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.92 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 6.84 (s,
1H), 3.91 (s, 3H); 19F{1H} NMR (376 MHz, CDCl3) δ -80.9 − -81.0 (m, 3F), -111.0 (t, J = 13.7 Hz,
2F), -121.7 − -121.8 (m, 2F), -125.8 − -125.9 (m, 2F).
8-Chloro-3-(perfluorobutyl)-2H-chromen-2-one (5i). White solid (33 mg, 53%), m.p. 68−69 ℃;
IR (KBr) ν 3325, 2921, 1731, 1350, 1194, 973, 695, 458 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.13
(s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.30-7.35 (m, 1H); 19F{1H} NMR (376
MHz, CDCl3) δ -80.9 − -80.8 (m, 3F), -111.2 (t, J = 13.2 Hz, 2F), -121.6 − -121.4 (m, 2F), -125.9
− -125.6 (m, 2F); 13C{1H} NMR (100 MHz, CDCl3, one of Ar-C and C-C4F9-carbons lost in the
background noise) δ 155.7, 154.7, 142.9 (t, JC-F = 8.2 Hz), 134.8, 134.1, 125.8, 115.8; HRMS (ESI):
+
C13H4ClF9NaO2 [M+Na]+ calcd 420.9648, found 420.9644.
1
3-(Perfluorohexyl)-2H-chromen-2-one (5j).19 White solid (45 mg, 48%); H NMR (400 MHz,
CDCl3) δ 8.15 (s, 1H), 7.63-7.71 (m, 2H), 7.37-7.40 (m, 2H); 19F{1H} NMR (376 MHz, CDCl3) δ
-80.7 – -80.9 (s, 3F), -111.0 – -111.1 (m, 2F), -120.8 (s, 2F), -121.7 (s, 2F), -122.7 (s, 2F), -126.1
(s, 2F).
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6-Chloro-3-(perfluorohexyl)-2H-chromen-2-one (5k). White solid (33 mg, 53%), m.p. 97-98 ℃;
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6
1
IR (KBr) ν 2924, 1748, 1468, 1282, 1017, 744, 460 cm-1; H NMR (400 MHz, CDCl3) δ 8.09 (s,
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9
1H), 7.63-7.65 (m, 2H), 7.36 (d, J = 9.2 Hz, 1H); 19F{1H} NMR (376 MHz, CDCl3) δ -80.8 (t, J =
9.9 Hz, 3F), -111.2 (t, J = 14.2 Hz, 2F), -119.9 – -121.1 (m, 2F), -121.7 (s, 2F), -122.7 (s, 2F) , -
126.2 (td, J = 14.4, 6.5 Hz, 2F); 13C{1H} NMR (100 MHz, CDCl3, C-C6F13-carbons lost in the
background noise) δ 154.8, 153.3, 145.3 (t, JC-F = 8.2 Hz), 134.7, 130.6, 128.6, 118.4, 117.9; HRMS
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+
(ESI): C15H4ClF13NaO2 [M+Na]+ calcd 520.9584, found 520.9589.
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3-(Perfluorooctyl)-2H-chromen-2-one (5l).17 White solid (50 mg, 44%): H NMR (400 MHz,
CDCl3) δ 8.14 (s, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 6.8 Hz, 1H), 7.36-7.41 (m, 2H); 19F{1H}
NMR (376 MHz, CDCl3) δ -80.9 (t, J = 9.8 Hz, 3F), -111.0 (t, J = 14.1 Hz, 2F), -120.6 (s, 2F), -
121.7 (s, 2F), -121.9 (s, 2F), -121.4 (s, 2F), -122.7 (s, 2F), -126.0 – -126.2 (m, 2F).
3-(iso-Perfluoropropyl)-2H-chromen-2-one (5m). White solid (33 mg, 53%), m.p. 68-70 ℃; IR
(KBr) ν 2924, 1748, 1468, 1201, 1017, 970, 460 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H),
7.63-7.71 (m, 2H), 7.37-7.42 (m, 2H); 19F{1H} NMR (376 MHz, CDCl3) δ -73.9 (d, JC-F = 5.0 Hz
6F), -175.2 (br s, 1F); 13C{1H} NMR (100 MHz, CDCl3, C-F(CF3)2 lost in the background noise) δ
155.8 (d, JC-F = 6.2 Hz), 154.4, 145.5 (d, JC-F = 16.9 Hz), 134.4, 129.3, 125.2, 120.1 (qd, JC-F
=
288.0, 27.3 Hz, CF3), 117.2 (d, JC-F = 2.5 Hz), 116.8, 115.9 (d, JC-F = 22.7 Hz); HRMS (ESI):
+
C12H5F7NaO2 [M+Na]+ calcd 337.0070, found 337.0079.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
10.1021/acs.joc.xxxxxxx
The setup for this blue LEDs-driven reaction.
1H NMR spectra for compounds 1a-1p.
1H NMR and 19F NMR spectra for compounds 3a-3t and 5a-5m.
13C NMR spectra for the new compounds of 1, 3 and 5.
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AUTHOR INFORMATION
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Corresponding author
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*Tel.: +86-731-88830833; e-mail: xianghaoyue@csu.edu.cn.
*Tel.: +86-731-88830833; e-mail: hyangchem@csu.edu.cn.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the financial support from the National Natural Science foundation of
China (21576296, 21676302, 21776318 & 81703365), Hunan Provincial Natural Science
Foundation of China (2017JJ3401) and Central South University.
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