Ring-Opening Functionalization of Simple gem-Difluorocyclopropanes by Single-Electron Oxidants

Article abstract of DOI:10.1021/acs.joc.9b01078

It was reported for the first time that single-electron oxidants such as CAN or K₂S₂O₈ affected facile ring opening of simple gem-difluorocyclopropanes to afford 1,3-dibromo-2,2-difluoropropanes in good yields by the action of KBr, and the appropriate choice of conditions allowed to incorporate not only second halogen atoms but also hydroxy or acetamido groups at the C¹ position in the difluoropropane structures in a regiospecific fashion after initiation of the reaction by the introduction of the first bromine atom at the C³ position. ?

Full text of DOI:10.1021/acs.joc.9b01078

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Article
Ring-Opening Functionalization of Simple gem-
Difluorocyclopropanes by Single Electron Oxidants
Toshihito Goto, Tomoko Kawasaki-Takasuka, and Takashi Yamazaki
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01078 • Publication Date (Web): 02 Jul 2019
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The Journal of Organic Chemistry
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Ring-Opening Functionalization of Simple gem-Difluorocyclopropanes
by Single Electron Oxidants
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Toshihito Goto, Tomoko Kawasaki-Takasuka,* and Takashi Yamazaki
Division of Applied Chemistry, Institute of Engineering, Tokyo University of Agriculture and Technology, 2-24-16
Nakamachi, Koganei, 184-8588 (Japan)
KEYWORDS gem-Difluorocyclopropane, ring-opening, 1,3-difunctionalization
R1 X / OH / NHAc
X
radical source and/or
MX / H2O / CH3CN
F
F
2
Mild conditions
Various nucleophiles
R1
R2
R2
Solv., Temp., Time
1
3
F
F
ABSTRACT: It was reported for the first time that single electron oxidants such as CAN or K2S2O8 affected facile ring-
opening of simple gem-difluorocyclopropanes to afford 1,3-dibromo-2,2-difluoropropanes in good yields by the action of
KBr, and appropriate choice of conditions allowed to incorporate not only second halogen atoms but also hydroxy or
acetamido groups at the C1 position in the difluoropropane structures in a regiospecific fashion after initiation of the
reaction by introduction of the first bromine atom at the C3.
INTRODUCTION
and also developed the convenient route to 2,2-difluoro
homoallylic alcohols via the photo-irradiative aerobic
oxidation (Scheme 1 (e)).14 However, problems occurred in
most of such transformations were the general
requirement of special structural features in substrates
whose preparation should be involved multi-step
syntheses. To the best of our knowledge, since there is no
transformation methods applicable to simple F2CPs except
for the one in Scheme 1 (a), it is significantly important to
exploit an
gem-Difluorocyclopropanes (F2CPs) constitute one of the
most attractive components in organic syntheses,1 and
their ring-opening readily afforded the corresponding
difluoromethylenated compounds some of which have
been paid special attention because of their actual
application as biologically active substances2 shown in
Figure 1.3,4 This would at least in part attribute to their
unique structural characteristics which nicely bring about
metabolic stability enhancement5 and biological similarity
to phosphoric ester oxygen (bioisosteres).6
Scheme 1. Ring-opening functionalization of
cyclopropanes
F
F
N
N
F
N
(a)
F
F
2
N
[Pd], H2
F
F
F
F
Me
N
HO
H3C CH3
OH
R2
R1
R1
N
O
R1
R2
Br
1
3
F
F
NH2
F
Cl
allylBu3Sn,
cat. AIBN
(b)
F
F
anti-Alzheimer's disease
anti-type 2 diabetes
antifungal
PhH
R1
Figure 1. Biologically active compounds with
difluoromethylene moiety.
a
(c)
(d)
F
F
Br
F
F
Br
H3C
H3CO
H2O
Br
One of the most convenient and promising routes to get
access to this framework would be the utilization of ring-
opening reactions of gem-F2CPs, and various protocols
have been developed for this purpose since 1980s: they
are, for example, by way of Pd-catalyzed hydrogenation
(a),7 radical-type ring-opening allylation (b)8 and
bromination (c and d),9,10 with other type of radical-based
ring opening protocols11,12 (Scheme 1). Very recently, the
Itoh group achieved the synthesis of cycloalkenes with
gem-difluoromethylene moiety as the extension of (b),13
Br2
O
F
F
F
F
H3C
H3C
Br
Ts
R2
MeCN,
heating
H3C CH
3 Br
F
Ts
R2
Fluorescein,
TMEDA,
35% aq. H2O2
(e)
F
F
F
I
R1
470 nm LED,
DMF, air rt
R1
OH
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adequate pathway from such simple substrates to
efficiently construct various compounds with
unambiguously manifested the possible plural routes
related to the C1-C3 bond cleavage of the
1
2
3
4
5
6
7
8
difluoromethylene units by way of the ready and
straightforward direct ring-opening technique. Additional
advantage would be the inclusion of plural functionalities
in this ring-opening products which would be nicely
employed as versatile building blocks for installation of a
CF2 group. Because we have recently found out a more
convenient preparation method of F2CPs starting from
methyl 2,2-difluoro-2-(fluorosulfonyl)acetate and styrene
derivatives by slight modification15 of the Dolbier’s
procedure,16 utilization of these products17 was explored at
the next step for demonstration of their synthetic
importance as potent building blocks. With reference to
the reported method on the Br radical-promoted
(di)bromination of alkenes18 as well as non-fluorinated
cyclopropanes,19 our own modification led to a facile and
mild protocol which was affected by a mixture of KBr and
CAN. This transformation realized not only 1,3-
dibromination but also 1,3-bromohydroxylation as well as
1,3-bromoamidation just from simple F2CPs without any
special structural devices (Scheme 2). Results along this
line are reported in detail in this article.
Table 1. Optimization of dibrominative ring opening
conditionsa
X eq. CAN
Y eq. KBr
F
F
2
H3C Br
H3C
Ph
Ph
F
Br
Solv./H2O (v/v=1/1),
Temp., Time
3
1
F
1a
2a
9
X
(eq.)
Y
Temp.
Time
(h)
Yieldb
(%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
entry
Solv.
(eq.)
2.2
2.2
2.2
2.2
1.0
3.0
2.2
2.2
2.2
2.2
2.2
2.2
2.2
2.2d
2.2d
(°C)
25
25
25
25
25
25
0
1
2
2.3
2.3
2.3
2.3
1.0
3.0
2.3
2.3
2.3
2.3
2.3
2.3
2.3c
2.3
2.3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
3
6
61
74
[81]
76
17
53
43
50
0
3
9
4
12
9
5
6
9
Scheme 2. The present ring-opening functionalization
of simple F2CPs (this work)
7
9
R1 X / OH / NHAc
X
8
40
25
25
25
25
25
25
25
9
CAN or K2S2O8
KBr or KI
F
F
2
R1
R2
R2
CH2Cl2 or MeCN
w/o H2O
9
9
1
3
F
F
10
11
12
13
14
15
DME
MeOH
MeCN
DCM
DCM
DCM
9
0
RESULTS AND DISCUSSION
9
18
(28)
27
77
73
First of all, for optimization of the reaction conditions of
CAN and KBr-mediated dibromination, we employed (2,2-
difluoro-1-methylcycloprop-1-yl)benzene 1a as the model
substrate which was readily prepared from the reaction of
1-methylstyrene and methyl 2,2-difluoro-2-(fluoro-
9
9
sulfonyl)acetate.12 Entries 1-4 in Table
1
clearly
9
demonstrated that 9 h was the adequate reaction time for
the conversion of 1a to 2a. This protocol furnished not
only the desired 1,3-dibromobutane 2a but also (1,2,4-
9
tribromo-3,3-difluorobutan-2-yl)benzene
3a
as
a
aReactions were performed in a 0.5 mmol scale with 5 mL
each of H2O and an appropriate solvent. bYields of 2a were
determined by 19F NMR analyses. The numbers in bracket
(entry 3) and parenthesis (entry 12) were the yields of the
isolated 2a and 4-bromo-3,3-difluoro-2-phenylbutan-2-ol 4a,
byproduct in 2-18% yields. In our system, the regiospecific
cleavage of the C1-C3 bond was realized without formation
of any other compounds stemmed from the C1-C2 and/or
C2-C3 bond disconnection. The amounts of CAN of 2.3 eq.
and KBr of 2.2 eq. were the best among tested (entries 3
vs 5-6), and room temperature was found to be the most
appropriate in terms of the yield of 2a (entries 3 vs 7-8). In
this system, dichloromethane (DCM) was suitable and
other solvents did not give any fruitful outcome (entries 3
vs 9-11) although decolorization of the reaction mixture
c
d
respectively. Ce(SO4)2·4H2O was employed instead of CAN.
NaBr (entry 14) and LiBr (entry 15) were employed instead of
KBr.
F2CPs. Lower efficiency of Ce(SO4)2·4H2O was noticed
when compared with CAN (entry 13), and the almost equal
potency was exerted by NaBr and LiBr to KBr (entries 3 vs
14-15). Finally, the condition of entry 3 was determined as
the best of all.
was
noticed
in
tetrahydrofuran
(THF),
1,2-
dimethoxyethane (DME) or methanol (MeOH) solvents
which clearly indicated the consumption of CAN. Because
the substrate 1a was recovered in a larger amount in these
instances, we assumed that these solvents would disturb
the generation or presence of Br• species. Aqueous
The scope and limitation of the present dibrominative
ring-opening were shown in Figure 2. (2,2-Difluoro-
cycloprop-1-yl)benzenes 1a or 1e with or without a
methyl substituent at the benzylic position led to efficient
formation of the 1,3-dibromoalkanes 2a or 2e in excellent
acetonitrile (MeCN) (entry 12) afforded
byproduct in 28% yield which was identified as 4-bromo-
3,3-difluoro-2-phenylbutan-2-ol (4a). This result
a different
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The Journal of Organic Chemistry
yields, respectively. Smooth C-C bond cleavage was also
noticed for substrates with Br as R2 (1b and 1f), while the
the detailed reaction condition search, this unprecedented
1
2
3
4
5
6
7
8
product 5a was nicely isolated in 67% yield as a white
solid by the alternative stepwise reactions of
dibrominative
F
F
R1 Br
R1
Br
Scheme 3. Bromohydroxylation and bromoamidation
F
F
R2
R2
R
OH
2
2
R1=CH3
R1=CH3
1a
1b
1c
1d
2a
2b
2c
2d
: R =H
: R =H
81%
MeCN/H2O
(v/v=1/1)
61%
2
2
: R =Br
: R =Br
73%
49%
Ph
4a
Br
(R=CH3)
2
2
F
F
: R =NO2
: R =NO2
2.3 eq. CAN
2.2 eq. KBr
F
F
2
2
: R =OCH3 [17%]a
9
: R =OCH3
H3C
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
60 °C, 9 h
2
2
R1=H
R1=H
1e
2e
: R =H
: R =H
R2=Br
84%
69%
[44%]a
75%b
H3C NHAc
Ph
path A
1f
2f
:
R2=Br
:
Br
1a
2
2
MeCN
1g
1h
2g
2h
: R =NO2
: R =NO2
23%
F
F
2
2
: R =OCH3
: R =OCH3
5a
path B
4.0 eq.
FeCl3
MeCN,
refl., 6 h
H3C Br
F
F
69%
R3
F
H3C
Br
2.3 eq. CAN
2.2 eq. KBr
H3C Br
R3
F
3
3
a
1i
1j
Ph
F
Br
F
: R =2-naphthyl
2i
2j
: R =2-naphthyl17% [35%]
DCM/H2O (v/v=1/1),
25 °C , 9 h
3
3
: R =C9H19
: R =C9H19
73%
2a
81%
a The numbers in brackets were determined by 19F NMR analyses.
b The reaction was performed at 70 °C in DCE.
The numbers in brackets were determined by 19F NMR analyses.
5a
The isolated yield of
was the figure after recrystalization.
Figure 2. Dibromination of various substrates.
ring-opening, followed by treatment with FeCl3 under
reflux in MeCN (path B).22
strongly electron-withdrawing nitro moiety at the same posi-
tion (1c and 1g) did not allow full conversion with recovery of
substrates to some extent. On the other hand, a complicated
reaction was occurred for 1d possessing the electron-donating
methoxy group as R2, which recorded a quite low material
balance because of significant decomposition of the
substrate and/or product under the conditions employed.
The fact that substitution of a Me group as R1 for H led to a
decent production of the desired 2h in 75% yield would be
due to the different stability of the resultant intermediate
(vide infra). 2-(2,2-Difluoro-1-methylcyclo-prop-1-yl)-
naphthalene 1i was not a good candidate for this reaction
with 50% recovery of 1i but the alkyl substituent instead
of the naphthalene ring worked nicely for construction of
the corresponding product 2j in 71% yield.
As described in Figure 2, success of this dibromination was
highly dependent on the presence of the benzylic methyl
group in the case of substrates with the 4-methoxyphenyl
group, i.e. 1d and 1h. In Table 2 was shown their direct
reactivity comparison when potassium persulfate (K2S2O8)
was used because CAN affected about 40% decomposition
Table 2. Reactivity difference between 1d and 1h
F
F
R
1d
1h
: R=H
: R=CH3
Ar
Ar=4-CH3OC6H4
Br
H3C Br
2.3 eq. CAN
2.2 eq. KBr
Ar
F
Br
Ar
Br
Under the condition of entry 12 in Table 1, 4-bromo-3,3-
difluoro-2-phenylbutan-2-ol (4a) was obtained in 28%
yield possibly as the consequence of ring opening of 1a,
followed by acceptance of the H2O attack at the benzylic
position. After briefly checking the reaction conditions,
raising the reaction temperature from 25 °C to 60 °C
allowed to increase its isolated yield to the acceptable level
of 61% (Scheme 3). This transformation is interesting
because only two precedented methods were available at
present to get access to this type of brominated alcohols:
they are 1) 2,2,3,3-tetrafluorooxetane opening by Grignard
reagents (R=aryl)20 and 2) reduction of the corresponding
3-bromo-2,2-difluoropropan-1-one (R=H).21 The most
significant advantage of our method is to perform the
reaction under open-air in aqueous solvents using easily
available F2CPs. Furthermore, it was found out that the
absence of H2O conveniently modified this process to form
N-(4-bromo-3,3-difluoro-2-phenylbutan-2-yl)acetamide
5a in 23% yield (path A) via the Ritter-type pathway. In
spite of difficulty in improvement of this process even after
F
F
F
2d
2h
: 75%
: [17%]
DCM/H2O (v/v=1/1)
25 °C, 9 h
DCE/H2O (v/v=1/1)
70 °C, 9 h
NHAc
Br
2.0 eq. K2S2O8
1.5 eq. NaBr
No reaction
Recovery 79%
Ar
Ar
Br Ar
Br
MeCN,
100 °C, 24 h
F
F
F F
5h
2h
: 48%
: [26%]
2.0 eq. K2S2O8
1.1 eq. KI
DCE/H2O
(v/v=1/1)
OH
O
H3C OH
Ar
I
I
Ar
I
I
I
Ar
Ar
I
F
F
F
F
F
F
F
F
60 °C, 6 h
6d
7d
6h
8h
: [4%]
: 68%
: [22%]
: 57%
OH
NHAc
H3C OH
Ar
2.0 eq. K2S2O8
1.1 eq. KI
MeCN,
90 °C, 16 h
Ar
Ar
I
I
F
F
F
F
F
F
F
F
7d
6d
6h
9h
: 56%
: 11%
: 47%
: 11%
O
Ar
I
F
F
8h
: [6%]
The numbers in brackets were determined by 19F NMR analyses.
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of 1d and/or 2d. KBr (17% yield) and NaBr (79% recov
Scheme 4. Investigations on the reaction mechanism
(1)
1
2
3
4
5
6
7
8
ery) were proved to be ineffective as a Br source for 1d, in
sharp contrast to the structurally similar compound 1h
which was transformed to the difluoroamide 5h in moder-
ate yield by treatment with NaBr. Iodohydroxylation of 1d
and 1h was also achieved by use of KI to nicely provide 6d
and 6h, respectively. In the case of 1d, exchange of the
solvent to MeCN altered the main route to furnish the
difluoroalkene 7d with the benzylic alcohol 6d as a
byproduct. On the other hand, iodohydroxylation of 1h
was realized by K2S2O8 and the difluoropropanol 6h was
obtained as the main product along with the
corresponding ketone 8h and/or acetamide 9h as
byproducts in DCE/H2O and MeCN solvents, respectively.
Furthermore, halohydroxylation and bromoamidation of
different substrates were also performed (Figure 3). Based
on the procedure for the conversion of 1a to 4a in Scheme
3, 2,2-difluoro-3-bromo-1-(4-tert-butylphenyl)propan-2-ol 4l
was obtained by increasing the reaction temperature to 80 °C.
When KI was employed instead of KBr, formation of the
corresponding iodopropanol 4l’ was realized in high yield.
Dibromopropane and other unidentified byproducts were
also observed by 19F NMR measurement. In the case of
bromoamidation, it was interesting to note that the
corresponding deacetylated 3-bromopropyl-amine 5l’ was
isolated along with the desired N-[3-bromo-2,2-difluoro-1-(4-
tert-butylphenyl)prop-1-yl]acetamide 5l in favor of the
former. Iodohydroxylation by K2S2O8 was also applicable to 1-
(2,2-difluoro-1-methylcyclo-propyl)-2-methoxy-benzene (1k),
leading to formation of the desired product in good yield.
(a)
CAN
2.2 eq. KBr
,
F
F
H3C Br
BrH2C Br
Ph
H3C
Ph
Ph
F
Br
Br
+
DCM/H2O
(v/v=1/1),
25 °C , 9 h
F
F
F
1a
2a
3a
CAN
19F NMR yield (%)
86% 6%
(eq.) light atmosphere
2.3
O
air
9
(Table 1, entry 3)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2.3
2.3
2.3
3.5
X
O
X
air
Ar
Ar
Ar
45%
40%
30%
73%
26%
trace
17%
0%
O
(b)
Br
1.1 eq.
2
1a
2a
+
3a
DCM,
25 °C , 9 h, under air
19F NMR yield (%)
light
1.1 eq. TEMPO
O
O
54%
0%
30%
0%
X
O
1a
(Recovery of ; 98%)
X
54%
11%
20%
X
X
12W white LED 77%
and 2a was actually obtained in 54% yield by the action of
Br2 in DCM23 instead of a combination of CAN and KBr
(Scheme 4b). In spite of known procedures for non-
fluorinated cyclopropane ring opening affected by the
direct submission of Br2, the grad- ual generation of Br•/Br2
by the present CAN/KBr system seemed to be superior in
terms of the suppressed formation of the undesired
tribromide 3a. It is quite interesting to note that this
reaction didn’t proceed at all in the presence of 1.1 eq. of
TEMPO with 98% recovery of the substrate 1a. In spite of
the fact that dibromination by Br2 in the dark actually
occurred, almost complete inhibition of the reaction by the
addition of TEMPO strongly suggested the radical
character of this reaction course.
OH
NHR
X
Br
F
F
F
F
t-Bu
4l
t-Bu
5l
5l
: X=Br Y. 47% [95%]
4l'
Y. 67% [89%]
: R=Ac Y. 22%
Y. 56%
': R=H
[quant.]
: X=I
H3C OH
I
F
F
Scheme 5. Investigations on the reaction mechanism
(2)
OCH3
6k:
Y. 63% [68%]
The numbers in brackets were conversion yields
determined by 19F NMR analyses.
F
F
H3C
Figure 3. Halohydroxylation and bromoamidation.
H3C
For obtaining further information on the reaction
mechanism, the present dibromination was performed in
the dark (Scheme 4a) which allowed to decrease the yield
of the dibrominated butane 2a from 86% under the
standard conditions to 45% with a larger amount of the
side product, tribrominated 3a in 26% yields. In spite of
great suppression of the formation of 2a (40% yield)
under an argon atmosphere with irradiation of light, usage
of 1.5 times of CAN under such conditions accomplished
the similar level of the yield of 2a (73%) to the one under
the original conditions (Table 1, entry 3). These results led
to a clear conclusion that both light and oxygen worked at
least in a supportive manner and thus, it is strongly
considered that the radical mechanism is involved in the
present reaction. In this system, the construction of 3a
expected us the in situ generation of molecular bromine,
1m
condition A
2.3 eq. CAN
condition B
10 mol% AIBN
2.0 eq. NBS
2.2 eq. KBr
DCM/H2O (v/v=1/1),
25 °C , 9 h
CCl4, 70 °C , 15 h
(Table 1, entry 3)
F
F
H3C
unidentified
byproducts
+
Br
10m
condition A
Y. [89%]
Y. [11%]
Y. [11%]
condition B Y. [47%]
Yields were determined by 19F NMR analyses.
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1
The Journal of Organic Chemistry
CeIII
CeIV
Scheme 5 demonstrated an exceptional example where 1-
(2,2-difluoro-1-methylcycloprop-1-yl)-4-methylbenzene
Br2
Br
Br
2
3
4
5
6
7
1m preferentially experienced bromination at the benzylic
position to yield 10m under the original conditions (Table
1, entry 3). A similar trend was observed by the Whol-
Ziegler bromination conditions by N-bromosuccinimide
(NBS) in the presence of a catalytic amount of AIBN in CCl4,
which again assumed the radical mechanism.
F
F
2
+
H3C
R
Br
3
1
1
8
9
Br
H3C OH
Ph
CH3
F
H3C Br
R
For obtaining further information, computation was
performed whose results were summarized in Table 3.24
On the basis of the orbital energies, the Br radical SOMO
and the occupied orbital of 1a should be responsible for
this reaction because of their least energy gap, and the
present reaction was considered to be initiated by the
bond forma- tion of Br• and the C3 atom at least in a
regioselective manner because 1) the occupied lobe by two
electrons on the C1-C3 bond is the energetically highest of
all the cyclo-propane-related lobes and thus should be
responsible for the ring opening, and 2) the attack at C3
should be facile due to its lower steric hindrance, and
afford the thermodynamically more favorable benzylic
radical species. It is interesting to note that the
regioselective ring-opening of the same type of F2CPs was
also realized at the other C-C bonds by emnploying totally
different reaction conditions and/or substrate substituent
patterns.17b,25 After ring opening, further one electron
oxidation of the resultant radical intermediate seemed to be the
next step and further reaction with Br2 (or Br– ion), H2O, or
acetonitrile readily furnished the corresponding adducts 2, 4a,
and 5a, respectively. Formation of the tribromide 3a was also
ex plained by the proton elimination from the intermediary
benzyl cation, where the addition of Br2 was occurred. In the
case of 1m, the lobe at the benzylic C-H bond was calculated
to be at the energy level of –10.549 eV which is 0.466 eV
higher than the case of the one at the C1-
OH
Br
Br
Br
R
Br
F F
4a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R=Ph
F
2
F
F
R=Ph
H
MeCN
BrH2C Br
Ph
H3C NHAc
Ph
Br2
Br
Ph
Br
F
3a
F
F
5a
F
F
F
Figure 4. Proposed reaction mechanism.
C3 bond (–11.015 eV) which unambiguously explained the
preferential bromination at the benzylic position as shown in
Scheme 5.
On the bases of the experimental as well as computational
results described above, the following reaction mechanism
was considered to be plausible (Figure 4). At first, Br radical
was produced by ready oxidation of the corresponding anion
by CAN. After attack of this active species at the sterically
least hindered C3 atom in the electronically highest occupied
molecular orbital at the cyclopropane ring, following one
electron oxidation of the resultant radical intermediate seemed
to occur and the resultant benzylic cation would react with
such nucleophiles as Br– (or Br• before one electron
oxidation), H2O, or MeCN. Alternative pathway is to lose
proton from the benzylic methyl group to afford the styrene
type intermediate whose fate would react with Br2 to give the
corresponding tribromide.
Table 3. Computational results for 1a and Br2 or Br•
The electron-withdrawing nature of fluorine affected the
inherently lower stability of the neighboring carbocation
when compared with the case of the corresponding non-
fluorinated counterparts. The impact of the methoxy
group in 1d on a benzene ring should be in a dual
manner, thus causing stabilization of the benzylic radical
(or cation) as well as activation of the benzene ring
toward electrophilic attack by the in situ generated Br2
molecule. However, this is not the case for 1-(2,2-
Energy level (eV)
F
F
2
H3C
Ph
Singlet
Triplet
1
3
Unoccupied
Occupied
Occupied
Unoccupied
C1-C2
C1-C3
C2-C3
0.739
0.413
0.610
0.544 ()
0.559 ()
0.433 ()
0.433 ()
0.735 ()
0.734 ()
14.796
difluorocycloprop-1-yl)-4-methoxybenzene
1h
12.495 ()
12.626 ()
12.710
13.838
7.982
(substitution of a CH3 group in 1d for hydrogen) which
was nicely transformed into the desired 2h at the
elevated temperature of 70 °C in a 1,2-dichloroethane
(DCE) solvent. These phenomena would be understood as
the consequence of the "adequately unstable" secondary
radical formation from 1h which might permit the
promotion of the selective second bromination at this
site. Relatively lower yields of the products with a 4-
nitrophenyl group (2c and 2g) on the benzene ring would
be stemmed from the less stable benzylic cation because
of the presence of the strongly electron-withdrawing NO2
substituent.
Br2
Br•
4.238
8.898 ()
8.519 ()
0.114 ()
6.535()
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CONCLUSION
Hz), 1.40 (1H, ddd, J = 12.3, 7.7, 4.5 Hz) ppm. 13C{1H} NMR 
1
2
3
4
5
6
7
8
139.1 (t, J = 2.5 Hz), 128.5, 128.3 (d, J = 2.4 Hz), 127.2, 114.5
(dd, J = 288.7, 286.9 Hz), 31.2 (dd, J = 11.2, 9.3 Hz), 22.5 (t, J =
9.9 Hz), 21.4 (dd, J = 6.2, 1.8 Hz) ppm. 19F NMR  133.49 ~
134.06 (1F, m), 138.50 ~ 139.08 (1F, m) ppm. The NMR
data are agreement with previously reported.
In summary, we have successfully demonstrated hitherto
unknown and easy-to-use methods for regiospecific ring
opening of the simple gem-difluorocyclopropanes
without installation of any specific functions in the
presence of single electron oxidants such as CAN (IV) or
K2S2O8. This process readily furnished 1,3-dibromo-2,2-
difluoropropane derivatives in good yields when KBr was
1-Bromo-4-(2,2-difluoro-1-methylcyclopropyl)benzene
(1b).
Method A, 4.0 equiv. of KI and MDFA, 1.15 g (4.66 mmol, yield
93%, colorless oil. Rf = 0.26 (hexane). 1H NMR  7.51-7.45 (2H,
m), 7.26-7.17 (2H, m), 1.64 (1H, ddd, J = 13.5, 7.8, 3.6 Hz), 1.49
(3H, dd, J = 3.0, 2.1 Hz), 1.42 (1H, ddd, J = 12.3, 7.5, 4.5 Hz)
ppm. 13C{1H} NMR:  138.1 (t, J = 1.9 Hz), 131.7, 130.1 (d, J =
2.5 Hz), 121.2, 114.1 (dd, J = 289.0, 285.4 Hz), 30.6 (dd, J =
11.2, 9.3 Hz), 22.5 (t, J = 9.9 Hz), 21.1 (dd, J = 6.2, 2.5 Hz) ppm.
19F NMR:  133.70 (1F, dd, J = 150.5, 11.4 Hz), 138.87 (1F,
dd, J = 150.5, 11.4 Hz) ppm. IR (CHCl3)  3019, 2984, 1492,
1470, 1370, 1216, 1173, 1094, 1005, 759 cm. HRMS (FAB+,
m/z) [M]+ calcd for C10H9F2Br, 245.9856; Found, 245.9885.
employed in
a DCM/H2O (v/v=1/1) mixed solvent.
9
Characteristic feature of the present reaction was noticed
for the realization of bromohydroxylation and -amidation
just by changing the solvent system. These products with
a difluoromethylene moiety are considered as excellent
building blocks for pharmaceuticals and functional
materials. Further functionalization of these products are
ongoing in our laboratory whose results would be
presented in due course.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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25
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27
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29
30
31
32
33
34
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EXPERIMENTAL SECTION
1-(2,2-Difluoro-1-methylcyclopropyl)-4-nitrobenzene
(1c).
Unless otherwise mentioned, the NMR spectra for H, 13C, and
1
Method A, 4.0 equiv. of KI and MDFA, 0.828 g (2.22 mmol,
19F were recorded at 300, 75.5, and 282 MHz, respectively in
CDCl3 unless otherwise noted on JEOL JMN AL-300, with
chemical shifts being reported in ppm downfield from internal
TMS (: 0.00) for 1H, CDCl3 (: 77.0) for 13C{1H} NMR, and
BTF (: –64.00) or C6F6 (: –163.00) for 19F NMR spectra. Data
were tabulated in the following order: a number of protons or
fluorines, multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; quint, quintet; m, multiplet; br, broad peak), and
coupling constants in Hertz. IR spectra were reported in wave
numbers (cm1) on JASCO FTIR-6100. High resolution mass
spectra were obtained by double-focusing mass spectrometer
in the FAB mode by using JEOL JMS-700. Elemental analyses
were recorded on Perkin Elmer CHNS/O Analyzer 2400.
yield 89%), white solid. mp: 53.6-53.9 °C. Rf
= 0.20
1
(hexane:Et2O = 25:1). H NMR:  8.11 (2H, d, J = 8.7 Hz), 7.41
(2H, d, J = 8.7 Hz), 1.70-1.62 (1H, m), 1.50-1.42 (4H, m) ppm.
13C{1H} NMR:  147.0, 146.4 (dd, J = 2.5, 1.9 Hz), 129.4 (dd, J =
1.9, 0.6 Hz), 123.8, 113.6 (dd, J = 290.3, 286.6 Hz), 30.8 (dd, J =
11.5, 9.6 Hz), 22.8 (t, J = 9.9 Hz), 20.8 (dd, J = 6.2, 1.8 Hz) ppm.
19F NMR:  133.07 ~ 138.81 (1F, m), 138.24 ~ 138.81
(1F, m) ppm. IR (KBr)  3117, 3085, 2976, 1599, 1517, 1347,
1222, 1005, 856, 725 cm1. HRMS (FAB+, m/z) [M+H]+ calcd
for C10H10F2NO2, 214.0680; Found, 214.0702.
1-(2,2-Difluoro-1-methylcyclopropyl)-4-methoxybenzene
(1d).16 Method A, 4.0 equiv. of KI and MDFA, 2.35 g (11.9
mmol, yield 99%), pale yellow oil. Rf = 0.57 (hexane:CH2Cl2 =
1:1). 1H NMR:  7.26-7.22 (2H, m), 6.90-6.85 (2H, m), 3.80 (3H,
s), 1.63(1H, ddd, J = 13.5, 7.5, 3.6 Hz), 1.49 (3H, dd, J = 2.7, 1.8
Hz), 1.36 (1H, ddd, J = 12.3, 7.5, 4.2 Hz) ppm. 13C{1H} NMR: 
158.6, 131.2, 129.4, 114.8 (dd, J = 288.7, 286.3 Hz), 113.9, 55.2,
30.5 (dd, J = 10.6, 10.0 Hz), 22.5 (dd, J = 10.0, 9.9 Hz), 21.5 (d, J
Preparation of gem-difluorinated cyclopropanes 1.
Method A16: To a mixture of KI (2.0 or 4.0 equiv.) and an
alkene (1.0 equiv.) in EtCN (1.0 M to alkene), methyl 2,2-
difluoro-2-(fluorosulfonyl)acetate (MDFA, 2.0 or 4.0 equiv.)
was added at room temperature and the resultant solution
was stirred at 50 °C (oil bath temperature) for 24 h. After
cooling to room temperature, the reaction mixture was
quenched by water and extracted by hexane three times. The
combined hexane layer was successively washed with water,
sat. aq. NaHCO3 and brine. After drying over anhydrous
Na2SO4, followed by concentration under reduced pressure,
the crude product was purified by silica gel column
chromatography. Method B26: To a mixture of NaI (0.2 equiv.)
and an alkene (1.0 equiv.) in anhydrous THF (3.4 M to alkene)
under argon atmosphere was added TMSCF3 (2.5 equiv.) and
the resultant solution was stirred at 65 °C (oil bath
temperature) until the starting material was disappeared
(judged by TLC). After cooling to room temperature and
evaporation to dryness under reduced pressure, water (20
mL) was added to the residue which was extracted by Et2O
three times. The combined extract was washed with water,
sat. aq. Na2S2O3 and brine. After drying over anhydrous
Na2SO4 and concentration, the crude product was purified by
silica gel column chromatography.
=
6.2 Hz) ppm. 19F NMR:  133.72
~ 134.29 (1F,
m), 138.67 ~ 139.25 (1F, m) ppm. The NMR data are
agreement with previously reported.
(2,2-Difluoro-1-cyclopropyl)benzene (1e).26 Method B, 1.36 g
(8.81 mmol, yield 88%), pale yellow oil. Rf = 0.75 (hexane). 1H
NMR:  7.34-7.20 (5H, m), 2.79-2.68 (1H, m), 1.86-1.73 (1H,
m), 1.66-1.55 (1H, m) ppm. 13C{1H} NMR:  133.7, 128.4, 128.0
(dd, J = 1.9, 1.2 Hz), 127.1, 112.6 (dd, J = 285.9, 283.4 Hz), 27.2
(t, J = 11.2 Hz), 17.0 (t, J = 10.1 Hz) ppm. 19F NMR:  126.84 ~
127.47 (1F, m), 143.39 ~ 144.00 (1F, m) ppm. The NMR
data are agreement with previously reported.
1-Bromo-4-(2,2-difluorocyclopropyl)benzene (1f).26 Method A,
4.0 equiv. of KI and MDFA, 1.85 g (7.93 mmol, yield 82%),
colorless oil. Rf = 0.57 (hexane). 1H NMR:  7.44 (2H, d, J = 8.1
Hz), 7.09 (2H, d, J = 8.4 Hz), 2.75-2.64 (1H, m), 1.90-1.76 (1H,
m), 1.64-1.35 (1H, m) ppm. 13C{1H} NMR:  132.7, 131.6,
129.7, 121.0, 112.2 (dd, J = 286.6, 283.4 Hz), 26.6 (dd, J = 11.7,
11.2 Hz), 17.1 (dd, J = 10.6, 10.5 Hz) ppm. 19F NMR:  127.09
~ 127.72 (1F, m), 143.27 ~ 143.89 (1F, m) ppm. The NMR
data are agreement with previously reported.
(2,2-Difluoro-1-methylcyclopropyl)benzene (1a).16 Method A,
2.0 equiv. of KI and MDFA, 5.31 g (31.6 mmol, yield 79%),
colorless oil. Rf = 0.42 (hexane). H NMR  7.37-7.26 (5H, m),
1.68 (1H, ddd, J = 13.7, 7.7, 3.6 Hz), 1.52 (3H, dd, J = 2.7, 1.8
1
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The Journal of Organic Chemistry
1-(2,2-Difluorocyclopropyl)-4-nitrobenzene (1g).27 Method B,
= 7.8 Hz), 2.72 (1H, m), 1.79 (1H, ddd, J = 12.0, 7.2, 4.5 Hz),
1.60 (1H, ddd, J = 12.3, 8.1, 3.9 Hz), 1.31 (9H, s) ppm. 13C{1H}
NMR:  150.1, 130.7, 127.7, 125.4, 112.7 (t, J = 286.6 Hz), 34.5,
31.3, 26.8 (t, J = 11.2 Hz), 17.0 (d, J = 10.6 Hz) ppm. 19F NMR:
 127.16 (1F, dtd, J = 152.9, 13.8, 4.8 Hz), 143.53 (1F, ddd, J
= 152.6, 12.8, 4.5 Hz) ppm. The NMR data are agreement with
previously reported.
1
2
3
4
5
6
7
8
0.880 g (4.42 mmol, yield 88%), yellow oil. Rf = 0.28
(hexane:AcOEt = 10:1). 1H NMR:  8.18 (2H, d, J = 8.7 Hz), 7.38
(2H, d, J = 8.7 Hz), 2.91-2.80 (1H, m), 2.05-1.93 (1H, m), 1.80-
1.69 (1H, m) ppm. 13C{1H} NMR:  147.0, 141.4, 128.7 (t, J =
1.9 Hz), 123.6, 111.9 (dd, J = 287.7, 283.5 Hz), 27.0 (dd, J =
12.4, 11.2 Hz), 17.9 (t, J = 10.6 Hz) ppm. 19F NMR:  126.40 ~
127.04 (1F, m), 142.83 ~ 143.44 (1F, m) ppm. The NMR
data are agreement with previously reported.
1-(2,2-Difluoro-1-methylcyclopropyl)-4-methylbenzene (1m).
Method A, 4 eq. of KI and MDFA, 0.702 g (3.85 mmol, yield
77%), colorless oil. Rf = 0.45 (hexane). 1H NMR:  7.20 (2H, d, J
= 8.4 Hz), 7.14 (2H, d, J = 8.4 Hz), 2.32 (3H, s), 1.63(1H, ddd, J =
13.5, 7.5, 3.6 Hz), 1.47 (3H, dd, J = 2.7, 1.5 Hz), 1.35 (1H, ddd, J
= 12.3, 7.5, 4.5 Hz) ppm. 13C{1H} NMR:  136.9, 136.1, 129.2,
128.2 (d, J = 1.9 Hz), 114.7 (dd, J = 289.0, 286.6 Hz), 30.9 (dd, J
= 11.2, 10.0 Hz), 22.4 (t, J = 9.9 Hz), 21.4 (dd, J = 6.8, 2.5 Hz),
21.0 ppm. 19F NMR:  133.81 (1F, dd, J = 148.1, 13.5 Hz),
138.9 (1F, dd, J = 148.1, 12.5 Hz) ppm. IR (CHCl3)  3019,
(1h).26
9
1-(2,2-Difluorocyclopropyl)-4-methoxybenzene
Method A, 4.0 equiv. of KI and MDFA, 1.36 g (8.81 mmol, yield
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
88%), colorless oil. Rf = 0.31 (hexane:Et2O = 25:1). H NMR: 
7.16 (2H, d, J = 8.3 Hz), 6.87 (2H, d, J = 8.3 Hz), 3.80 (3H, s),
2.77-2.66 (1H, m), 1.85-1.72 (1H, m), 1.61-1.50 (1H, m) ppm.
13C{1H} NMR:  158.7, 129.2, 125.6, 113.9, 112.7 (dd, J = 286.3,
283.2 Hz), 55.2, 26.4 (t, J = 11.2 Hz), 16.9 (dd, J = 10.8, 10.2 Hz)
ppm. 19F NMR:  127.30 ~ 127.93 (1F, m), 141.66 ~
142.25 (1F, m) ppm. The NMR data are agreement with
previously reported.
2981, 2927, 1518, 1472, 1371, 1217, 1007, 821, 759 cm1
.
HRMS (FAB+, m/z): [M]+ calcd for C11H12F2, 182.0907, Found,
182.0915.
2-(2,2-Difluoro-1-methylcyclopropyl)naphthalene
(1i).
General procedure of dibromination: (2,4-Dibromo-3,3-
difluorobut-2-yl)benzene (2a). To a mixture of (2,2-difluoro-1-
methylcycloprop-1-yl)benzene 0.0841 g (0.50 mmol) and KBr
0.1309 g (1.10 mmol) in CH2Cl2 5.0 mL, aqueous solution of
Ce(NH4)2(NO3)6 0.6304 g (1.15 mmol) in H2O 5.0 mL was
added at room temperature. After stirring for 9 h, the reaction
mixture was extracted with CH2Cl2 three times and the
organic layer was washed with brine. After dried over
anhydrous Na2SO4, the crude product was evaporated and
purified by silica gel column chromatography by using hexane
as an eluent. 0.1325 g (0.40 mmol), yield 81%, colorless oil. Rf
Method A, 4.0 equiv. of KI and MDFA, 1.09 g (4.97 mmol, yield
99%), colorless oil. Rf = 0.30 (hexane). 1H NMR:  7.85-7.71
(4H, m), 7.51-7.43 (3H, m), 1.80 (1H, ddd, J = 13.5, 7.5, 3.6 Hz),
1.60 (3H, dd, J = 2.7, 1.8 Hz), 1.48 (1H, ddd, J = 12.0, 7.5, 4.2
Hz) ppm. 13C{1H} NMR:  136.5 (dd, J = 2.5, 1.8 Hz), 133.3,
132.5, 128.3, 127.7, 127.6, 127.0 (d, J = 2.5 Hz), 126.5 (d, J =
1.9 Hz), 126.2, 126.0, 114.7 (dd, J = 289.7, 286.6 Hz), 31.3 (dd,
J = 10.9, 9.7 Hz), 22.5 (t, J = 10.0 Hz), 21.2 (dd, J = 6.8, 5.0 Hz)
ppm. 19F NMR:  133.72 (1F, dd, J = 150.7, 13.9 Hz), 138.61
(1F, dd, J = 150.4, 11.6 Hz) ppm. IR (CHCl3)  3019, 1477,
1466, 1216, 1006, 904, 859, 820, 759, 670 cm1. HRMS (FAB+,
m/z): [M+H]+ calcd for C14H13F2, 219.0985, Found, 219.1010.
1
= 0.29 (hexane). H NMR:  7.69-7.66 (2H, m), 7.40-7.35 (3H,
m), 3.82 (1H, ddd, J = 27.6, 12.0, 3.3 Hz), 3.57 (1H, ddd, J =
27.3, 12.0, 3.3 Hz), 2.33 (3H, s) ppm. 13C{1H} NMR:  138.3,
129.0, 128.7 (t, J = 1.5 Hz), 128.3, 118.6 (dd, J = 252.4, 250.6
Hz), 65.9 (t, J = 26.0 Hz), 30.3 (t, J = 27.3 Hz), 27.4 (dd, J = 3.8,
2.5 Hz) ppm. 19F NMR:  104.38 (1F, dd, J = 237.1, 27.4
Hz), 106.72 (1F, dd, J = 237.1, 27.4 Hz) ppm. IR (CHCl3) 
3014, 1496, 1446, 1422, 1384, 1275, 1216, 1038, 1016, 750
cm1. Anal. Calcd for C10H10Br2F2: C, 36.63; H, 3.07. Found: C,
36.76; H, 2.94.
1-(2,2-Difluoro-1-methylcyclopropyl)nonane (1j). Method A,
4.0 equiv. of KI and MDFA, 0.993 g (4.55 mmol, yield 91%),
1
colorless oil. Rf = 0.60 (hexane). H NMR:  1.42-1.37 (4H, m),
1.31-1.21 (12H, m), 1.16-1.15 (3H, m), 1.02-0.91 (2H, m),
0.90-0.86 (3H, m) ppm. 13C{1H} NMR:  116.9 (dd, J = 288.4,
287.8 Hz), 32.7 (dd, J = 4.9, 1.2 Hz), 31.9, 29.6, 29.6, 29.5, 29.3,
26.3 (d, J = 4.1 Hz), 26.1 (t, J = 9.9 Hz), 22.7, 22.3 (t, J = 10.0
Hz), 16.1 (dd, J = 6.8, 1.3 Hz), 14.1 ppm. 19F NMR:  138.84 ~
139.42 (1F, m), 140.38 ~ 140.97 (1F, m) ppm. IR
(CHCl3)           
 cm1. HRMS (FAB+, m/z) [M]+ calcd for C13H24F2, 218.1846;
Found, 218.1850.
(1,2,4-Tribromo-3,3-difluorobut-2-yl)benzene (3a). Several
bathes were gathered and purified. White solid. mp: 64.0-64.4
°C. Rf = 0.15 (hexane). 1H NMR:  7.65-7.62 (2H, m), 7.44-7.40
(3H, m), 4.54 (1H, d, J = 12.0 Hz), 4.26 (1H, d, J = 11.7 Hz), 4.08
(1H, ddd, J = 29.4, 12.3, 2.4 Hz), 3.35 (1H, ddd, J = 27.9, 12.3,
3.3 Hz) ppm. 13C{1H} NMR:  134.2 (d, J = 1.8 Hz), 129.5, 129.1
(dd, J = 2.5, 1.2 Hz), 128.7, 118.6 (dd, J = 255.5, 251.8 Hz), 71.7
(t, J = 24.1 Hz), 37.5 (dd, J = 4.3, 3.1 Hz), 30.8 (t, J = 26.0 Hz)
ppm. 19F NMR:  103.17 (1F, dd, J = 237.1, 22.9 Hz), 106.51
(1F, dd, J = 237.1, 28.3 Hz) ppm. IR (KBr)  3050, 2991, 1493,
1443, 1432, 1420, 1274, 1258, 1220, 1190 cm1. Anal. Calcd
for C10H9Br3F2: C, 29.52; H, 2.23. Found: C, 29.73; H, 2.08.
1-(2,2-Difluoro-1-methylcyclopropyl)-2-methoxybenzene (1k).
Method A, 4 eq. of KI and MDFA, 1.54 g (7.77 mmol, yield
78%), colorless oil. Rf = 0.71 (hexane:AcOEt = 4:1). 1H NMR:
 7.20-7.26 (2H, m), 6.91 (1H, dt, J = 7.2, 1.2 Hz), 6.89 (1H, d, J
= 8.1 Hz), 3.87 (3H, s), 1.53(1H, ddd, J = 13.5, 7.8, 3.9 Hz), 1.44
(3H, dd, J = 2.7, 1.8 Hz), 1.36 (1H, ddd, J = 12.3, 7.8, 4.8 Hz)
ppm. 13C{1H} NMR:  158.5, 129.7, 128.7, 127.5, 120.4, 114.9
(t, J = 286.0 Hz), 110.7, 55.4, 28.4 (t, J = 10.6 Hz), 22.4 (t, J =
10.0 Hz), 19.4 (d, J = 5.6 Hz) ppm. 19F NMR:  134.78 (1F, dd,
J = 150.7, 11.6 Hz), 140.3 (1F, dd, J = 150.7, 11.6 Hz) ppm. IR
(neat)  2972, 2940, 2839, 1498, 1468, 1275, 1245, 1211,
1-Bromo-4-(2,4-dibromo-3,3-difluorobut-2-yl)benzene
(2b).
0.148 g (0.365 mmol, yield 73%), colorless oil. Rf = 0.17
(hexane). 1H NMR:  7.58-7.49 (4H, m), 3.83 (1H, ddd, J = 26.7,
12.3, 3.9 Hz), 3.61 (1H, ddd, J = 26.7, 12.0, 4.2 Hz), 2.31 (3H,
dd, J = 1.2, 0.9 Hz) ppm. 13C{1H} NMR:  137.4, 131.5, 130.4 (t,
J = 1.8 Hz), 123.6, 118.4 (dd, J = 252.5, 251.2 Hz), 64.8 (t, J =
26.0 Hz), 30.0 (t, J = 27.6 Hz), 27.5 (t, J = 3.1 Hz) ppm. 19F
NMR:  104.63 (dd, J = 240.5, 27.1 Hz) ppm, 106.52 (dd, J =
1007, 756 cm1 HRMS (FAB+, m/z): [M+H]+ calcd for
.
C11H13F2O, 199.0934, Found, 199.0961.
1-(2,2-Difluorocyclopropyl)-4-tert-butylbenzene
(1l).28
Method B, 1.04 g (4.95 mmol, yield 99%), colorless oil. Rf =
0.50 (hexane). 1H NMR:  7.35 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J
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Page 8 of 12
240.5, 27.4 Hz) ppm. IR (CHCl3)  3019, 1589, 1490, 1397,
246.2, 11.3 Hz), 103.99 (1F, dq, J = 246.2, 11.3 Hz) ppm. IR
(CHCl3)  3013, 2840, 1610, 1514, 1297, 1256, 1180, 1100,
1027, 757 cm1 HRMS (FAB+, m/z) [M+H]+ calcd for
1215, 1084, 1040, 1010, 758, 670 cm1. Anal. Calcd for
C10H9Br3F2: C, 29.52; H, 2.23. Found: C, 29.31; H, 1.96.
1
2
3
4
.
C10H11Br2F2O, 342.9139, Found, 342.9150.
1-(2,4-Dibromo-3,3-difluorobut-2-yl)-4-nitrobenzene
(2c).
0.091 g, (0.245 mmom, yield 49%), pale yellow oil. Rf = 0.32
(hexane:Et2O = 4:1). 1H NMR:  8.26-8.21 (2H, m), 7.90 (2H, d,
J = 9.3 Hz), 3.94-3.66 (2H, m), 2.38 (3H, s) ppm. 13C{1H} NMR:
 147.8, 144.9, 130.2 (t, J = 1.9 Hz), 123.2, 118.4 (t, J = 251.9
Hz), 63.8 (t, J = 26.7 Hz), 29.8 (t, J = 27.2 Hz), 27.7 (t, J = 3.1
Hz) ppm. 19F NMR:  104.56 (1F, ddd, J = 241.7, 22.9, 6.8 Hz),
105.71 (1F, ddd, J = 241.7, 22.9, 6.8 Hz) ppm. IR (CHCl3) 
3020, 1526, 1352, 1216, 1063, 1043, 1016, 862, 763, 472
cm1. HRMS (FAB+, m/z) [M+H]+ calcd for C10H10Br2F2NO2,
371.9046; Found, 371.9062.
2-(2,4-Dibromo-3,3-difluorobut-2-yl)naphthalene (2i). 0.032 g
(0.085 mmol, yield 17%), white solid. mp: 62.9-63.8 °C. Rf =
0.14 (hexane). 1H NMR:  8.11-8.06 (1H, m), 7.88-7.81 (4H,
m), 7.55-7.52 (2H, m), 3.87-3.74 (1H, m), 3.68-3.53 (1H, m),
2.44 (3H, s) ppm. 13C{1H} NMR:  135.6, 133.0, 132.4, 128.5,
128.2, 127.8 (dd, J = 1.8, 1.2 Hz), 127.4 (d, J = 0.6 Hz), 127.3,
126.8, 126.3 (t, J = 2.5 Hz), 118.7 (dd, J = 252.4, 250.1 Hz), 65.9
(t, J = 25.4 Hz), 30.3 (t, J = 27.2 Hz), 27.5 (dd, J = 3.7, 2.4 Hz).
19F NMR:  102.93 ~ 103.86 (1F, m), 105.56 ~ 106.52
(1F, m) ppm. IR (CHCl3)  3052, 2991, 2943, 1596, 1273,
1384, 1273, 1013, 796, 756 cm1. HRMS (FAB+, m/z): [M]+
calcd for C14H12Br2F2, 375.9274, Found, 375.9291.
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6
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13
14
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19
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22
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32
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34
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1-(2,4-Dibromo-3,3-difluorobut-2-yl)-4-methoxybenzene (2d).
Only 19F NMR data were shown due to impossible isolation of
this compound. Yield 17% (by 19F NMR). 19F NMR:  104.25
(dd, J = 237.1, 27.1 Hz), 106.67 (dd, J = 237.1, 27.4 Hz) ppm.
1,3-Dibromo-2,2-difluoro-3-methyldodecane (2j). 0.134
g
1
(0.364 mmol, yield 73%), colorless oil. Rf = 0.48 (hexane). H
NMR:  4.09-4.01 (1H, m), 3.98-3.90 (1H, m), 2.00-1.81 (2H,
m), 1.78 (3H, s), 1.65-1.41 (2H, m), 1.32-1.28 (12H, m), 0.89
(3H, t, J = 6.3 Hz) ppm. 13C{1H} NMR:  119.4 (t, J = 250.0 Hz),
66.7 (t, J = 25.5 Hz), 38.9 (dd, J = 2.5, 1.8 Hz), 31.8, 30.8 (t, J =
27.3 Hz), 29.54, 29.48, 29.4, 29.3, 25.1, 24.7 (t, J = 3.1 Hz),
22.7, 14.1 ppm. 19F NMR:  106.68 ~ 107.65 (1F, m),
108.64 ~ 109.61 (1F, m) ppm. IR (CHCl3)  2927, 2855,
1466, 1422, 1382, 1216, 1052, 1031, 761, 652 cm1. HRMS
(FAB+, m/z) [M+Na]+ calcd for C13H24Br2F2Na, 399.0111,
Found, 399.0137.
(1,3-dibromo-2,2-difluoropropyl)benzene (2e). 0.131 g, (0.419
mmol, yield 84%), colorless oil. Rf = 0.29 (hexane). 1H NMR:
 7.54-7.50 (2H, m), 7.39-7.36 (3H, m), 5.36 (1H, dd, J = 13.8,
12.3 Hz), 3.73 (1H, q, J = 12.0 Hz), 3.45 (1H, dt, J = 14.1, 12.0
Hz) ppm. 13C{1H} NMR:  134.1 (d, J = 3.1 Hz), 129.7, 129.3
(dd, J = 1.9, 1.3 Hz), 128.8, 118.2 (t, J = 248.0 Hz), 50.1 (t, J =
26.7 Hz), 29.7 (t, J = 32.2 Hz) ppm. 19F NMR:  102.35 (dq, J =
246.2, 11.3 Hz), 103.71 (dq, J = 246.2, 11.3 Hz) ppm. IR
(CHCl3)  3109, 1455, 1421, 1264, 1216, 1103, 1026, 754, 700,
671 cm1. HRMS (FAB+, m/z) [M]+ calcd for C9H8Br2F2,
311.8961, Found, 311.8971.
Procedure of bromohydroxylation by CAN: 4-Bromo-3,3-
difluoro-2-phenylbutan-2-ol (4a). To
difluoro-1-methylcycloprop-1-yl)benzene 0.0841
a
mixture of (2,2-
(0.50
g
1-Bromo-4-(1,3-dibromo-2,2-difluoropropyl)benzene
(2f).
mmol) and KBr 0.1309 g (1.10 mmol) in MeCN 5.0 mL,
Ce(NH4)2(NO3)6 0.6304 g (1.15 mmol) in H2O 5.0 mL was
added at room temperature. After stirring at 60 °C (oil bath
temperature) for 9 h, the reaction mixture was extracted with
CH2Cl2 three times, washed with brine, and dried over
anhydrous Na2SO4. After evaporation, the crude product was
0.136 g, (0.346 mmol, yield 69%), colorless oil. Rf = 0.26
(hexane). 1H NMR (acetone-d6)  7.53 (2H, m), 7.41 (2H, m),
5.33 (1H, t, J = 12.8 Hz), 3.78 (1H, dq, J = 24.3, 12.0 Hz), 3.48
(1H, dq, J = 24.6, 12.0 Hz) ppm. 13C{1H} NMR:  133.1 (dd, J =
1.9, 1.3 Hz), 132.0, 131.0 (t, J = 1.2 Hz), 124.0, 118.1 (t, J =
248.7 Hz), 49.0 (t, J = 27.3 Hz), 29.6 (t, J = 32.8 Hz) ppm. 19F
NMR:  103.31 ~ 103.44 ppm (m) . IR (CHCl3)  3015,
purified
by
silica
gel
coumn
chromatography
1591, 1490, 1421, 1408, 1264, 1216, 1100, 1076, 1026 cm1
.
(hexane:CH2Cl2=1:1) to yield 4-bromo-3,3-difluoro-2-
phenylbutan-2-ol 0.081 g (0.306 mmol, yield 61%) as a
HRMS (FAB+, m/z) [M]+ calcd for C9H7Br3F2, 389.8066, Found,
389.8075.
1
colorless oil. Rf = 0.30 (hexane: CH2Cl2 = 1:1). H NMR:  7.54
(2H, d, J = 7.8 Hz), 7.41-7.33 (3H, m), 3.79 (1H, ddd, J = 30.0,
12.0, 2.4 Hz), 3.46 (1H, ddd, J = 28.5, 12.3, 3.3 Hz), 2.38 (1H, br
s), 1.77 (3H, s) ppm. 13C{1H} NMR:  139.8 (d, J = 4.3 Hz),
128.4, 128.2, 125.7 (dd, J = 2.5, 1.2 Hz), 119.7 (dd, J = 251.8,
250.0 Hz), 75.9 (dd, J = 27.3, 25.4 Hz), 30.2 (t, J = 26.7 Hz), 24.1
(dd, J = 3.1, 2.5 Hz) ppm. 19F NMR:  112.14 (1F, dd, J = 241.9,
31.7 Hz), 115.47 (1F, dd, J = 243.9, 27.4 Hz). IR (CHCl3) 
3601, 3459, 3017, 1449, 1216, 1141, 1073, 1037, 761, 703
cm1. Anal. Calcd for C10H11BrF2O: C, 45.31; H, 4.18. Found: C,
45.53; H, 4.31.
1-(1,3-Dibromo-2,2-difluoropropyl)-4-nitrobenzene (2g). Only
1H, 13C and 19F NMR data and HRMS were shown due to
impossible isolation of this compound. Yield 44% (by 19F
1
NMR). H NMR:  8.25 (2H, d, J = 8.4 Hz), 7.73 (2H, d, J = 8.4
Hz), 5.46 (1H, dd, J = 15.3, 10.2 Hz), 3.88 (1H, ddd, J = 16.8,
11.1, 9.9 Hz), 3.56 (1H, q, J = 11.7 Hz) ppm. 13C{1H} NMR: 
148.4, 140.7, 130.6, 123.8, 118.2 (t, J = 249.3 Hz), 47.8 (t, J =
27.5 Hz), 29.5 (t, J = 32.6 Hz) ppm. 19F NMR:  100.98 ~
102.62 (1F, m) ppm, 103.77 ~ 105.58 (1F, m) ppm. HRMS
(FAB+, m/z) [M+H]+ calcd for C9H8Br2F2NO2, 357.8890, Found,
357.8874.
3-Bromo-1-(4-tert-butylphenyl)-2,2-difluoropropan-2-ol (4l).
The reaction was conducted at 80 °C (oil bath temperature)
for 9 h. 0.072 g (0.234 mmol, yield 47%) as a colorless oil. Rf =
1-(2,4-Dibromo-3,3-difluorobut-2-yl)-4-methoxybenzene (2h).
1
0.40 (hexane:AcOEt = 4:1). H NMR:  7.40 (4H, m), 5.12 (1H,
0.130 g (0.377 mmol, yield 75%), pale yellow oil. Rf = 0.20
1
ddd, J = 11.7, 9.0, 4.2 Hz), 3.75 (1H, dt, J = 18.0, 12.0 Hz), 3.46
(1H, ddd, J = 18.3, 12.0, 8.7 Hz), 2.44 (1H, br d, J = 4.2 Hz), 1.33
(9H, s) ppm. 13C{1H} NMR:  152.2, 132.5, 127.1, 125.5, 119.2
(t, J = 246.9 Hz), 73.4 (t, J = 27.9 Hz), 34.6, 31.2, 29.2 (t, J = 30.4
Hz) ppm. 19F NMR:  104.87 (1F, m), 106.14 (1F, m) ppm. IR
(KBr)  3415, 2965, 2905, 2870, 1108, 1036, 735, 588, 478,
(hexane:Et2O = 20:1). H NMR:  7.44 (2H, d, J = 7.8 Hz), 6.88
(2H, d, J = 7.2 Hz), 5.35 (1H, dd, J = 14.1, 11.4 Hz), 3.80 (3H, s),
3.71 (1H, dd, J = 23.7, 11.7 Hz), 3.44 (1H, dd, J = 26.1, 12.0 Hz)
ppm. 13C{1H} NMR:  160.4, 130.6, 126.1 (d, J = 3.8 Hz), 118.2
(dd, J = 248.8, 247.4 Hz), 114.1, 55.3, 50.2 (t, J = 26.6 Hz), 29.7
(dd, J = 33.5, 32.2 Hz) ppm. 19F NMR:  102.20 (1F, dq, J =
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The Journal of Organic Chemistry
470 cm1
.
HRMS (FAB+, m/z) [M+Na]+ calcd for
(CHCl3:MeOH = 10:1). H NMR:  7.33 (2H, d, J = 8.6 Hz), 6.91
(2H, d, J = 8.6 Hz), 6.15 (1H, br s), 5.61 (1H, ddd, J = 15.3, 12.9,
9.3 Hz), 3.81 (3H, s), 3.57-3.32 (2H, m), 2.05 (3H, s) ppm.
13C{1H} NMR:  169.5, 159.9, 129.4, 126.5 (d, J = 3.8 Hz), 119.7
(dd, J = 250.6, 247.5 Hz), 114.3, 55.3, 54.5 (t, J = 23.5 Hz), 30.0
(t, J = 30.4 Hz), 23.3 ppm. 19F NMR:  107.77 ~ 108.79 (1F,
m), 108.93 ~ 109.94 (1F, m) ppm. IR (KBr)  3292, 3045,
2840, 1901, 1664, 1516, 1369, 1188, 1041, 809 cm1. HRMS
(FAB+, m/z): [M+H]+ calcd for C12H15BrF2NO2, 322.0254;
Found, 322.0224.
1
1
2
3
4
5
6
7
8
C13H17BrF2NaO, 329.0329, Found, 329.0304.
1-(4-tert-Butylphenyl)-2,2-difluoro-3-iodopropan-2-ol (4l’). KI
0.1829 g (1.10 mmol) was employed instead of KBr. The
reaction was conducted at 80 °C (oil bath temperature) for 9
h. 0.103 g (0.335 mmol, yield 67%) as a white solid. mp: 83.0-
84.0 °C. Rf = 0.46 (hexane:AcOEt = 4:1). 1H NMR:  7.40 (4H,
m), 5.09 (1H, td, J = 9.0, 3.9 Hz), 3.59 (1H, ddd, J = 24.0, 11.7,
8.4 Hz), 3.29 (1H, ddd, J = 23.6, 11.7, 7.5 Hz), 2.46 (1H, br d, J =
4.2 Hz), 1.32 (9H, s) ppm. 13C{1H} NMR:  152.2, 132.7 (d, J =
1.9 Hz), 126.9, 125.5, 119.3 (t, J = 246.3 Hz), 73.6 (t, J = 28.5
Hz), 34.6, 31.2, 1.44 (t, J = 28.6 Hz) ppm. 19F NMR:  104.20
(1F, ddt, J = 244.2, 18.4, 9.0 Hz), 106.25 (1F, ddt, J = 243.9,
18.4, 9.0 Hz) ppm. IR (KBr)  3557, 2962, 2870, 1509, 1214,
1141, 1075, 1015, 846, 863 cm1. HRMS (FAB+, m/z) [M+Na]+
calcd for C13H17F2NaIO, 377.0190, Found, 377.0210.
9
N-[3-Bromo-1-(4-tert-butylphenyl)-2,2-difluoroprop-1-yl]acet-
amide (5l). 0.0384 g (0.110 mmol, yield 22%) as a yellow
solid. mp: 132.0 – 133.0 °C. Rf = 0.15 (hexane:AcOEt = 4:1). 1H
NMR:  7.40 (2H, dt, J = 8.4, 2.1 Hz), 7.32 (2H, d, J = 8.4 Hz),
6.22 (1H, br s), 5.64 (1H, ddd, J = 14.7, 12.6, 9.3 Hz), 3.46 (2H,
m), 2.05 (3H, s), 1.32 (9H, s) ppm. 13C{1H} NMR:  169.6,
152.0, 131.5 (d, J = 3.2 Hz), 127.8, 125.9, 119.5 (dd, J = 247.5,
250.0 Hz), 54.8 (t, J = 23.6 Hz), 34.6, 31.2, 30.1 (t, J = 29.8 Hz),
23.2 ppm. 19F NMR:  108.13 (1F, dq, J = 244.2, 14.4 Hz),
109.27 (1F, dq, J = 246.2, 13.6 Hz) ppm. IR (KBr)  3361,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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31
32
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34
35
36
37
38
39
40
41
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44
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48
49
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56
57
58
59
60
Procedure of bromoamidation by CAN: N-(4-Bromo-3,3-
difluoro-2-phenylbut-2-yl)acetamide (5a). To a mixture of (2,2-
difluoro-1-methylcycloprop-1-yl)benzene 0.0838
2968, 2866, 1928, 1660, 1534, 1286, 1044, 849, 591 cm1
.
HRMS (FAB+, m/z): [M+H]+ calcd for C15H21BrF2NO2,
348.0774; Found, 348.0779.
g
(0.50
mmol) and KBr 0.1308 g (1.10 mmol) in MeCN 5.0 mL,
Ce(NH4)2(NO3)6 0.6311 g (1.15 mmol) was added at room
temperature. After stirring at 60 °C (oil bath temperature) for
9 h, the reaction mixture was quenched by water 5.0 mL. The
usual work-up and recrystallization from chloroform yielded
N-(4-bromo-3,3-difluoro-2-phenylbut-2-yl)acetamide 0.035 g
(0.114 mmol, yield 23%) as a white solid. mp: 178.2-179.0 °C.
Rf = 0.10 (CH2Cl2). 1H NMR (DMSO-d6)  8.41 (1H, s), 7.34-
7.27 (5H, m), 4.05 (1H, ddd, J = 29.4, 12.0, 3.6 Hz), 3.87 (1H,
ddd, J = 29.4, 12.3, 3.0 Hz), 1.93 (3H, s), 1.88 (3H, s) ppm.
13C{1H} NMR (DMSO-d6)  169.1, 139.0, 127.9, 127.3, 127.1,
119.6 (t, J = 250.0 Hz), 62.5 (t, J = 23.5 Hz), 31.5 (t, J = 25.4 Hz),
23.5, 20.4 (dd, J = 3.1, 2.5 Hz) ppm. 19F NMR:  109.9 (1F, dd,
J = 241.6, 27.4 Hz), 112.6 (1F, ddd, J = 239.4, 27.4, 4.5 Hz)
ppm. IR (KBr)  3274, 3082, 2992, 1649, 1563, 1372, 1308,
1228, 1206, 1057 cm1. HRMS (FAB+, m/z) [M+H]+ calcd for
C12H15BrF2NO, 306.0305, Found, 306.0293.
3-Bromo-1-(4-tert-butylphenyl)-2,2-difluoropropan-2-amine
(5l’). 0.0852 g (0.278 mmol, yield 56%) as a yellow solid. mp:
44.0 – 45.0 °C. Rf = 0.68 (hexane:AcOEt = 4:1). 1H NMR:  7.44
(2H, d, J = 8.4 Hz), 7.38 (2H, d, J = 8.4 Hz), 5.35 (1H, dd, J =
14.1, 11.1 Hz), 3.73 (1H, q, J = 12.0 Hz), 3.46 (1H, dt, J = 14.1,
11.7 Hz), 1.32 (9H, s) ppm. 13C{1H} NMR:  152.9, 131.1 (d, J =
3.1 Hz), 129.0, 125.8, 118.2 (t, J = 248.2 Hz), 50.2 (t, J = 26.7
Hz), 34.7, 31.2, 29.8 (t, J = 32.3 Hz) ppm. 19F NMR:  101.99
(1F, dq, J = 246.5, 11.3 Hz), 103.91 (1F, dq, J = 246.2, 11.5 Hz)
ppm. IR (KBr)  3042, 2962, 2867, 1918, 1798, 1685, 1612,
1196, 1035, 608 cm1. HRMS (ESI, m/z): [M+H]+ calcd for
C13H19BrF2N, 306.0663; Found, 306.0683.
General procedure of iodohydroxylation by K2S2O8: 3,3-
difluoro-4-iodo-2-(4-methoxyphenyl)butan-2-ol (6d). A mixture
of (2,2-difluoro-1-methylcycloprop-1-yl)benzene 0.0841
g
Procedure of bromoamidation by FeCl3: N-(4-Bromo-3,3-
difluoro-2-phenylbut-2-yl)acetamide (5a). To a mixture of (2,4-
dibromo-3,3-difluorobut-2-yl)benzene (2a) 0.1402 g (0.43
mmol) in MeCN (1.1 mL), anhydrous FeCl3 0.2774g (1.71
mmol) was added at room temperature. The reaction mixture
was stirred at reflux for 6 h in an oil bath. After cooling to
room temperature the reaction mixture was quenched by
water 2.0 mL and extracted with Et2O three times. The organic
layer was successively washed with 1 M HCl aq., water, and
brine, and dried over anhydrous Na2SO4. Then the crude
product was recrystallized from chloroform to yield N-(4-
bromo-3,3-difluoro-2-phenylbut-2-yl)acetamide (5a) 0.090 g
(0.294 mmol, yield 67%) as a white solid.
(0.50 mmol), KI 0.0830 g (0.55 mmol), K2S2O8 0.2307 g (1.00
mmol) in DCE 0.75 mL and water 0.75 mL in a pressure tight
glass tube was stirred at 60 °C (oil bath temperature) for 6 h,
and the reaction mixture was extracted CH2Cl2 three times.
After the usual work-up and chromatography on silica gel
(hexane:CH2Cl2=1:1 v:v) yielded 3,3-difluoro-4-iodo-2-(4-
methoxyphenyl)butan-2-ol 0.1163 g (0.340 mmol, yield 68%.)
as a white solid. mp: 63.5-64.0 °C. Rf = 0.20 (hexane:CH2Cl2 =
1:1). 1H NMR:  7.48-7.42 (2H, m), 6.92-6.87 (2H, m), 3.81 (3H,
s), 3.65 (1H, ddd, J = 32.7, 12.0, 2.4 Hz), 3.03 (1H, ddd, J = 31.2,
12.0, 3.2 Hz), 2.34 (1H, s), 1.74 (3H, dd, J = 1.5, 1.2 Hz) ppm.
13C{1H} NMR:  159.3, 132.2 (dd, J = 3.7, 1.2 Hz), 127.0 (dd, J
=2.5, 1.3 Hz), 120.2 (t, J = 250.3 Hz), 113.6, 75.0 (dd, J = 27.9
Hz), 55.2, 24.3 (t, J = 2.5 Hz), 2.9 (t, J = 28.5 Hz) ppm. 19F NMR:
 105.97 (1F, dd, J = 239.4, 31.9 Hz), 108.35 (1F, dd, J =
239.4, 31.7 Hz) ppm. IR (KBr)  3518, 2952, 2933, 1515,
1257, 1207, 1171, 1025, 1001, 819 cm1. HRMS (FAB+, m/z):
[M]+ calcd for C11H13F2IO2, 341.9928, Found, 341.9904.
Procedure of bromoamidation by K2S2O8: N-[3-Bromo-2,2-
difluoro-1-(4-methoxyphenyl)prop-1-yl]acetamide (5h).
mixture of (2,2-difluorocycloprop-1-yl)-4-methoxybenzene
0.0921 g (0.50 mmol), NaBr 0.0771 g (0.75 mmol), K2S2O8
0.2307 g (1.00 mmol) in MeCN 1.50 mL in a pressure tight
glass tube was stirred at 100 °C (oil bath temperature) for 24
h, and the usual work-up and recrystallization from
A
2,2-Difluoro-3-iodo-1-(4-methoxyphenyl)propan-2-ol
(6h).
0.094 g (0.285 mmol, yield 57%). Colorless oil. Rf = 0.32
chloroform
yielded
N-[3-bromo-2,2-difluoro-1-(4-
1
(hexane:CH2Cl2 = 1:2). H NMR:  7.37 (2H, d, J = 8.4 Hz), 6.91
methoxyphenyl)prop-1-yl]acetamide 0.0773 g (0.240 mmol,
yield 48%) as a white solid. mp: 147.7-149.0 °C. Rf = 0.50
(2H, d, J = 9.0 Hz), 5.05 (1H, ddd, J = 9.9, 8.1, 3.6 Hz), 3.81 (3H,
s), 3.56 (1H, ddd, J = 23.7, 12.0, 9.0 Hz), 3.28 (1H, ddd, J = 23.1,
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12.0, 7.8 Hz), 2.64 (1H, s) ppm. 13C{1H} NMR:  160.1, 128.6,
127.8, 119.3 (dd, J = 253.7, 249.4 Hz), 73.4 (t, J = 27.9 Hz),
55.3, 1.4 (t, J = 28.5 Hz) ppm. 19F NMR:  104.56 (1F, ddt, J =
244.2, 22.9, 9.0 Hz), 106.53 (1F, ddt, J = 243.9, 22.8, 9.0 Hz)
ppm. IR (KBr)  3598, 3453, 3008, 2840, 1613, 1515, 1253,
1176, 1085, 1013 cm1. HRMS (FAB+, m/z): [M]+ calcd for
C10H11F2IO2, 327.9772, Found, 327.9774.
1-(Bromomethyl)-4-(2,2-difluoro-1-methylcycloprop-1-
1
2
3
4
5
6
7
8
yl)benzene (10m). By using general procedure of
dibromination, 10m was obtained with unidentified
byproducts. Yield 89% (by 19F NMR). Rf = 0.33 (hexane). 1H
NMR:  7.38 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 4.49
(2H, s), 1.67 (1H, ddd, J = 13.5, 7.8, 3.6 Hz), 1.51 (3H, dd, J =
2.7, 1.8 Hz), 1.42 (1H, ddd, J = 12.6, 7.8, 4.8 Hz) ppm. 13C{1H}
NMR:  139.4, 136.7, 129.2, 128.8, 114.3 (dd, J = 289.0, 286.6
Hz), 33.0, 30.8 (t, J = 9.9 Hz), 22.5 (t, J = 9.9 Hz), 21.1 (d, J = 6.2
Hz). 19F NMR:  133.79 (1F, dd, J = 150.4, 13.6 Hz), 138.77
(1F, dd, J = 150.7, 11.3 Hz) ppm. HRMS (FAB+, m/z) [MH]+
calcd for C11H12BrF2, 261.0090, Found, 261.0090.
2,2-difluoro-3-iodo-1-(4-methoxyphenyl)propan-1-one (8h).21
Yield 4% (by 19F NMR). White solid. Rf = 0.43 (hexane:CH2Cl2
1
9
= 1:1). H NMR:  8.11 (2H, d, J = 9.3 Hz), 6.98 (2H, d, J = 9.3
Hz), 3.91 (3H, s), 3.76 (1H, t, J = 16.2 Hz) ppm. 13C{1H} NMR:
185.1 (t, J = 31.0 Hz), 164.8, 132.8 (t, J = 3.1 Hz), 124.1 (t, J =
3.2 Hz), 115.7 (t, J = 254.3 Hz), 114.1, 55.6, 1.3 (t, J = 27.2 Hz)
ppm. 19F NMR :  95.32 (t, J = 16.1 Hz) ppm.
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Procedure of bromination by NBS and AIBN: 1-
(Bromomethyl)-4-(2,2-difluoro-1-methylcycloprop-1-yl)benzene
(10m). A mixture of 1-(2,2-difluoro-1-methylcyclopropyl)-4-
methylbenzene 0.0906 g (0.5 mmol), N-bromosuccinimide
0.1779 g (1.0 mmol) and azobis(isobutyronitrile) 0.0164 g
(0.1 mmol) in carbontetrachloride 5 mL was stirred at 70 °C
for 15 h. After usual workup and chromatography on silica gel
(hexane) to obtain 1-(bromomethyl)-4-(2,2-difluoro-1-
methylcycloprop-1-yl)benzene (10m) with unidentified
byproducts. Yield 47% (by 19F NMR).
3,3-Difluoro-4-iodo-2-(2-methoxyphenyl)butan-2-ol (6k). The
reaction was performed with KI 0.1826 g (1.10 mmol), K2S2O8
0.5406 g (2.00 mmol) in DCE 1.00 mL and water 3.00 mL in a
pressure tight glass tube and stirred at 60 °C (oil bath
temperature) for 24 h. 0.108 g (0.317 mmol, yield 63%) as a
white solid. mp: 60.5-61.0 °C. Rf = 0.46 (hexane:AcOEt = 4:1).
1H NMR:  7.36-7.28 (2H, m), 7.04-6.96 (2H, m), 3.93 (3H, s),
3.78-3.57 (2H,m), 1.73(3H, s) ppm. 13C{1H} NMR:  157.7,
129.7 (d, J = 6.3 Hz), 127.3, 121.5, 120.4 (t, J = 251.9 Hz),
112.4, 77.2 (t, J = 26.0 Hz), 56.2, 23.9, 3.1 (t, J = 28.6 Hz) ppm.
19F NMR:  104.87 (1F, dm, J = 239.4 Hz), 106.14 (1F, dm, J
= 239.4 Hz) ppm. IR (KBr)  3432, 3041, 2986, 2954, 1601,
1583, 1466, 1014, 762, 525 cm1. HRMS (FAB+, m/z): [M+Na]+
calcd for C11H13F2NaIO2, 364.9826, Found, 364.9837.
ASSOCIATED CONTENT
Supporting Information. Spectroscopic data of new
compounds and computational details were shown. This
material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Procedure of iodoalkenylation by K2S2O8: 1-(3,3-Difluoro-
Corresponding Author
4-iodobut-1-en-2-yl)-4-methoxybenzene (7d).
A mixture of
(2,2-difluoro-1-methylcycloprop-1-yl)benzene 0.0995 g (0.50
mmol), KI 0.0827 g (0.55 mmol), K2S2O8 0.2302 g (1.00 mmol)
in MeCN 1.50 mL in a pressure tight glass tube was stirred at
90 °C (oil bath temperature) for 16 h. The usual work-up and
chromatography on silica gel (hexane:CH2Cl2=1:1 v:v)
*E-mail: takasuka@cc.tuat.ac.jp
ORCID
Tomoko Kawasaki-Takasuka: 0000-0002-8468-7553
afforded
1-(3,3-difluoro-4-iodobut-1-en-2-yl)-4-
Takashi Yamazaki: 0000-0002-1460-3086
methoxybenzene 0.091 g (0.281 mmol, yield 56%) as a pale
yellow oil and 6d as a byproduct. Colorless oil. Rf = 0.64
Author Contributions
1
(hexane:CH2Cl2 = 1:1). H NMR:  7.36 (2H, d, J = 8.7 Hz), 6.88
The manuscript was written through contributions of all
authors.
(2H, d, J = 8.7 Hz), 5.78 (1H, s), 5.50, (1H, s), 3.82 (3H, s), 3.43
(2H, t, J = 14.8 Hz) ppm. 13C{1H} NMR:  159.8, 141.5 (t, J =
22.9 Hz), 129.4, 128.3, 119.0 (t, J = 8.1 Hz), 118.6 (t, J = 243.8
Hz), 113.9, 55.2, 4.8 (t, J = 32.9 Hz) ppm. 19F NMR:  94.31 (t,
J = 13.7 Hz) ppm. IR (neat)  2959, 2935, 2837, 1609, 1514,
1251, 1180, 1034, 1009, 837 cm1. HRMS (FAB+, m/z): [M]+
calcd. for C11H11F2IO, 323.9823, Found, 323.9818.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We greatly appreciate Associate Professor Tomoko Yajima
at Ochanomizu University for the kind assistance for the
performance of photo irradiation reactions and ESI MS
measurement, and Tosoh Finechem Corporation for the
generous gift of methyl 2,2-difluoro-2-(fluorosulfonyl)acetate.
N-[2,2-difluoro-3-iodo-1-(4-methoxyphenyl)prop-1-yl]acetam-
ide (9h). When 1h was employed as a substrate, the product
6h was yielded mainly with 8h and 9h as byproducts. 0.021 g
(0.057 mmol, yield 11%, white solid. mp: 155.0-156.0 °C. Rf =
1
0.19 (CH2Cl2). H NMR:  7.32 (2H, d, J = 8.4 Hz), 6.90 (2H, d, J
REFERENCES
= 9.0 Hz), 6.32 (1H, d, J = 9.0 Hz), 5.60 (1H, ddd, J = 15.3, 12.6,
9.6 Hz), 3.81 (3H, s), 3.34 (2H, m), 2.04 (3H, s) ppm. 13C{1H}
NMR:  169.5, 160.0, 129.3, 126.9 (d, J = 3.8 Hz), 119.7 (t, J =
247.5 Hz), 114.8, 55.3, 54.8 (t, J = 24.1 Hz), 23.3, 2.4 (t, J = 29.1
Hz) ppm. 19F NMR:  102.06 ~ 103.08 (1F, m), 103.80
~ 104.81 (1F, m) ppm. IR (KBr)  3291, 3038, 2966, 1662,
1515, 1367, 1257, 1186, 1022, 809 cm1. HRMS (FAB+, m/z):
[M+H]+ calcd for C12H15F2INO2, 370.0116; Found, 370.0142.
(1) (a) Song, X.-N.; Xu, C.; Wang, M. Transformations based on
ring-opening of gem-difluorocyclopropanes. Tetrahedron Lett.
2017, 58, 1806-1816 and references cited therein. (b)
Thankachan, A. P.; Sindhu, K. S.; Krishnan, K.; Anilkumar, G.
Recent advances in the syntheses, transformations and
applications of 1,1-dihalocyclopropanes. Org. Biomol. Chem.
2015,
13,
8780-8802.
(c)
Itoh,
H.
12
gem-
Difluorocyclopropanes as key building blocks for novel
biologically active molecules. In Fluorine in Medicinal
ACS Paragon Plus Environment

Page 11 of 12
The Journal of Organic Chemistry
Chemistry and Chemical Biology; Ojima, I. Ed.; Wiley-Blackwell:
UK, 2009; pp 313-334.
(13) Masuhara, Y.; Tanaka, T.; Takenaka, H.; Hayase, S.;
1
2
3
4
5
6
7
8
Nokami, T.; Itoh, T. Synthesis of gem-difluoromethylene
containing cycloalkenes via the ring-opening reaction of gem-
difluorocyclopropanes and subsequent RCM reaction. J. Org.
Chem. 2019, 84, 5400-5449.
(2) (a) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and
Medicinal Chemistry of Fluorine; Wiley & Sons, Inc.: US, 2008.
(b) Yamazaki, T.; Taguchi, T.; Ojima, I. Fluorine in Medicinal
Chemistry and Chemical Biology; Ojima, I. Ed.; John Wiley &
Sons, Ltd, 2009, pp. 1-46. (c) Orsi, D. L.; Altman, R. A.
Exploiting the unusual effects of fluorine in methodology.
Chem. Commun. 2017, 53, 7168-7181.
(14) Takenaka, H.; Masuhara, Y.; Narita, K.; Nokami, T.; Itoh, T.
Synthesis of 2,2-difluorohomoallylic alcohols via ring-opening
of gem-difluorocyclopropane and aerobic oxidation by photo-
irradiation in the presence of an organic pigment. Org. Biomol.
Chem. 2018, 16, 6106-6114.
(3) Imaizumi, H.; Kajita, T.; Takashima, K.; Yotsuji, M.;
Moriyama, K.; Yotsuji, A.; Hukuoka, Y.; Sakai, H.; Narita, H.
Preparation of 1-triazolyl-2,4-pentanediol derivatives as
antibacterial agents. JP Patent 1992-208268.
9
(15) Unpublished work. Although the Dolbier’s procedure was
excellent for various alkenes, long reaction time (2 days) was
required. For electron-rich alkene substrates, we found that
the reaction time could be reduced to 24 h when EtCN was
employed as a solvent.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(4) Narquizian, R.; Woltering, T.; Wostl, W. 1,4-Oxazepines as
BACE1 and/or BACE2 inhibitors. US Patent 2012-0253035.
(16) Eusterwiemann, S.; Martinez, H.; Dolbier, W. R., Jr. Methyl
(5) (a) Magerlein, B. J.; Miller, W. L. 16-Fluoroprostaglandins.
Prostaglandins 1975, 9, 527-530. (b) Fried J.; Mitra, D. K.;
Nagarajan, M.; Mehrotra, M. M. 10,10-Difluoro-13-
dehydroprostacyclin: a chemistry and metabolically stabilized
potent prostacyclin. J. Med. Chem. 1980, 23, 234-237. (c)
Plunkett, W.; Huang, P.; Gandhi, V. Gemcitabine: actions and
interactions. Nucleoside Nucleotides 1997, 16, 1261-1270.
2,2-difluoro-2-(fluorosulfonyl)acetate,
a
difluorocarbene
reagent with reactivity comparable to that of trimethylsilyl
2,2-difluoro-2-(fluorosulfonyl)acetate (TFDA). J. Org. Chem.
2012, 77, 5461-5464.
(17) Recently 1,3-difunctionalization of cyclopropanes has
been paid attention. See, (a) Pitts, C. R.; Ling, B.; Snyder, J. A.;
Bragg, A. E.; Lectka, T. Aminofluorination of cyclopropanes: a
multifold approach through a common, catalytically generated
intermediate. J. Am. Chem. Soc. 2016, 138, 6598-6609. (b)
Banik, S. M.; Mennie, K. M.; Jacobsen, E. N. Catalytic 1,3-
difunctionalization via oxidative C-C bond activation. J. Am.
Chem. Soc. 2017, 139, 9152-9155. (c) Ilchenko, N. O.; Hedberg,
M.; Szabó, K. J. Fluorinative ring-opening of cyclopropanes by
hypervalent iodine reagents. An efficient method for 1,3-
oxyfluorination and 1,3-difluorination. Chem. Sci. 2017, 8,
1056-1061. (d) Wang, D.; Xue, X.-S.; Houk, K. N.; Shi, Z.-Z. Mild
(6) (a) Hakogi, T.; Yamamoto, T.; Fujii, S.; Ikeda, K. Katsuura,
S. Synthesis of sphingomyelin difluoromethylene analogue.
Tetrahedron Lett. 2006, 47, 2627-2630. (b) Xu, Y.; Aoki, J.;
Shimizu, K.; Umezu-Goto, M.; Hama, K.; Takanezawa, Y.; Yu, S.-
X.; Mills, G. B.; Arai, H.; Qian, L.; Prestwich, G. D. Structure-
activity relationships of fluorinated lysophosphatidic acid
analogues. J. Med. Chem. 2005, 48, 3319-3327.
(7) (a) Roth, W. R.; Kirmse, W.; Hoffmann, W.; Lennartz, H.-W.
Heats of hydrogenation. III. Effect of fluoro substituents on the
thermal rearrangement cyclopropane systems. Chem. Ber.
1982, 115, 2508-2515. (b) Isogai, K.; Nishizawa, N.; Saito, T.;
Sakai, J-I. Catalytic hydrogenolysis of 1,1-difluoro-2-phenyl-
and 1,1-difluoro-3-methyl-2-phenylcyclopropane. Bull. Chem.
Soc. Jpn. 1983, 56, 1555-1556. (c) Isogai, K.; Sakai, J-I.; Kosugi,
K. Regioselectivity in the catalytic hydrogenolysis of 7-fluoro-
1-phenylbicyclo[4.1.0]heptanes. Bull. Chem. Soc. Jpn. 1986, 59,
1349-1353. (d) Bessard, Y.; Schlosser, M. Catalytic
ring-opening
1,3-hydroborations
of
non-activated
cyclopropanes. Angew. Chem. Int. Ed. 2018, 57, 16861-16865.
(18) Nair, V.; Panicker, S. B.; Augustine, A.; George, T. G.;
Thomas, S.; Vairamani, M. An efficient bromination of alkenes
using cerium(IV) ammonium nitrate (CAN) and potassium
bromide. Tetrahedron, 2001, 57, 7417-7422.
(19) Nair, V.; Panicker, S. B.; Mathai, S. Bromination of
cyclopropanes using potassium bromide and cerium(IV)
ammonium nitrate (CAN): synthesis of 1,3-dibromides. Res.
Chem. Intermed. 2003, 29, 227-231.
hydrogenolysis of cyclopropanes: metal insertion into
a
saturated carbon-carbon bond as the key step. Tetrahedron
1991, 47, 1231-1238.
(8) Munenori, D.; Narita, K.; Nokami, T.; Itoh, T. Synthesis of
gem-difluoromethylene building blocks through regioselective
allylation of gem-difluorocyclopropanes. Org. Lett. 2014, 16,
2638-2641.
(20) Yamada, S.; Kato, M.; Komori, Y.; Konno, T.; Ishihara, T.
Easy access to CF2-conatining molecules based on the reaction
of 2,2,3,3-tetrafluorooxetane with various nucleophiles. Org.
Biomol. Chem. 2011, 9, 5493-5502.
(9) Gassen, K.-R.; Bielefeldt, D.; Marnold, A.; Andres, P.
Synthese von -fluoracrylsäure und derivaten. J. Fluorine
Chem. 1991, 55, 149-162.
(21) Fedorov, N. D.; Kosobokov, M. D.; Levin, V. V.; Struchkova,
M. I.; Dilman, A. D. Halogenative difluorohomologation of
ketones. J. Org. Chem. 2015, 80, 5870-5876.
(22) Karabulut, H. R. F.; Kacan, M. A new method for the
synthesis of N-benzylamides. Synth. Commun. 2002, 32, 2345-
2348.
(10) Hang, X.-C.; Chen, X.-Y.; Xiao, J.-C. Ring-opening reactions
of difluoro(methylene)cyclopropanes with halogens and
amines. J. Org. Chem. 2008, 73, 8598-8600 and correction, J.
Org. Chem. 2011, 76, 2384.
(23) The free radical bromination methods of non-fluorinated
cyclopropanes were reported. See, (a) Kharasch, M. S.;
Fineman, M. Z.; Mayo, F. R. The oxygen effect in the reaction of
cyclopropane with bromine and with hydrogen bromide. J.
Am. Chem. Soc. 1939, 61, 2139-2142. (b) LaLonde, R. T.;
Ferrara, P. B.; Debboli, A. D., Jr. Characteristics of various
reactions of bromine with arylcyclopropanes. J. Org. Chem.
1972, 37, 1094-1099. (c) Tanko, J. M.; Mas, R. H.; Suleman, N.
K. Stereoelectronic effects on chemoselectivity in the free
radical bromination of arylcyclopropanes. J. Am. Chem. Soc.
1990, 112, 5557-5562.
(11) Morikawa, T.; Uejima, M.; Kobayashi, Y. Radical induced
regio-
and
stereoselective
ring-opening
of
gem-
difluorocyclopropanes: synthesis of the (E)-difluoroallylic
system. Chem. Lett. 1988, 1407-1410.
(12) Morikawa, T. Uejima, M.; Yoda, K.; Taguchi, T. Iodine
atom-transfer
ring-opening
of
1,1-difluoro-2-(1-
iodoalkyl)cyclopropanes by free-radical reaction. Chem. Lett.
1990, 467-468.
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The Journal of Organic Chemistry
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(24) Computation was carried out by using Gaussian 09W
1
2
3
4
5
6
7
8
(Rev. D.01) with the B3LYP/6-31+G* level of theory. Frisch, M.
J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.;
Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.;
Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.;
Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.;
Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin,
R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, ?.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian:
Wallingford, CT, 2009.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(25) (a) Kobayashi, Y.; Morikawa, T.; Taguchi, T. Studies on
organic fluorine compounds. XL. Ring-opening reactions of
gem-difluorocyclopropyl carbinols. Chem. Pharm. Bull. 1983,
31, 2616-2622. (b) Yang, Z.-Y.; Krusic, P. J.; Smart, B. E. Ring-
opening reactions of fluorocyclopropanes with halogens: A
general and useful route to 1,3-dihalofluoropropane
derivatives. J. Am. Chem. Soc. 1995, 117, 5397-5398.
(26) Wang, F.; Luo, T.; Hu, J.-B.; Wang, Y.; Krishnan, H. S.; Jog,
P. V.; Ganesh, S. K.; Prakash, G. K. S.; Olah, G. A. Synthesis of
gem-difluorinated
cyclopropanes
and
cyclopropenes:
trifluoromethyltrimethylsilane as a difluorocarbene source.
Angew. Chem. Int. Ed. 2011, 50, 7153-7157.
(27) Zheng, J.; Lin, J.-H.; Cai, J.; Xiao, J.-C. Conversion between
difluorocarbene and difluoromethylene ylide. Chem. Eur. J.
2013, 19, 15261-15266.
(28) Oshiro, K.; Morimoto, Y.; Amii, H. Sodium
bromodifluoroacetate:
a difluorocarbene source for the
synthesis of gem-difluorocyclopropanes. Synthesis 2010,
2080-2084.
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