Bromodifluoromethylation of heteroaromatics with sodium bromodifluoromethanesulfinate

Article abstract of DOI:10.1016/j.tetlet.2016.04.095

The bromodifluoromethylation of heteroaromatics (benzofuran, benzo[b]thiophene, and 2H-chromen-2-one) with sodium bromodifluoromethanesulfinate (BrCF₂SO₂Na) was developed. This reaction proceeded smoothly at room temperature to affor

Full text of DOI:10.1016/j.tetlet.2016.04.095

Tetrahedron Letters 57 (2016) 2462–2464
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Tetrahedron Letters
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Bromodifluoromethylation of heteroaromatics with sodium
bromodifluoromethanesulfinate
Jin Zhang a, Xiu-Hua Xu b, Feng-Ling Qing a,b,
⇑
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The bromodifluoromethylation of heteroaromatics (benzofuran, benzo[b]thiophene, and 2H-chromen-2-
one) with sodium bromodifluoromethanesulfinate (BrCF2SO2Na) was developed. This reaction proceeded
smoothly at room temperature to afford the bromodifluoromethylated products in moderate to high
yields.
Received 13 March 2016
Revised 24 April 2016
Accepted 26 April 2016
Available online 26 April 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Radical
Bromodifluoromethylation
Benzofuran
Heteroaromatics
Fluoroalkylation
The growing presence of fluorine in pharmaceuticals and agro-
chemicals1 has stimulated renewed interest in methods for the
preparation of fluorine-containing compounds.2 Bromodifluo-
romethylated compounds are well known as good candidates for
the formation of halogen bonding3 and important intermediates
of the preparation of valuable fluorinated compounds.4 Especially,
bromodifluoromethylated aromatics have served as precursors of
Encouraged by these achievements, we anticipated that a similar
reagent, sodium bromodifluoromethanesulfinate (BrCF2SO2Na),
might be used as a radical bromodifluoromethylating reagent in
the presence of an oxidant. Although BrCF2SO2Na has been
reported for more than twenty years,11 its application has been lar-
gely unexplored.12 As part of our continuing research interest in
fluoroalkylation of aromatic compounds,13 herein we describe a
direct bromodifluoromethylation of heteroaromatics with
BrCF2SO2Na in the presence of tert-butylhydroperoxide (TBHP)
(Scheme 1d). This reaction provided a convenient approach to
CF2Br-containing heteroaromatics.
We initiated our investigation on the reaction of benzofuran 1a
with BrCF2SO2Na and TBHP at room temperature (Table 1). The reac-
tion was sensitive to solvent choice. Among the common organic
solvents including DCM, CH3CN, MeOH, acetone, and DMF, CH3CN
was most effective to afford the bromodifluoromethylated product
2a in 32% yield (entries 1–5). HOAc led to a moderate yield of 54%
(entry 6). To our delight, the yield was further improved by using
binary solvent mixture (entries 7–10). The highest yield was
observed in the mixture of CH3CN and CHCl3 with a ratio of 1:2
(entry 10). To further improve the reaction yield, different additives,
such as CuCl or K2CO3, were investigated (entries 11 and 12).
However, they had a negligible effect on the reaction. Finally, the
reaction temperature was screened, and neither lower (0 °C) nor
higher temperature (50 °C) could improve the outcome (entries 13
and 14). Notably, none of the desired products could be detected
in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO),
[
18F]trifluoromethylated compounds for positron emission tomog-
raphy (PET) imaging.5 Despite the importance of bromodifluo-
romethylated aromatics, only a few methods are available for the
synthesis of these compounds. Normally, these compounds are
prepared by bromination of fluorine-containing compounds
(Scheme 1a)6 and transformation from CF2Br-containing building
blocks (Scheme 1b).7 In 2014, Shiosaki and Inoue reported a bro-
modifluoromethylation of aromatic Grignard reagents bearing
electron-withdrawing groups with CF2Br2 (Scheme 1c).8 However,
this reaction involves a difluorocarbene-mediated mechanism. The
direct incorporation of bromodifluoromethyl group into aromatic
substrates still remains a big challenge.
Recently, impressive progress has been made in the radical tri-
fluoromethyltion with different trifluoromethylating reagents.9 As
a typical radical trifluoromethylating reagent, sodium trifluo-
romethanesulfinate (CF3SO2Na) has attracted a lot of attention
for the preparation of trifluoromethylated compounds.10
⇑
Corresponding author. Tel.: +86 21 54925187; fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
http://dx.doi.org/10.1016/j.tetlet.2016.04.095
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

J. Zhang et al. / Tetrahedron Letters 57 (2016) 2462–2464
2463
H
previous work
CF2H
CF2Br
TBHP
R
+ BrCF2SO2Na
R
CF2Br
CF2Br
( )n
( )n
CH3CN/CHCl
3
X
X
bromination
rt
(a)
(b)
1
2
R
R
R
CN
CF2Br
Me
transformation
CF2Br
2b, 67%
CF2Br
R'
CF2Br
MgCl
O
O
O
R'
2a, 62%
2c, 66%
Me
Ph
t-Bu
CF2Br
n-Pent
CF2Br
CF2Br
CF2Br2
CF2Br
CF2Br
EWG
EWG
(c)
(d)
O
O
O
via [ CF2]
2d
2e
2f
, 70%
, 79%
, 66%
this work
Bn
CF2Br
c-Hex
CF2Br
CF2Br
H
BrCF2SO2Na, TBHP
via [ CF2Br]
Het
Het
R
R
O
O
O
2g, 80%
2h, 67%
2i, 64%
Scheme 1. Different approaches to bromodifluoromethylated aromatics.
PhO
CF2Br
MeO
Cl
F
CF2Br
CF2Br
CF2Br
O
O
O
which indicated that a radical process was probably involved in this
reaction (enrty 15).
2j, 44%
2k, 62%
2l, 48%
With the optimized reaction conditions in hand (Table 1, entry
10), we next examined the substrate scope of this radical bromod-
ifluoromethylation reaction (Scheme 2). Substrates 1b–r bearing
either electron-donating or electron-withdrawing groups at
different positions of the benzofuran ring reacted smoothly with
BrCF2SO2Na to afford the corresponding bromodifluoromethylated
products in moderate to high yields. In general, the electron-rich
substitutions resulted in slightly higher yields, whereas the elec-
tron-poor substitutions gave lower yields. It was noteworthy that
chloro- or bromo-containing substrates (1m, 1n, and 1p–r) were
compatible with the reaction, thus enabling further transforma-
tions via transition-metal-catalyzed cross-coupling reactions.
Importantly, this bromodifluoromethylation reaction could also
be extended to other heterocycles, such as benzo[b]thiophene
(1s) and 2H-chromen-2-one (1t), although the desired products
were obtained in low yields. In the cases of other substrates,
Br
MeO2C
CF2Br
CF2Br
O
O
O
2m, 50%
2n, 54%
2o, 40%
Br
CF2Br
CF2Br
CF2Br
2p, 50%
O
O
Br
O
Br
2q, 55%
2r, 47%
CF2Br
CF2Br
S
O
2t
O
2s
, 32%
, 44%
Scheme 2. Direct bromodifluoromethylation of heteroaromatics.
including methoxybenzene, furan, thiophene, and pyridine, low
conversion was observed. When 1H-indene was subjected to the
standard conditions, the reaction became complex. These results
showed that both of the phenyl ring and the heteroatom in
heteroaromatics were crucial to this reaction.
The characterization and assignment of products 2 was ascer-
tained by comparing the spectral characteristics with the corre-
sponding trifluoromethylated products reported earlier through
similar reaction sequences.10f,14 Furthermore, treatment of 2a
with TBAF gave a known trifluoromethylated product 3,13a,15
Table 1
Optimization of reaction conditionsa
TBHP, additive
solvent, temp.
CF2Br
+
BrCF2SO2Na
O
O
2a
1a
Entry
Additive
Solvent
Temp
Yieldb (%)
1c
2
3
4
5
—
DCM
Rt
Rt
Rt
Rt
8
32
3
11
3
which further confirms the structure of
2 (Scheme 3a).
—
CH3CN
Additionally, the reaction of 2e and PhONa in DMF at room
temperature afforded (aryloxy)difluoromethylated product 4 in
high yield (Scheme 3b). These transformations demonstrated the
—
MeOH
—
Acetone
—
DMF
Rt
6
7
8
9
10
11
12
13
14
15c
—
—
—
—
HOAc
Rt
Rt
Rt
Rt
Rt
Rt
Rt
0 °C
50 °C
Rt
54
57
59
62
68
Trace
6
4
52
0
DCM/MeOH (1:1)
DCM/CH3CN (1:1)
CH3CN/CHCl3 (1:1)
CH3CN/CHCl3 (1:2)
CH3CN/CHCl3 (1:2)
CH3CN/CHCl3 (1:2)
CH3CN/CHCl3 (1:2)
CH3CN/CHCl3 (1:2)
CH3CN/CHCl3 (1:2)
—
TBAF
CF2Br
CF3
(a)
(b)
CuCl
K2CO3
—
—
—
O
2a
DMF, 120 oC
O
3, 80%
t-Bu
t-Bu
PhONa
DMF, rt
a
CF2Br
CF2OPh
Reactions were carried out using 1a (0.2 mmol), BrCF2SO2Na (0.4 mmol,
O
2e
O
2.0 equiv) and additive (0.2 mmol, 1.0 equiv) in solvent (2.0 mL) for 16 h.
b
Yields were determined by 19F NMR spectroscopy of the crude reaction mixture
4, 94%
using benzotrifluoride as an internal standard.
c
TEMPO (0.4 mmol, 2.0 equiv) was added.
Scheme 3. Transformation of bromodifluoromethylated products.

2464
J. Zhang et al. / Tetrahedron Letters 57 (2016) 2462–2464
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utility of this protocol for the preparation of other fluoroalkylated
compounds.
In summary, we have developed an efficient bromodifluo-
romethylation of benzofurans, benzo[b]thiophene, and 2H-chro-
men-2-one with BrCF2SO2Na. The work represents the first
example of using BrCF2SO2Na as bromodifluoromethylating
reagent. The application of BrCF2SO2Na in other bromodifluo-
romethylation reactions is in progress in our laboratory.
Acknowledgments
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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