Dibromofluoromethylation of aryl Grignard reagents with dibromodifluoromethane in the presence of LiBr

Article abstract of DOI:10.1016/j.jfluchem.2015.04.013

The dibromofluoromethylation of aryl Grignard reagents bearing electron-withdrawing groups with dibromodifluoromethane (CF₂Br₂) proceeded in the presence of LiBr. The reaction gave the corresponding α,α-dibromo-α-fluorotoluene derivatives through halogen exchange reaction of intermediate difluorobenzyl anions.

Full text of DOI:10.1016/j.jfluchem.2015.04.013

Accepted Manuscript
Title: Dibromofluoromethylation of aryl Grignard reagents
with dibromodifluoromethane in the presence of LiBr
Author: Masahiro Shiosaki Munenori Inoue
PII:
S0022-1139(15)00119-0
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2015.04.013
FLUOR 8551
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
2-2-2015
17-4-2015
18-4-2015
Please cite this article as: M. Shiosaki, M. Inoue, Dibromofluoromethylation of aryl
Grignard reagents with dibromodifluoromethane in the presence of LiBr, Journal of
Fluorine Chemistry (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.04.013
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Highlights
•
•
•
The dibromofluoromethylation of aryl Grignard reagents was developed.
The reaction proceeded via a difluorocarbene-mediated mechanism.
,-Dibromo--fluorotoluene derivatives were obtained.
1
Page 1 of 29

Graphical Abstract
Dibromofluoromethylation of aryl Grignard
reagents with dibromodifluoromethane in the
presence of LiBr
2 2
CF Br (2.4 equiv.)
LiBr (2.4 equiv.)
F
Br
Br
MgBr
THF
rt to 35 °C
a,b
a,
FG
FG
Masahiro Shiosaki , Munenori Inoue *
2 5
FG = CN, CO Me, SF ,
a
Sagami Chemical Research Institute (SCRI), 2743-1 Hayakawa,
SO Ar, CF , Br, Cl
2
3
Ayase, Kanagawa 252-1193, Japan
b
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-Ku, Yokohama 226-8502, Japan
•
The dibromofluoromethylation of aryl Grignard reagents was developed. • The reaction proceeded via a
difluorocarbene-mediated mechanism. • ,-Dibromo--fluorotoluene derivatives were obtained.
Graphical Abstract
CF2Br2 (2.4 equiv.)
LiBr (2.4 equiv.)
F
MgBr
Br
Br
THF
rt to 35 °C
FG
FG
FG = CN, CO2Me, SF5,
SO Ar, CF , Br, Cl
2
3
2
Page 2 of 29

Dibromofluoromethylation
of
aryl
Grignard
reagents
with
dibromodifluoromethane in the presence of LiBr
a,b
a,
Masahiro Shiosaki , Munenori Inoue *
a
Sagami Chemical Research Institute (SCRI), 2743-1 Hayakawa, Ayase, Kanagawa
52-1193, Japan
2
b
Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta,
Midori-Ku, Yokohama 226-8502, Japan
Corresponding author. Tel.: +81 467−77−4208; fax: +81 467−77−4113.
*
E-mail address: inoue@sagami.or.jp (M. Inoue).
3
Page 3 of 29

Abstract—The dibromofluoromethylation of aryl Grignard reagents bearing
electron-withdrawing groups with dibromodifluoromethane (CF Br ) proceeded in the
2
2
presence of LiBr. The reaction gave the corresponding ,-dibromo--fluorotoluene
derivatives through halogen exchange reaction of intermediate difluorobenzyl anions.
Keywords: Dibromofluoromethylation, Aromatic Grignard reagents, Difluorocarbene,
Organofluorine compounds
1. Introduction
In the previous paper, we reported that the bromodifluoromethylation of aromatic
Grignard
dibromodifluoromethane (CF
-bromo-,-difluorotoluene
-cyanophenylmagnesium chloride (2a) and CF
-bromo-,-difluorotoluene 3a was produced along with several side products
reagents
possessing
Br
derivatives
electron-withdrawing
at −78 °C afforded the corresponding
[1]. In the reaction between
Br , a 77% GC yield of
groups
with
2
2
)

4
2
2

including -bromo--chloro--fluorotoluene 4a and bromide 6a as shown in Scheme 1.
After publishing the paper, we carefully reinvestigated the side products and realized
that ,-dibromo--fluorotoluene 8a was also formed in less than 2% yield by GC
analysis.
4
Page 4 of 29

i-PrMgCl
(1.06 equiv.)
NC
I
NC
MgCl
THF
–
40 °C to rt
1a
2a
CF Br
2
2
(
1.2 equiv.)
NC
CF Br
+
NC
R
2
THF
–
78 °C to rt
3a (77%)
4a: R = CFClBr (3%)
8
h
5
6
7
8
a: R = CF CF Br (< 1%)
a: R = Br (5%)
a: R = H (5%)
2 2
a: R = CFBr (< 2%)
2
Scheme 1. Bromodifluoromethylation of 4-cyanophenylmagnesium chloride (2a) [1].

,-Dibromo--fluorotoluene derivatives are a little-known class of organofluorine
compounds and only the following synthetic examples have been disclosed so far.
Prakash et al reported that halogen-exchange reaction of ,,-trifluorotoluene with
BBr produced a 43% yield of -bromo-,-difluorotoluene as the major product with
3
the formation of a trace amount (0.3%) of ,-dibromo--fluorotoluene as depicted in
Scheme 2 [2]. As an alternative method, the bromine-fluorine exchange reaction of
,,-tribromotoluene with HF-pyridine was disclosed by Cai et al [3], where
,-dibromo--fluorotoluene was obtained in 25% yield. Furthermore,
,-dibromo--fluorotoluene was prepared from -bromo--fluorotoluene in 64%
through radical bromination using N-bromosuccinimide and AIBN by Kusei et al, who
used it as a precursor of fluorophenylcarbene [4].
5
Page 5 of 29

BBr3
F
F
F
(
0.3%, ref. 2)
CF Br
F
Br
Br
Br
Br
Br
2
2
HF-py
MgBr
LiBr
this work
(25%, ref. 3)
R
R
(
R = EWG)
F
NBS, AIBN
64%, ref. 4)
Br
(
H
Scheme 2. Formation of ,-dibromo--fluorotoluene derivatives.
Since organofluorine compounds are of great importance in the areas of
pharmaceutical, agrochemical and material sciences [5], we envisaged
,-dibromo--fluorotoluene derivatives would also potentially serve as biologically
active molecules [6]. In addition, they could be transformed into other important
fluorinated compounds by nucleophilic substitution reactions of the
2 2
dibromofluoromethyl (CFBr ) group. Several transformations of the CFBr group, such
as 1,2-difluroalkene synthesis [7], Reformatsky reaction [8] and aldol reaction [9] of
dibromofluoroacetic acid derivatives [10], azide substitution [11], manganation [12],
magnesiation [13], and zincation [14], have been reported, however, in terms of
,-dibromo--fluorotoluene derivatives, their reactivity is not studied at all except for
Kusei’s work [4]. The reported methods of synthesizing ,-dibromo--fluorotoluene
derivatives as mentioned in Scheme 2 required harsh reaction conditions and
inaccessible starting materials, and had limited substrate scope. Therefore, as an
extension of our previous research, we initiated to study the reaction conditions to
obtain ,-dibromo--fluorotoluene derivatives as major products and explore the
6
Page 6 of 29

reactivity of these compounds. Herein, we would like to present the
dibromofluoromethylation of aromatic Grignard reagents with CF
LiBr (Scheme 2).
2 2
Br in the presence of
2. Results and discussion
2 2
As well as other bromodifluoromethylations using CF Br as a source of the
bromodifluoromethyl group [15], we speculated that our developed aromatic
bromodifluoromethylation (Scheme 1) proceeded via a difluorocarbene-mediated
mechanism as shown in Scheme 3. The reaction initiated by bromination of aryl
Grignard reagent (2, X=Cl) with CF
2
Br
2
to produce aryl bromide 6 and
bromodifluoromethyl anion A, which was immediately decomposed to difluorocarbene
B. The key intermediate in this reaction was difluorobenzyl anion C derived from aryl
Grignard reagent 2 and difluorocarbene B. When the reaction was carried out at −78 °C
in the absence of LiCl (= LiX) as an additive, the major product was
bromodifluoromethyl compound 3, which indicated that bromination of C (path A)
predominantly took place. As side products, bromochlorofluoromethyl compound 4 and
dibromofluoromethyl compound 8 were formed in less than 3% yield, respectively, by a
halogen exchange reaction via arylfluorocarbene D (C −> D −> E) [16], followed by
bromination of E (path B). The suppression of these undesired side reactions may be
due to the slow -elimination (C −> D) rate at −78 °C [17]. Therefore, from the
viewpoint of the reaction mechanism, the acceleration of the halogen exchange reaction
(
C −> E) should be the key to success for obtaining dibromofluoromethyl compound 8
as a major product. We envisioned that undertaking the reaction at ambient temperature
to accelerate the -elimination and increasing the concentration of bromide ion by using
7
Page 7 of 29

Ar-MgBr as 2 and the addition of lithium bromide to the reaction media would improve
the yield of 8.
ArMgX(•LiX)
2
CF Br
2
2
F
Br
Z
ArBr
Ar
4
: Z=Cl
6
8
: Z=Br
CF BrMgY•LiY'
CF Br
2
2
2
A
path B
F
Ar
Z
MgF(•LiZ')
MgBrY
+ LiY'
path A
F
Ar
F
E
F
MgFZ(•LiZ')
Ar
Br
F
D
3
Ar
F
CF Br
2
2
MgZ(•LiZ')
CF2
C
B
Y = X, F, or Br, Y' = X, F, or Br
Z = X, F, or Br, Z' = X, F, or Br
ArMgX(•LiX)
2
Scheme 3. Plausible reaction mechanism of aromatic trihalomethylations.
Initially, we investigated the reaction between 4-cyanophenylmagnesium reagent
and CF Br in the presence of LiBr at ambient temperature as shown in Table 1.
Exposure of ArMgCl 2aa, prepared from 4-iodobenzonitrile 1a and i-PrMgCl in the
presence of LiBr [18], to a solution of 2.4 equiv. of CF Br in THF at room temperature
2
2
2
2
produced a 23% GC yield of the targeted compound 8a (entry 3). Compared to the
previously reported conditions (entries 1 and 2), in which the reaction was carried out at
−78 °C, the yield of 8a was increased and formation of 3a was dramatically suppressed
8
Page 8 of 29

as expected. Unfortunately, the yield of bromochlorofluoromethyl compound 4a was
also increased to 18%. Next, i-PrMgBr was used for the magnesiation of 1a to eliminate
the chlorine atom source of 4a (entry 4). The reaction afforded a 41% GC yield of 8a
without formation of 4a. Since the yield of 8a was decreased in the absence of LiBr
(
entry 5), the addition of LiBr is effective. Furthermore, we carried out the reaction at
between room temperature to 35 °C, giving rise to an improved yield of the product
49% GC yield, entry 6). The yield of the desired product was decreased when the
reaction was performed at 60 °C (entry 7). Using an excess amount of CF Br (4.8
(
2
2
equiv.) in the reaction was not effective (entry 8). Next, we evaluated the effect of other
bromide salts, such as NaBr, KBr, and tetra-n-butylammonium bromide (TBAB)
(entries 9−11), however, the yield was not improved. The reaction conditions in entry 6
gave the best result and the desired product 8a was isolated in 43% yield after
purification by silica gel column chromatography and recycle GPC to remove the side
products.
Table 1
a
Dibromofluoromethylation of aryl Grignard reagent 2.
i-PrMgX (1.06 equiv.)
Salt (2.4 equiv.)
NC
I
NC
MgX
THF, – 40 °C ~ rt
1a
2aa: X = Cl
ab: X = Br
2
CF Br (2.4 equiv.)
2
2
NC
CFBr2
+
NC
R
THF, temp, 1 h
8a
3a: R = CF Br
2
4
6
a: R = CFClBr
a: R = Br
b
Entry
X
Salt
Temperature GC yield (%)
9
Page 9 of 29

8
3
2
a
3a
50
77
2
4a
7
6a
13
5
c
c
1
2
3
4
5
6
7
8
9
1
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
Br
Br
LiCl
−78 °C
−78 °C
rt
None
LiBr
LiBr
None
LiBr
LiBr
LiBr
NaBr
KBr
3
23
18
0
1
rt
41
5
4
rt
32
19
2
0
5
d
rt ~ 35 °C
60 °C
49 (43)
32
0
4
11
2
0
2
e
rt ~ 35 °C
rt ~ 35 °C
rt ~ 35 °C
rt ~ 35 °C
40
0
4
21
16
17
7
0
6
0
29
0
7
f
1
1
TBAB
13
0
4
a
The Grignard reagent was added dropwise into a solution of CF
2
Br
2
in THF.
b
c
Determined by GC analysis using undecane as an internal standard.
See ref. 1. The yield of 8a was obtained after its publication.
d
e
f
Isolated yield.
4
.8 equiv. of CF
2 2
Br were used.
1
.2 equiv. of tetrabutylammonium bromide (TBAB) were used.
With the optimized conditions, the substrate scope of this dibromofluoromethylation
was evaluated by using several aryl Grignard reagents 2 bearing electron-withdrawing
groups as shown in Table 2. The dibromofluoromethylation of m- and o-cyanophenyl
2 2
Grignard reagents with CF Br gave the corresponding products in 25 and 37% isolated
yields, respectively. Since the yield of the m-cyano substituted substrate was slightly
reduced compared with those of the o- and p-isomers, the o- and p-cyano groups
stabilized the intermediate anions C and E and this resonance effect facilitated the
reaction. In the case of the o- and p-cyanophenyl Grignard reagents substituted by
electron donating groups, such as methyl and methoxy groups, the desired products
8
d~8g were obtained in 12~32% yields. Interestingly, in the reaction with
4-cyano-3-fluorophenylmagnesium bromide, the desired dibromofluoromethyl
1
0
Page 10 of 29

compound 8h was not afforded and the corresponding bromodifluoromethyl compound
was mainly produced. We regarded that the inductive effect of the fluorine atom along
with the resonance effect of the cyano group stabilized the intermediate C and delayed
the halogen exchange reaction. Next, we examined aromatic Grignard reagents
possessing other electron-withdrawing groups. 4-(Methoxycarbonyl)phenylmagnesium
bromide and 4-(pentafluorosulfanyl)phenylmagnesium bromide were allowed to react
2 2
with CF Br in the presence of LiBr, affording 8i and 8j in around 30% yields. In
addition, the reaction of (arylsulfonyl)phenylmagnesium bromides proceeded with the
formation of 8k and 8l in moderate yields. From 2-bromo-1,3-dichloro-5-iodobenzene,
the regioselective dibromofluoromethylation occurred to produce 8m. While the yield
was diminished to 6%, 4-(trifluoromethyl)phenylmagnesium iodide gave 8n. This
reaction was also applicable to a pyridyl Grignard reagent to obtain 8o. Unfortunately,
phenylmagnesium bromide and 4-methoxyphenylmagnesium bromide did not offer the
desired products (8p and 8q, respectively) at all. At the moment, this reaction is limited
to aromatic Grignard reagents possessing electron-withdrawing groups. In the reported
bromodifluoromethylation of aromatic Grignard reagents with CF
the reaction was dependent on the substituent on the aromatic ring and the preferred
order is –CN > −SO Ph > −CO R > −CF . In this dibromofluoromethylation, the order
2 2
Br [1], the yield of
2
2
3
is the same. With decreasing the yield of the desired dibromofluoromethylated product,
the formation of the brominated product, the protonated product, and unidentified
products detected by GC and NMR was increased. A plausible mechanism of this
reaction is postulated as shown in Scheme 3 (X = Z = Br). As expected, the reaction
temperature (at between room temperature and 35 °C) and the increasing concentration
11
Page 11 of 29

of bromide ion are keys to accelerate the fluorine-bromine exchange reaction (C to E)
and progress the desired reaction.
Table 2
a
Scope of the dibromofluoromethylation of several (hetero)aryl Grignard reagents.
i-PrMgBr
(
1.06 equiv.)
LiBr
2.4 equiv.)
CF Br
2.4 equiv.)
2
2
Y
Y
Y
F
(
(
X
MgBr·LiBr
Br
THF, – 40 °C to rt
3 h
THF
rt to 35 °C
Br
FG
FG
FG
1
h
1
2
8
(X = Br, I
Y = CH, N)
CN
CFBr2
NC
CN
MeO
NC
CFBr2
b (25%)b
CFBr2
CFBr2
Me
8
8c (37%)b
Me
8d (30%)c
8e (32%)c,d
Me
F
MeO C
CFBr2
2
NC
CFBr2 NC
f (12%)c,d
CFBr2 NC
8g (22%)c
CFBr2
8h (0%)c
8
8i (28%)b
O
O
S
F S
5
CFBr2 Me
j (32%)b
S
CFBr2
F
CFBr2
O
O
8
8k (31%)b
8l (49%)b
Cl
CFBr2
Br
CFBr2
F3C
CFBr2
F3C
N
Cl
8
m (21%)b
8n (6%)b
8q (0%)c
8o (24%)c
CFBr2
p (0%)c,e
MeO
CFBr2
8
a
Isolated yield.
1
2
Page 12 of 29

b
c
d
e
Aryl iodide 1 was used for the reaction.
Aryl bromide 1 was used for the reaction.
2.12 equiv. of i-PrMgBr were used.
Mg (1.2 equiv.) was used instead of i-PrMgBr.
Finally, we surveyed the reactivity of ,-dibromo--fluorotoluene derivatives as
depicted in Scheme 4. At the beginning, we evaluated the stability of these compounds
under acidic and basic conditions. Subjection of dibromofluoromethyl compound 8k to
a mixture 1M aq. HCl-THF at 50 °C for 36 hrs resulted in no decomposition of 8k,
which was quantitatively recovered. In contrast, gradual degradation of 8k to the
corresponding carboxylic acid 9 [19] was observed under basic condition (1M aq.
NaOH-THF at 50 °C). Next, we examined reduction of 8k with NaBH
producing -bromo--fluorotoluene derivative 10 in 65% yield. Complete reduction of
k to -fluorotoluene 11 was achieved under radical reaction conditions (AIBN and
n-Bu SnH). The nucleophilic substitution reaction of 8k with 4-nitorophenoxide
4
in EtOH,
8
3
afforded a 70% yield of diphenylacetal 12. While this method was not applicable to the
reaction of catechol, cyclic acetal 13 [20] was obtained in 67% yield by heating of 8k in
2 3
the presence of 2,2’-dihydroxybiphenyl and K CO .
1
3
Page 13 of 29

1
M aq. NaOH-THF
Ts
Ts
CO H
2
50 °C, 36 h
9
(quant.)
F
Br
H
NaBH (2 equiv.)
4
EtOH, rt, 2h
10 (65%)
AIBN (0.5 equiv.)
F
Br
Br
F
Bu Sn-H (4 equiv.)
3
Ts
Ts
H
toluene, 100 °C
overnight
H
8k
11 (quant.)
p-nitrophenol
NO2
(2.2 equiv.)
F
O
O
Ts
K CO (3.0 equiv.)
2
3
DMF
00 °C, overnight
1
NO2
12 (70%)
2
,2'-dihydroxybiphenyl
F
(1.2 equiv.)
O
O
Ts
K CO (3.0 equiv.)
2
3
DMF
00 °C, overnight
1
13 (67%)
Scheme 4. Derivatization of 8k.
3
. Conclusion
In this paper, we described the novel dibromofluoromethylation of aryl Grignard
reagents having electron-withdrawing groups with CF Br in the presence of LiBr at
2
2
between room temperature and 35 °C, producing ,-dibromo--fluorotoluene
derivatives. Several substrates with electron-withdrawing groups including –CN,
–CO
2 5 2 3
Me, –SF , –SO Ar, –CF , and halides, were applicable to this reaction. Although
the resulting products were stable under acidic condition, they were hydrolyzed to the
1
4
Page 14 of 29

carboxylic acids under basic condition. In addition, the dibromofluoromethyl group was
successfully converted to the corresponding bromofluoromethyl, fluoromethyl, and
bis(aryloxy)fluoromethyl groups by nucleophilic substitution reactions.
4. Experimental
4.1. General
All reactions involving air- and moisture–sensitive reagents were carried out using
oven-dried glassware and standard syringe-septum cap techniques. Routine monitoring
of reaction was carried out using glass-supported Merck silica gel 60 F254TLC plates.
Flash column chromatography was performed on Kanto chemical Silica Gel 60 N
3
(spherical, neutral 40–50 μm). Recycle GPC was conducted using CHCl as eluent on a
JAI LC-9104. All solvents and reagents were obtained from commercial supplier and
were used without further purification. Infrared (IR) spectral measurements were carried
1
13
19
out with a HORIBA FT-720 spectrometer. H, C, and F NMR spectra were
measured with a Bruker AVANCE III spectrometer. Chemical shifts are expressed in
1
13
6 6
parts per million (ppm) using tetramethylsilane (δ= 0, H NMR and C NMR) and C F
1
9
(
(
δ = –163.0, F NMR) as standard substances. Multiplicities are indicated by s
singlet), d (doublet), t (triplet), qui (quintet), dd (doublet of doublet), td (triplet of
doublet), ddd (double of doublet of doublet), and m (multiplet). Melting points were
taken on Mettler Toledo MP70 melting point system and uncorrected. Low-resolution
mass (MS) spectra were measured on a Shimadzu GCMS-QP2010. High-resolution
mass (HRMS) spectra were measured on a JEOL MStation JMS-700 mass
spectrometer.
1
5
Page 15 of 29

4.2. General procedure for the dibromofluoromethylation of aryl Grignard reagent 2,
prepared from aryl halide (Ar-X, 1) and i-PrMgBr, with CF Br in the presence of LiBr.
2
2
To a stirred mixture of Ar-X (1, 1.0 mmol) and lithium bromide (208 mg, 2.4 mmol)
in THF (3.5 mL) was added dropwise a solution of i-PrMgBr in THF (2.0 M, 0.53 mL,
1
.06 mmol) at –40 °C under Ar and the resulting mixture was stirred at –40 °C for 10
min and at room temperature for 3 h. To a stirred solution of dibromodifluoromethane
CF Br ) in THF (4.90 M, 0.49 mL, 2.4 mmol) was added dropwise the prepared
solution of ArMgBr 2 in THF via cannula at between room temperature and 35 °C over
min. and the resulting solution was stirred for 1 h. The reaction was quenched with
saturated aqueous NH Cl (10 mL) and extracted with EtOAc (10 mL x 3). The
combined extracts were dried over Na SO . Concentration of the solvent in vacuo
afforded a residue, which was purified by silica gel column chromatography
(
2
2
1
4
2
4
(
hexane/EtOAc = 10/1) and recycle GPC to give ,-dibromo--fluorotoluene
derivative 8.
4.2.1. 4-(Dibromofluoromethyl)benzonitrile (8a). The reaction was carried out
according to the general procedure using 4-iodobenzonitrile as Ar-X. White solid (124.1
mg, 43%). mp: 86.9–88.4 °C. IR (neat): 2235, 1406, 1270, 1230, 1047, 1016, 872, 752,
–
1 1
6
2
96 cm . H NMR (400 MHz, CDCl
3
): δ 7.78 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.6 Hz,
13
H). C NMR (100 MHz, CDCl
3
): δ 148.3 (d, J = 21.0 Hz, 1C), 132.3 (s, 2C), 124.9 (d,
19
J = 7.1 Hz, 2C), 117.6 (s, 1C), 114.5 (s, 1C), 88.4 (d, J = 314.8 Hz, 1C). F NMR (376
+
+
MHz, CDCl
100), 133 [M–2Br] (41.3), 102 [M–CBr
Br FN: 290.8695 ; found: 290.8702.
3
): δ –58.0 (s, 1F). GCMS-EI: m/z 214 [M+2–Br] (97.7), 212 [M–Br]
+
+
+
(
2
F] (1.0). HRMS-EI: m/z [M] Calcd for
C
8
H
4
2
1
6
Page 16 of 29

4.2.2. 3-(Dibromofluoromethyl)benzonitrile (8b). The reaction was carried out
according to the general procedure using 3-iodobenzonitrile as Ar–X. White solid (73.6
mg, 25%). mp. 46.3–47.8 °C. IR (neat): 2235, 1479, 1423, 1323, 1250, 1147, 1103, 941,
–
1 1
9
7
7
1
1
26, 742, 681, 656 cm . H NMR (400 MHz, CDCl
3
): δ 7.95 (dd, J = 1.1, 1.3 Hz, 1H),
.90 (ddd, J = 1.1, 1.3, 8.0 Hz, 1H), 7.70 (ddd, J = 1.3, 1.3, 7.8 Hz, 1H), 7.58 (dd, J =
13
.8, 8.0 Hz, 1H). C NMR (100 MHz, CDCl
3
): δ 145.8 (d, J = 21.3 Hz, 1C), 133.9 (s,
C), 129.6 (s, 1C), 128.4 (d, J = 6.6 Hz, 1C), 127.7 (d, J = 7.4 Hz, 1C), 117.5 (s, 1C),
19
13.0 (s, 1C), 88.0 (d, J = 314.3 Hz, 1C). F NMR (376 MHz, CDCl
3
): δ –57.7 (s, 1F).
+
+
+
GCMS-EI: m/z 214 [M+2–Br] (98.4), 212 [M–Br] (100), 133 [M–2Br] (42.6), 102
+
+
[M–CBr
2
F] (1.1). HRMS-EI: m/z [M] Calcd for C
8 4 2
H Br FN: 290.8695; found:
290.8695.
4.2.3. 2-(Dibromofluoromethyl)benzonitrile (8c). The reaction was carried out
according to the general procedure using 2-iodobenzonitrile as Ar–X. White solid
(107.7 mg, 37%). mp. 87.9–91.2 °C. IR (neat): 2227, 1487, 1442, 1288, 1259, 1225,
–
1 1
1
7
7
1
144, 1117, 1036, 893, 866, 754, 694, 667, 631 cm . H NMR (400 MHz, CDCl
3
): δ
.83 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.58 (t, J =
13
.6 Hz, 1H). C NMR (100 MHz, CDCl
3
): δ 145.8 (d, J = 20.7 Hz, 1C), 135.5 (s, 1C),
32.5 (d, J = 1.6 Hz, 1C), 130.7 (s, 1C), 124.2 (d, J = 11.0 Hz, 1C), 116.0 (s, 1C), 109.4
19
(
d, J = 3.1 Hz, 1C), 86.1 (d, J = 313.9 Hz, 1C). F NMR (376 MHz, CDCl
3
): δ –55.5 (s,
+
+
+
1
1
2
F). GCMS-EI: m/z 214 [M+2–Br] (97.3), 212 [M–Br] (100), 133 [M–2Br] (39.1),
+
+
02 [M–CBr
90.8695.
2 8 4 2
F] (0.7). HRMS-EI: m/z [M] Calcd for C H Br FN: 290.8695; found:
1
7
Page 17 of 29

4.2.4. 2-(Dibromofluoromethyl)-4-methylbenzonitrile (8d). The reaction was carried out
according to the general procedure using 2-bromo-4-methylbenzonitrile as Ar–X. White
solid (78.8 mg, 30%). mp. 134.6–136.2 °C. IR (neat): 2360, 2225, 1601, 1495, 1286,
–
1 1
1
244, 1163, 1132, 1053, 953, 827, 818, 789, 762, 702, 644 cm . H NMR (400 MHz,
CDCl ): δ 7.70 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.31 (d, J = 7.9 Hz, 1H), 2.48 (s, 3H).
C NMR (100 MHz, CDCl ): δ 145.6 (d, J = 20.3 Hz, 1C), 143.9 (s, 1C), 135.4 (s, 1C),
31.3 (s, 1C), 124.9 (d, J = 10.9 Hz, 1C), 116.3 (s, 1C), 106.3 (d, J = 3.2 Hz, 1C), 86.3
3
13
3
1
19
(
d, J = 314.0 Hz, 1C), 22.0 (s, 1C). F NMR (376 MHz, CDCl
3
): δ –55.3 (s, 1F).
+
+
+
GCMS-EI: m/z 228 [M+2–Br] (99.2), 226 [M–Br] (100), 147 [M–2Br] (14.2), 116
+
+
[M–CBr
2
F] (0.5). HRMS-EI: m/z [M] Calcd for C
9 6 2
H Br FN: 304.8851; found:
304.8854.
4.2.5. 4-(Dibromofluoromethyl)-2-methoxybenzonitrile (8e). The reaction was carried
out according to the general procedure using 4-bromo-2-methoxybenzonitrile as Ar–X
except for using 2.12 equiv. of i-PrMgBr. Yellow solid (103.8 mg, 32%). mp. 72.2–74.3
°
C. IR (neat): 2227, 1604, 1572, 1500, 1464, 1408, 1286, 1273, 1225, 1198, 1169, 1113,
–
1 1
1
057, 1018, 933, 839, 796, 748, 719 cm . H NMR (400 MHz, CDCl
.2 Hz, 1H), 7.32 (dd, J = 1.7, 8.2 Hz, 1H), 7.21 (d, J = 1.7 Hz, 1H), 4.01 (s, 3H).
): δ 160.9 (s, 1C), 149.9 (d, J = 20.9 Hz, 1C), 133.9 (s, 1C),
16.7 (d, J = 7.2 Hz, 1C), 115.2 (s, 1C), 107.0 (d, J = 7.9 Hz, 1C), 103.8 (s, 1C), 88.4
3
): δ 7.63 (d, J =
13
8
C
NMR (100 MHz, CDCl
3
1
19
(
d, J = 314.9 Hz, 1C), 56.4 (s, 1C). F NMR (376 MHz, CDCl
3
): δ –57.4 (s, 1F).
+
+
+
+
GCMS-EI: m/z 325 [M+4] (2.1), 323 [M+2] (4.2), 321 [M] (2.2), 244 [M+2–Br]
1
8
Page 18 of 29

+
+
(
99.0), 242 [M–Br] (100). HRMS-EI: m/z [M] Calcd for C
9 6 2
H Br FNO: 320.8800 ;
found:320.8797.
4.2.6. 4-(Dibromofluoromethyl)-2-methylbenzonitrile (8f). The reaction was carried out
according to the general procedure using 4-bromo-2-methylbenzonitrile as Ar–X except
for using 2.12 equiv. of i-PrMgBr. Yellow oil (36.9 mg, 12%). IR (neat): 2231, 1738,
–1
1
564, 1491, 1446, 1392, 1385, 1282, 1209, 1124, 1034, 939, 833, 818, 754, 692 cm .
1
H NMR (400 MHz, CDCl
3
): δ 7.76 (d, J = 8.8 Hz, 1H), 7.57–7.55 (m, 2H), 2.69 (s,
H). C NMR (100 MHz, CDCl ): δ 145.3 (d, J = 18.6 Hz, 1C), 136.4 (d, J = 2.7 Hz,
C), 136.2 (s, 1C), 129.5 (d, J = 2.3 Hz, 1C), 124.9 (s, 1C), 117.6 (s, 1C), 114.5 (s, 1C),
13
3
1
8
3
19
8.6 (d, J = 313.7 Hz, 1C), 20.9 (s, 1C). F NMR (376 MHz, CDCl
3
): δ –50.4 (s, 1F).
+
+
+
GCMS-EI: m/z 228 [M+2–Br] (95.1), 226 [M–Br] (100), 147 [M–2Br] (86.3), 116
+
+
[M–CBr
2
F] (0.9). HRMS-FAB: m/z [M+H] Calcd for C
9 7 2
H Br FN: 305.8929; found:
305.8929.
4.2.7. 4-(Dibromofluoromethyl)-3-methylbenzonitrile (8g). The reaction was carried out
according to the general procedure using 4-bromo-3-methylbenzonitrile as Ar–X.
Yellow oil (65.1 mg, 22%). IR (neat): 2231, 1560, 1489, 1456, 1394, 1282, 1209, 1124,
–1 1
1
034, 939, 889, 833, 818, 758, 692 cm . H NMR (400 MHz, CDCl
3
): δ 7.76 (d, J =
13
8
.8 Hz, 1H), 7.58–7.54 (m, 2H), 2.69 (s, 3H). C NMR (100 MHz, CDCl ): δ 145.3 (d,
3
J = 18.4 Hz, 1C), 136.4 (d, J = 2.8 Hz, 1C), 136.3 (s, 1C), 129.5 (d, J = 2.2 Hz, 1C),
19
1
24.8 (s, 1C), 117.6 (s, 1C), 114.5 (s, 1C), 88.6 (d, J = 313.7 Hz, 1C), 20.9 (s, 1C). F
+
NMR (376 MHz, CDCl
3
): δ –50.4 (s, 1F). GCMS-EI: m/z 228 [M+2–Br] (98.1), 226
1
9
Page 19 of 29

+
+
+
+
[
2 2
M–Br] (100), 147 [M–2Br] (81.8), 116 [M–CBr F] (0.9), 90 [M–CN–CBr F] (0.8).
+
HRMS-FAB: m/z [M+H] Calcd for C
9
H
7
Br
2
FN: 305.8929; found: 305.8936.
4.2.8. Methyl 4-(dibromofluoromethyl)benzoate (8i). The reaction was carried out
according to the general procedure using methyl 4-iodobenzoate as Ar–X. White solid
(90.9 mg, 28%). mp. 39.2–41.9 °C. IR (neat): 2952, 1722, 1435, 1408, 1275, 1221,
–
1 1
1
109, 1049, 1018, 872, 818, 785, 721, 681 cm . H NMR (400 MHz, CDCl
3
): δ 8.09
):
δ 165.8 (s, 1C), 148.3 (d, J = 20.4 Hz, 1C), 132.0 (s, 1C), 129.7 (s, 2C), 124.2 (d, J =
13
(
d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 3.95 (s, 3H). C NMR (100 MHz, CDCl
3
19
6
.9 Hz, 2C), 89.5 (d, J = 314.7 Hz, 1C), 52.5 (s, 1C). F NMR (376 MHz, CDCl
3
): δ
+
+
–
56.4 (s, 1F). GCMS-EI: m/z 297 [M+4–OMe] (2.5), 295 [M+2–OMe] (5.3), 293
+
+
+
+
[
M–OMe] (2.7), 247 [M+2–Br] (97.8), 245 [M–Br] (100), 214 [M–Br–OMe] (9.5),
+
+
1
2 9 8 2 2
35 [M–CBr F] (1.0). HRMS-FAB: m/z [M+H] Calcd for C H Br FO : 324.8875;
found: 324.8876.
4
.2.9. 1-(Dibromofluoromethyl)-4-(pentafluorosulfanyl)benzene (8j). The reaction was
carried out according to the general procedure using
-iodo-4-(pentafluorosulfanyl)benzene as Ar–X. White gam (127.1 mg, 32%). IR
1
–1 1
(
neat): 1410, 1232, 1201, 1103, 1053, 808, 750, 696, 656 cm . H NMR (400 MHz,
1
3
CDCl
CDCl
3
3
): δ 7.83 (d, J = 9.0 Hz, 2H), 7.76 (d, J = 9.0 Hz, 2H). C NMR (100 MHz,
): δ 154.9 (qui, J = 18.1 Hz, 1C), 147.3 (d, J = 21.0 Hz, 1C), 126.3 (qui, J = 4.6
19
Hz, 2C), 124.7 (d, J = 7.1 Hz, 2C), 88.3 (d, J = 314.3 Hz, 1C). F NMR (376 MHz,
CDCl ): δ –81.4 (qui, J = 150.7 Hz, 1F), –61.3 (d, J = 150.7 Hz, 4F), –57.4 (1F).
3
2
0
Page 20 of 29

+
+
+
GCMS-EI: m/z 315 [M+2–Br] (100), 313 [M–Br] (97.3). HRMS-EI: m/z [M] Calcd
for C Br S: 391.8305; found: 391.8309.
7
H
4
2 6
F
4.2.10. 4-(Dibromofluoromethyl)phenyl 4-methylphenyl sulfone (8k). The reaction was
carried out according to the general procedure using 4-iodophenyl 4-methylphenyl
sulfone as Ar–X. White solid (132.0 mg, 31%). mp. 158.8–160.3 °C. IR (neat): 1603,
–1 1
1
495, 1286, 1246, 1203, 1165, 1136, 1036, 958, 804, 777, 715, 652 cm . H NMR (400
MHz, CDCl ): δ 7.97 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.5 Hz,
3
13
2
H), 7.34 (d, J = 8.5 Hz, 2H), 2.42 (s, 3H). C NMR (100 MHz, CDCl
3
): δ 148.4 (d, J
=
21.0 Hz, 1C), 144.8 (s, 1C), 144.0 (s, 1C), 137.8 (s, 1C), 130.2 (s, 2C), 128.0 (s, 2C),
19
127.7 (s, 2C), 125.1 (d, J = 7.0 Hz, 2C), 88.6 (d, J = 314.7 Hz, 1C), 21.6 (s, 1C).
F
+
+
(376 MHz, CDCl
3
): δ –57.3 (s, 1F). GCMS-EI: m/z 343 [M+2–Br] (37.4), 341 [M–Br]
+
+
+
(
36.8), 139 [MeC
6
H
4
SO] (100), 91 [MeC
6 4 6 5
H ] (19.2), 77 [C H ] (10.8). HRMS-FAB:
+
m/z [M+H] Calcd for C14
H
12Br
2
FO S: 420.8909; found: 420.8910.
2
4.2.11. 4-(Dibromofluoromethyl)phenyl 4-fluorophenyl sulfone (8l). The reaction was
carried out according to the general procedure using 4-fluorophenyl 4-iodophenyl
sulfone as Ar–X. White solid (207.0 mg, 49%). mp. 91.1–92.8 °C. IR (neat): 1589,
1
6
2
491, 1402, 1323, 1290, 1240, 1217, 1161, 1149, 1097, 1047, 870, 847, 820, 756, 727,
–1 1
92, 658 cm . H NMR (400 MHz, CDCl
3
): δ 8.02–7.96 (m, 4H), 7.79 (d, J = 8.7 Hz,
13
H), 7.22 (dd, J = 8.5, 8.7 Hz, 2H). C NMR (100 MHz, CDCl ): δ 165.8 (d, J = 255.5
3
Hz, 1C), 148.7 (d, J = 21.1 Hz, 1C), 143.5 (s, 1C), 136.8 (d, J = 3.0 Hz, 2C), 130.8 (d, J
9.5 Hz, 2C), 127.8 (s, 2C), 125.2 (d, J = 7.2 Hz, 1C), 116.9 (d, J = 22.6 Hz, 2C), 88.4
=
19
(
3
d, J = 314.7 Hz, 1C). F NMR (376 MHz, CDCl ): δ –56.5 (s, 1F), –104.3 (m, 1F).
2
1
Page 21 of 29

+
+
+
GCMS-EI: m/z 347 [M+2–Br] (43.8), 345 [M–Br] (43.6), 143 [FC
6
H
4
SO] (100), 95
+
+
[FC
6
H
4
] (22.9). HRMS-FAB: m/z [M+H] Calcd for C13
9 2 2 2
H Br F O S: 424.8658; found:
424.8655.
4
.2.12. 2-Bromo-1,3-dichloro-5-(dibromofluoromethyl)benzene (8m). The reaction was
out according to the general procedure using
-bromo-1,3-dichloro-5-iodobenzene as Ar–X. Yellow oil (88.6 mg, 21%). IR (neat):
carried
2
1
–1 1
549,1417, 1375, 1228, 1196, 1066, 1024, 947, 877, 810, 744, 717, 694 cm . H NMR
13
(
400 MHz, CDCl
3
): δ 7.65 (s, 2H). C NMR (100 MHz, CDCl
3
): δ 144.8 (d, J =21.9 Hz,
1C), 133.6 (s, 2C), 126.2 (s, 1C), 124.0 (d, J = 7.3 Hz, 2C), 86.7 (d, J = 314.7 Hz, 1C).
19
3
F NMR (376 MHz, CDCl ): δ –57.6 (s, 1F). GCMS-EI: m/z 418 [M+6] (0.9), 416
+
+
[
[
M+4] (1.5), 414 [M+2] (1.1), 339 [M+6–Br] (31.0), 337 [M+4–Br] (88.0), 335
+
+
+
+
M+2–Br] (100), 333 [M–Br] (38.7), 223 [M–CBr
Br Cl F: 411.7068; found: 411.7064.
2
F] (1.8). HRMS-EI: m/z [M]
Calcd for C
7
H
2
3
2
4.2.13. 4-(Dibromofluoromethyl)benzotrifluoride (8n). The reaction was carried out
according to the general procedure using 4-iodobenzotrifluoride as Ar–X. Orange oil
(20.0 mg, 6%). IR (neat): 1412, 1323, 1221, 1171, 1130, 1122, 1068, 1018, 872, 850,
–
1 1
7
62, 706, 669 cm . H NMR (400 MHz, CDCl
3
): δ 7.79 (d, J = 8.4 Hz, 2H), 7.69 (d, J
): δ 147.7 (d, J =20.9 Hz, 1C), 132.5 (q, J =
3.0 Hz, 1C), 125.6 (q, J = 3.4 Hz, 2C), 124.6 (d, J = 7.0 Hz, 2C), 123.4 (q, J = 270.7
13
=
8.4 Hz, 2H). C NMR (100 MHz, CDCl
3
3
19
Hz, 1C), 89.0 (d, J = 314.4 Hz, 1C). F NMR (376 MHz, CDCl
3
): δ –56.8 (s, 1F), –64.3
+
+
+
(
s, 3F). GCMS-EI: m/z 319 [M+4–F] (0.6), 317 [M+2–F] (1.3), 315 [M–F] (0.7), 257
2
2
Page 22 of 29

+
+
+
+
[
M+2–Br] (95.9), 255 [M–Br] (100), 238 [M+2–Br–F] (5.2), 236 [M–Br–F] (5.4).
+
HRMS-EI: m/z [M] Calcd for C
8
H
4
Br
2
F
4
: 333.8616; found: 333.8608.
4
.2.14. 5-(Dibromofluoromethyl)-2-(trifluoromethyl)pyridine (8o). The reaction was
carried out according to the general procedure using
-bromo-2-(trifluoromethyl)pyridine as Ar–X. Colorless oil (82.0 mg, 24%). IR (neat):
5
1
–1
1
389, 1335, 1254, 1180, 1138, 1088, 1053, 1020, 874, 783, 775, 733, 688cm . H
3
NMR (400 MHz, CDCl ): δ 9.04 (d, J = 2.2 Hz, 1H), 8.14 (dd, J = 2.2, 8.4 Hz, 1H),
13
7
.77 (d, J = 8.4 Hz, 1H). C NMR (100 MHz, CDCl
3
): δ 149.7 (q, J = 35.3 Hz, 1C),
145.7 (d, J = 7.3 Hz, 1C), 142.8 (d, J = 21.1 Hz, 1C), 133.4 (d, J = 6.4 Hz, 1C), 120.9
19
(
q, J = 272 Hz, 1C), 120.1(s, 1C), 86.3 (d, J = 314 Hz, 1C). F NMR (376 MHz,
+
CDCl
3
): δ –59.2 (s, 1F), –69.4 (s, 3F). GCMS-EI: m/z 320 [M+4–F] (0.6), 318
+
+
+
+
[
M+2–F] (1.4), 316 [M–F] (0.7), 258 [M+2–Br] (96.8), 256 [M–Br] (100), 239
+
+
+
[
7 3 2 4
M+2–Br–F] (4.9), 237 [M–Br–F] (5.0). HRMS-EI: m/z [M] Calcd for C H Br F N:
334.8568; found: 334.8564.
4.3. Reaction of 4-(dibromofluoromethyl)phenyl 4-methylphenyl sulfone (8k) in 1M
aqueous NaOH to (p-tolylsulfonyl)benzoic acid (9) [19].
A solution of 4-(dibromofluoromethyl)phenyl 4-methylphenyl sulfone (8k) (20.0
mg, 0.047 mmol) in THF (1.0 mL) and 1M aq. NaOH (1.0 mL) was heated at 50 °C for
36 h. The reaction mixture was neutralized with 1M aq. HCl (1.9 mL) and extracted
with EtOAc (2.0 mL x 3). The combined extracts were dried over Mg
2
4
SO .
1
Concentration of the solvent in vacuo afforded 9 as a white solid (13.4 mg, quant.). H
2
3
Page 23 of 29

NMR (400 MHz, DMSO-d
6
)  13.5 (brs, 1H), 8.12 (d, J = 8.7 Hz, 2H), 8.05 (d, J = 8.7
Hz, 2H), 7.87 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 2.38 (s, 3H).
4.4. Preparation of 4-(bromofluoromethyl)phenyl 4-methylphenyl sulfone (10).
To a stirred solution of 4-(dibromofluoromethyl)phenyl 4-methylphenyl sulfone
(
4
8k) (50.0 mg, 0.12 mmol) in EtOH (1.0 mL) was added NaBH (9.7 mg, 0.24 mmol) at
room temperature under Ar and the resulting mixture was stirred for 2 h. The reaction
mixture was quenched with 1M aq. HCl (2.0 mL) and extracted with EtOAc (10 mL x
3
). The combined extracts were dried over MgSO
vacuo afforded a residue, which was purified by silica gel column chromatography
hexane/EtOAc = 3/1) to give 10 (26.5 mg, 65%) as a white solid. IR (neat): 1595, 1414,
4
. Concentration of the solvent in
(
1
6
315, 1292, 1219, 1190, 1151, 1103, 1072, 1030, 1016, 968, 887, 839, 810, 708, 690,
–1 1
3
58, 625 cm . H NMR (400 MHz, CDCl ): δ 7.98 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2
Hz, 2H), 7.61 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 49.3 Hz, 1H), 7.32 (d, J = 8.6 Hz, 2H),
13
2
.41 (s, 3H). C NMR (100 MHz, CDCl
3
): δ 144.3 (s, 1C), 141.6 (d, J = 17.3 Hz, 1C),
138.5 (s, 2C), 130.0 (s, 2C), 127.9 (s, 2C), 127.7 (s, 2C), 127.2 (d, J = 6.8 Hz, 2C), 83.2
19
(
3
d, J = 169.0 Hz, 1C), 21.6 (s, 1C). F NMR (376 MHz, CDCl ): δ –136.7 (d, J = 46.2
+
Hz, 1C). HRMS-EI: m/z [M] Calcd for C14
H
12BrFO
2
S: 341.9725; found: 341.9728.
4
.5. Preparation of 4-(fluoromethyl)phenyl 4-methylphenyl sulfone (11).
To a stirred solution of 4-(dibromofluoromethyl)phenyl 4-methylphenyl sulfone
8k) (50.0 mg, 0.12 mmol) in toluene (2.0 mL) was added n-Bu SnH (125 μl, 0.47
(
3
mmol) and 2,2’-azobisisobutyronitrile (AIBN, 9.7 mg, 59 μmol) and the resulting
mixture was heated at 100 °C for 12 h. The reaction mixture was cooled down to room
2
4
Page 24 of 29

temperature, diluted with H
combined extracts were dried over MgSO
afforded a residue, which was purified by silica gel column chromatography
2
O (5 mL), and extracted with EtOAc (10 mL x 3). The
4
. Concentration of the solvent in vacuo
(hexane/EtOAc = 3/1) to give 11 (31.1 mg, quant.) as a white solid. IR (neat): 2922,
–1 1
1
595, 1412, 1375, 1317, 1213, 1153, 1105, 978, 810, 796, 739, 706, 671, 646 cm . H
NMR (400 MHz, CDCl
8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 5.42 (d, J = 46.9 Hz, 2H), 2.40 (s, 3H).
NMR (100 MHz, CDCl ): δ 144.3 (s, 1C), 141.6 (d, J = 17.3 Hz, 1C), 138.5 (s, 2C),
30.0 (s, 2C), 127.9 (s, 2C), 127.7 (s, 2C), 127.2 (d, J = 6.8 Hz, 2C), 83.2 (d, J = 169.0
3
): δ 7.95 (d, J = 8.3 Hz, 2H), 7.83 (d, J = 8.3 Hz, 2H), 7.47 (d, J
13
=
C
3
1
19
Hz, 1C), 21.6 (s, 1C). F NMR (376 MHz, CDCl
3
): δ –215.8 (t, J = 46.9 Hz, 1F).
+
+
+
GCMS-EI: m/z 264 [M] (72.6), 155 [MeC
6
H
4
SO
2
] (6.1), 139 [MeC
6
H
4
SO] (100), 91
+
+
[MeC
6
H
4
] (63.5). HRMS-FAB: m/z [M+H] Calcd for C14
H14FO
2
S: 265.0699; found:
265.0700.
4.6. Preparation of 4-[fluorobis(4-nitrophenyloxy)methyl]phenyl 4-methylphenyl
sulfone (12).
To a stirred solution of 4-(dibromofluoromethyl)phenyl 4-methylphenyl sulfone
8k) (80.0 mg, 0.19 mmol) in DMF (2.0 mL) was added 4-nitrophenol (58.2 mg, 0.42
mmol) and K CO (78.8 mg, 0.57 mmol) at room temperature under Ar and the
resulting mixture was heated at 100 °C for 12 h. The reaction mixture was cooled down
to room temperature, diluted with H O (5 mL), and extracted with EtOAc (10 mL x 3).
The combined extracts were dried over MgSO . Concentration of the solvent in vacuo
afforded a residue, which was purified by silica gel column chromatography
hexane/EtOAc = 3/1) to give 12 (71.3 mg, 70%) as a light-yellow solid. IR (neat): 1612,
(
2
3
2
4
(
2
5
Page 25 of 29

1
8
8
8
1
1
1
591, 1518, 1512, 1489, 1342, 1325, 1294, 1273, 1236, 1157, 1099, 1038, 1012, 852,
–1 1
14, 744, 731, 663, 609 cm . H NMR (400 MHz, CDCl
3
): δ 8.16 (d, J = 9.2Hz, 4H),
.00 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H), 7.33 (d, J =
13
3
.2 Hz, 2H), 7.22 (d, J = 9.2 Hz, 4H), 2.42 (s, 3H). C NMR (100 MHz, CDCl ): δ
56.0 (s, 2C), 145.0 (s, 1C), 144.9 (s, 1C), 144.6 (s, 2C), 138.2 (d, J = 33.5 Hz, 1C),
37.6 (s, 1C), 130.2 (s, 2C), 128.1 (s, 2C), 128.0 (s, 2C), 127.5 (d, J = 4.5 Hz, 2C),
19
25.5 (s, 4C), 127.0 (s, 4C), 119.3 (d, J = 255.2 Hz, 1C), 21.6 (s, 1C). F NMR (376
+
MHz, CDCl
3
): δ –74.2 (s, 1F). HRMS-FAB: m/z [M+H] Calcd for C26
H
20FN
2
FO
8
S:
539.0924; found: 539.0927.
4
.7.
-fluoro-2-[4-(4-methylphenylsulfonyl)phenyl]-2H-dibenzo[d,f][1,3]dioxepin (13).
To a stirred solution of 4-(dibromofluoromethyl)phenyl 4-methylphenyl sulfone
8k) (80.0 mg, 0.19 mmol) in DMF (1.0 mL) was added 2,2’-dihydroxybiphenyl (38.9
mg, 0.21 mmol) and K CO (78.8 mg, 0.57 mmol) at room temperature under Ar and
the resulting mixture was heated at 100 °C for 12 h. The reaction mixture was cooled
down to room temperature, diluted with H O (5 mL), and extracted with EtOAc (10 mL
x 3). The combined extracts were dried over MgSO . Concentration of the solvent in
vacuo afforded a residue, which was purified by silica gel column chromatography
hexane/EtOAc = 3/1) to give 13 (56.8 mg, 67%) as a colorless solid. IR (neat): 1595,
Preparation
of
2
(
2
3
2
4
(
1
7
502, 1479, 1439, 1398, 1323, 1286, 1252, 1153, 1097, 1057, 1039, 1012, 812, 764,
–1 1
56, 721, 660 cm . H NMR (400 MHz, CDCl
3
): δ 7.97 (d, J = 8.4 Hz, 2H), 7.83 (d, J
=
8.4 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H), 7.58 (dd, J = 1.8, 7.5 Hz, 2H), 7.37 (td, J = 1.3,
13
7
.5 Hz, 2H), 7.34–7.28 (m, 4H), 7.00 (dd, J = 1.3, 7.8 Hz, 2H), 2.41 (s, 3H). C NMR
2
6
Page 26 of 29

(
100 MHz, CDCl
3
): δ 149.2 (s, 2C), 144.5 (s, 1C), 143.7 (s, 1C), 139.9 (d, J = 35.1 Hz,
C), 138.1 (s, 1C), 131.3 (s, 2C), 130.0 (s, 2C), 130.0 (s, 2C), 129.0 (s, 2C), 128.3 (s,
C), 127.9 (s, 2C), 127.5 (s, 2C), 127.1 (d, J = 3.7 Hz, 2C), 127.1 (d, J = 240 Hz, 1C),
1
2
1
19
3
22.7 (s, 2C), 21.6 (s, 1C). F NMR (376 MHz, CDCl ): δ –67.9 (s, 1F). HRMS-FAB:
+
m/z [M+H] Calcd for C26
H
20FO
4
S: 447.1066; found: 447.1077.
Acknowledgment
We greatly thank Tosoh F-Tech, Inc. for the generous gift of dibromodifluoromethane.
References
[
[
(
[
[
1] M. Shiosaki, M. Inoue, Tetrahedron Lett. 55 (2014) 6839-6843.
2] G.K.S. Prakash, J. Hu, J. Simon, D.R. Bellew, G.A. Olah, J. Fluorine Chem. 125
2004) 595-601.
3] G. Cai, J. Liu, CN 102516016A (2012).
4] E.Y. Kusei, M.S. Novikov, A.F. Khlebnikov, Russ. J. Gen. Chem. 75 (2005)
1
643-1647.
5] (a) T. Hiyama, K. Kanie, T. Kusumoto, Y. Morizawa, M. Shimizu, Organofluorine
Compounds: Chemistry and Applications, Springle-Verlag, Berlin, 2000;
[
(b) P. Kirsch, Modern Fluorooganic Chemistry, Wiley-VCH, Weinheim, 2004;
(c) J.-P. Bégué, D. Bonnet-Delpon, Bioorganic and Medicinal Chemistry of Fluorine,
John Wiley & Sons, Hoboken, New Jersey, 2008;
d) I. Ojima, Ed., Fluorine in Medicinal Chemistry and Chemical Biology,
Wiley-Blackwell, West Sussex, 2009.
(
2
7
Page 27 of 29

[
6] ,-Dibromo--fluorotoluene derivatives were reported as pyrethroid insecticides,
see: T. Zhang, C. Zhuang, W. Hu, Y. Ma, X. Jia, F. Jiang, CN 1406935A (2003).
[
[
(
(
7] B.R. Raju, E.K.P. Kumar, A.K. Saikia, Tetrahedron Lett, 47 (2006) 9245-9248.
8] (a) T. Ishihara, T. Matsuda, K. Imura, H. Matsui, H. Yamanaka, Chem. Lett. 23
1994) 2167-2170;
b) L. Zoute, G. Lemonnier, T.M. Nguyen, J.-C. Quirion, P. Jubault, Tetrahedron Lett.
5
2 (2011) 2473−2475;
c) G. Lemonnier, T. Poisson, S. Couve-Bonnaire, P. Jubault, X. Pannecoucke, Eur. J.
Org. Chem. (2013) 3278−3289;
d) A. Tarui, H. Nishimura, T. Ikebata, A. Tahira, K. Sato, M. Omote, H. Minami, Y.
Miwa, A. Ando, Org. Lett. 16 (2014) 2080-2083; and references cited therein.
(
(
[9] K. Iseki, Y. Kuroki, Y. Kobayashi, Tetrahedron 55 (1999) 2225-2236.
[10] Review of the reaction of ethyl dibromofluoroacetate, see: E. David, S.
Couve-Bonnaire, P. Jubault, X. Pannecoucke, Tetrahedron 69 (2013) 11039−11055; and
references cited therein.
[
(
[
[
[
[
11] Y. Takeuchi, M. Asahina, A. Murayama, K. Hori, T. Koizumi, J. Org. Chem. 51
1986) 955-956.
12] A. Saito, M. Nakagawa, T. Taguchi, J. Fluorine Chem. 126 (2005) 1166-1173.
13] I. Hemer, A. Pošta, V. Dědek, J. Fluorine Chem. 26 (1984) 467-479.
14] I. Hemer, J. Havliček, V. Dědek, J. Fluorine Chem. 34 (1986) 241-250.
15] (a) I. Rico, D. Cantacuzene, C. Wakselman, J. Chem. Soc., Perkin. Trans. 1 (1982)
1063-1065;
(b) M.G. Barlow, S. Tajammal, A.E. Tipping, J. Fluorine Chem. 64 (1993) 61-71;
2
8
Page 28 of 29

(c) P.-Y. Kwok, F. W. Muellner, C.-K. Chen, J. Fried, J. Am. Chem. Soc. 109 (1987)
3684-3692;
(
d) B. Xu, M. Mae, J.A. Hong, Y. Li, G.B. Hammond, Synthesis (2006) 803-806.
16] Bromination of the aryfluorocarbene with bromide salts, see: R.A. Moss, H. Fan, R.
[
Gurumurthy, G.J. Ho, J. Am. Chem. Soc. 113 (1991) 1435-1437.
17] Examples of aryldifluoromethyl metal species, see: (a) W.R. Dolbier, Jr., P. Xie, L.
Zhang, W. Xu, Y. Chang, K.A. Abboud, J. Org. Chem. 73 (2008) 2469-2472;
[
(
(
[
b) S.N. Tverdomed, J. Kolanowski, E. Lork, G.-V. Röschenthaler, Tetrahedron 67
2011) 3887-3903.
18] (a) P. Knochel, W. Dohle, N. Gommermann, F.F. Kneisel, F. Kopp, T. Korn, I.
Sapountzis, V.A. Vu, Angew. Chem., Int. Ed. 42 (2003) 4302-4320;
(b) A. Krasovskiy, P. Knochel, Angew. Chem., Int. Ed. 43 (2004) 3333-3336.
[19] D. Kumar, V. Arun, M. Pilania, K.P.C. Shekar, Synlett 24 (2013) 831-836.
[20] P. Kirsch, A. Taugerbeck, Eur. J. Org. Chem. (2002) 3923-3926.
2
9
Page 29 of 29