Visible light-induced monofluoromethylenation of heteroarenes with ethyl bromofluoroacetate

Article abstract of DOI:10.1039/c6nj00281a

Visible light-induced monofluoromethylenation of benzofurans and benzothiophenes with ethyl bromofluoroacetate was developed. This method provided a convenient access to novel α-fluoro-α-heteroarylesters under mild reaction conditions.

Full text of DOI:10.1039/c6nj00281a

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Visible light-induced monofluoromethylenation of heteroarenes
with ethyl bromofluoroacetate
Wei Yu,a Xiu-Hua Xua and Feng-Ling Qing*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A visible light-induced monofluoromethylenation of benzofurans
and benzothiophenes with ethyl bromofluoroacetate was
developed. This method provided a convenient access to novel α-
fluoro-α-heteroarylesters under mild reaction conditions.
Since Fried and Sabo’s discovery that the incorporation of a
fluorine atom into a corticosteroid derivative led to valuable
enhanced biological activity in 1954,1 fluorinated organic
compounds have attracted increasing attention for use in
pharmaceuticals and agrochemicals.2 The α-fluoro-α-
arylcarboxylic acid moiety is found in many active bioactive
compounds3 and has been widely used as a building block in
organic synthesis.4 Consequently, lots of efforts have been
devoted in the preparation of α-aryl-α-fluorocarbonyl
compounds. There are mainly two strategies for the
construction of α-aryl-α-fluorocarbonyl units. The first strategy
involves the direct fluorination of α-arylcarbonyl derivatives
using nucleophilic5 or electrophilic6 fluorinating reagents. The
second strategy involves the condensation reaction of
aromatic substrates and fluorine-containing building blocks.7,8
Compared to the direct fluorination strategy, the “building
block” strategy has been much less explored despite its
potential importance. Recently, Sanford7a as well as wang and
Zhou7b respectively reported the SNAr reaction of ortho-
fluoronitrobenzenes and 2-fluoromalonates for the
preparation of α-aryl-α-fluoroesters (Scheme 1a). Palladium-
Scheme
compounds.
1 Monofluoromethylenation of (hetero)aromatic
monofluoromethylenation of aryl C─H bonds remains a big
challenge.
Recently, visible light photoredox catalysis has emerged as
an efficient and eco-friendly tool in organic synthesis9 and has
been applied in the fluoroalkylation of organic compounds.10
In 2013, we reported a mild and versatile approach for the
direct introduction of ethoxycarbonyldifluoromethyl group to
heteroarenes with ethyl bromodifluoroacetate via visible light
photocatalysis.11 On the basis of this work, we anticipated that
a similar transformation with ethyl bromofluoroacetate might
8a,b
and nickel-catalyzed8c cross-coupling reactions of aromatic
allow
for
the
direct
introduction
of
substrates and fluorine-containing building blocks have
ethoxycarbonylmonofluoromethyl group to heteroarenes. In
continuous of our research interest in visible light-induced
fluoroalkyaltion reactions,10f,t,w,11 herein we describe the
reactions of benzofurans and benzothiophenes with ethyl
bromofluoroacetate under visible light photoredox conditions
(Scheme 1c). This reaction provides a convenient approach to
novel α-fluoro-α-heteroarylesters.
provided
an
efficient
strategy
to
incorporate
monofluoromethylene units into aromatic compounds
(Scheme 1b). However, both of the methods require the use of
prefunctionalized aromatic substrates. The direct
a.Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Science, Shanghai 200032, China.
E-mail: flq@mail.sioc.ac.cn
Initially, we investigated the model reaction of benzofuran
1a and ethyl bromofluoroacetate using blue LEDs as the source
of visible light (Table 1). Among the commonly used
photocatalysts, only fac-Ir(ppy)3 could promote the reaction
giving the desired product 2a in 55% yield, and no reaction
b.College of Chemistry, Chemical Engineering and Biotechnology, Donghua
University, Shanghai 201620, China
†
Electronic Supplementary Informaꢀon (ESI) available: Detailed experimental
data
procedures, and analytical
DOI: 10.1039/x0xx00000x
for all
new compounds. See
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Table 1. Optimization of reaction conditionsa
Table
2.
Substrate
scope
of
photocatalytic
monofluoromethylenation of heteroarenesa
visible light
fac-Ir(ppy)3 (5 mmol %)
F
F
+
R
R
K2HPO4 (2.0 equiv)
DMF/H2O (1:4)
rt, 12 h
X
Br
CO2Et
X
CO2Et
2
1
Entry
Photocat.
Base
Solvent
Yield (%)b
CN
F
F
F
1
Ru(bpy)3Cl2·6H2O
fac-Ir(ppy)3
Methylene Blue
Eosin Y
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2CO3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
0
2
55
0
O
CO2Et
O
O
CO2Et
CO2Et
3
2a, 62%
2b, 76%
2c, 77%
4
0
Me
Bn
n-Bu
n-Pent
5
[Ir(ppy)2Cl]2
[Ir(dtbbpy)(ppy)2][PF6]
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
29
12
43
52
23
12
21
13
54
46
49
F
F
F
6
O
O
CO2Et
CO2Et
O
CO2Et
7
2d, 60%
2e, 68%
2f, 63%
8
K3PO4
9
KOAc
c-Hex
t-Bu
F
F
F
10
11
12
13
14
15
16
t-BuONa
DBU
O
CO2Et
O
CO2Et
O
CO2Et
2g, 68%
2h, 50%
2i, 77%
DIPEA
K2HPO4
K2HPO4
K2HPO4
K2HPO4
Ph
MeO
PhO
F
F
F
DCM
O
CO2Et
O
O
CO2Et
CO2Et
THF
2j, 70%
2k, 50%
2l, 55%
DMF/H2O 74
aReaction conditions: 1a (0.1 mmol), ethyl bromofluoroacetate (0.2
mmol), photocat. (0.005 mmol), base (0.2 mmol), solvent (1.0 mL),
visible light, rt, under N2, 12 h. bYields determined by 19F NMR
spectroscopy using fluorobenzene as an internal standard.
F
Cl
Br
F
F
F
O
CO2Et
O
CO2Et
O
CO2Et
2m, 48%
2n, 70%
2o, 74%
EtO2C
F
F
F
occurred in the presence of Ru(bpy)3Cl2·6H2O, methylene blue,
or eosin Y (entries 1-4). Other iridium photocatalysts including
[Ir(ppy)2Cl]2 and [Ir(dtbbpy)(ppy)2][PF6] were found to be less
effective than fac-Ir(ppy)3 (entries 5 and 6). To increase the
yield, various inorganic and organic bases including K2CO3,
K3PO4, KOAc, t-BuONa, DBU, and DIPEA were tested (entries 7-
12). However, none of them gave higher yield. Further
screening of different solvents disclosed that DMF, DCM, and
THF gave the desired product in slightly lower yields than
MeCN (entries 13-15). To our delight, when the reaction was
performed in DMF/H2O, the yield of 2a was improved to 74%
(entry 16). It was noteworthy that this optimized yield is much
higher than the one obtained in the coupling reaction of
benzofuran-2-ylboronic acid and ethyl bromofluoroacetate.8b
With the optimized reaction conditions in hand, we next
examined the substrate scope of the visible light-promoted
direct monofluoromethylenation of heteroarenes (Table 2). A
O
O
CO2Et
O
CO2Et
CO2Et
Br
2q, 36%
2r, 40%
2p, 51%
Br
Cl
NC
Me
F
F
F
S
O
S
CO2Et
CO2Et
CO2Et
2t, 34%
2u, 51%
2s, 31%
OMe
F
F
N
Boc
CO2Et
CO2Et
MeO
2v, 47%
2w, 22%
aReaction conditions: 1 (0.5 mmol), ethyl bromofluoroacetate (1.0 mmol),
fac-Ir(ppy)3 (0.025 mmol), K2HPO4 (1.0 mmol), DMF/H2O (5.0 mL), visible
light, rt, under N2, 12 h, isolated yields.
moderate yields, respectively. The bromofluoromethylenation
of indole 1v gave the desired product 2v in 47% yield. However,
the electron-rich arene 1w displayed poor reactivity, with only
22% of product being obtained. In the cases of furan and
thiophene, low conversion was observed.
variety of benzofurans 1a
-
s
were employed to give the
in
corresponding 2-monofluoromethylenated products 2a
-s
moderate to excellent yields. The selective formation of 2-
substituted isomers is probably due to the generation of more
stable benzylic radical as an intermediate. Different functional
groups including ethers, esters, and nitriles were well tolerated.
Notably, substrates bearing fluoro, chloro, and bromo
substitutents on the arene rings are also compatible, thus
Finally, the control experiments were carried out to gain
insight of the reaction mechanism. No reaction took place in
the absence of visible light or fac-Ir(ppy)3, and the addition of
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), a known radical
scavenger, could totally inhibit the reaction. Based on above
results and the reported work,10a,12 a plausible reaction
mechanism was proposed in Scheme 2. Initially, the irradiation
of visible light excited fac-IrIII(ppy)3 to fac-IrIII(ppy)3*. Then, a
single-electron-transfer (SET) from fac-IrIII(ppy)3* to ethyl
providing opportunities for additional transformations (1m-1q).
With substrates (1r and 1s) containing electron-withdrawing
groups, the desired products were isolated in low yields. It is
noteworthy that the reaction could be extended to
benzothiophenes 1t and 1u, furnishing products 2t and 2u in
bromofluoroacetate generated the radical intermediate A,
2 | J. Name., 2012, 00, 1-3
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5
2.
In conclusion, we have developed a visible light-promoted
monofluoromethylenation of hetereoarenes with ethyl
bromofluoroacetate. This protocol does not require
prefunctionalization of the heteroaromatics and proceeds
under mild reaction conditions, which makes it attractive in
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General
procedure
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the
photocatalytic
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A 50 mL Schlenk flask equipped with a rubber septum and a
magnetic stir bar was charged with fac-Ir(ppy)3 (16.4 mg, 0.025
mmol, 5 mol %), K2HPO4 (174.1 mg, 1.0 mmol, 2.0 equiv), ethyl
bromofluoroacetate (184.9 mg, 1.0 mmol, 2.0 equiv), and
heteroarene (0.5 mmol, 1.0 equiv). DMF (1.0 mL) and H2O (4.0
mL) were added to the mixture. Then, the reaction mixture
was degassed three times by the freeze-pump-thaw procedure.
The flask was placed at a distance of 2 cm from the blue LEDs.
The mixture was stirred under nitrogen atmosphere and
irradiated by blue LEDs for 12 h. After the reaction was
complete, the reaction mixture was extracted by Et2O, and the
combined organic phase was dried over anhydrous Na2SO4.
The solvent was removed under vacuum and the residue was
purified by column chromatography on silica gel to give the
corresponding product.
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Acknowledgements
We thank the National Natural Science Foundation of China
(21272036, 21332010, 21421002) and the National Basic
Research Program of China (2012CB21600) for financial
support.
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Table of Cotents
A mild approach for the direct introduction of ethoxycarbonylmonofluoromethyl group to
heteroarenes via visible light photocatalysis has been developed.