Reactions of organozinc reagents with potassium bromodifluoroacetate

Article abstract of DOI:10.1016/j.jfluchem.2014.08.021

A practical method for the synthesis of gem-difluorinated compounds from organozinc reagents is described. Potassium bromodifluoroacetate serves as a source of CF₂-fragment, which is inserted into carbonzinc bond of organozinc reagents. The intermediate difluorinated organozinc species can be protonated, brominated or coupled with allylic electrophiles.

Full text of DOI:10.1016/j.jfluchem.2014.08.021

Accepted Manuscript
Title: Reactions of organozinc reagents with potassium
bromodifluoroacetate
Author: Vitalij V. Levin Artem A. Zemtsov Marina I.
Struchkova Alexander D. Dilman
PII:
S0022-1139(14)00260-7
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.jfluchem.2014.08.021
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28-8-2014
Please cite this article as: V.V. Levin, A.A. Zemtsov, M.I. Struchkova, A.D. Dilman,
Reactions of organozinc reagents with potassium bromodifluoroacetate, Journal of
Fluorine Chemistry (2014), http://dx.doi.org/10.1016/j.jfluchem.2014.08.021
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Reactions of organozinc reagents with potassium bromodifluoroacetate
Vitalij V. Levin, Artem A. Zemtsov, Marina I. Struchkova, Alexander D. Dilman*
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
Federation, Fax: +7-499-1355328, E-mail: adil25@mail.ru
Abstract A practical method for the synthesis of gem-difluorinated compounds from organozinc
reagents is described. Potassium bromodifluoroacetate serves as a source of CF2-fragment, which is
inserted into carbon-zinc bond of organozinc reagents. The intermediate difluorinated organozinc
species can be protonated, brominated or coupled with allylic electrophiles.
Keywords: organozinc reagents, gem-difluorinated compounds, potassium bromodifluoroacetate,
difluorocarbene
1. Introduction
Compounds bearing difluoromethylene fragment constitute an important class of fluorinated
molecules with potential applications in medicinal chemistry [1]. Owing to specific fluorine effect,
gem-difluorinated substances have been evaluated within a variety of structural settings, such as
carbohydrides [2], peptides [3], and aliphatic chains [4]. Several general approaches for the
preparation of compounds with CF2 unit have been reported [5] involving deoxofluorination [6], use
of building blocks [2a,5], and difluorocyclopropanation [7].
Recently we introduced a novel methodology for assembling gem-difluorinated compounds from
difluorocarbene, nucleophile and electrophile (Scheme 1) [8,9]. When organozinc reagents are used
as nucleophiles, the addition to difluorocarbene (step a) and reaction with electrophile (step b) can
be performed in a consecutive manner thereby allowing for independent variation of nucleophile
and electrophiles [10]. In these processes, (bromodifluoromethyl)trimethylsilane [11] activated by a
Lewis base was used as a source of difluorocarbene [12]. Though this silane can be made from the
Ruppert-Prakash reagent in one or two steps [9a,11a], it is quite expensive. Herein we demonstrate
that potassium bromodifluoroacetate (1), which can be obtained from readily available ethyl ester
[13], can serve as a practical alternative to Me3SiCF2Br in reaction with organozincs.
1
Page 1 of 14

F
F
F
F
C
Nu
E
E
Nu
F
F
Nu = RZnX
(a)
E
R
ZnX
(b)
O
Br
SiMe3
Br
F
F
OK
C
F F
F F
1
this work
previous work
Scheme 1. Assembling of molecules containing CF2-fragment.
2. Results and discussion
Benzylzinc bromide (2a) prepared from benzyl bromide in tetrahydrofuran was selected as a
model organozinc reagent and its reaction with potassium bromodifluoroacetate (1) was evaluated
(Table 1). Decarboxylation of bromodifluoroacetate anion requires elevated temperatures which
may cause decomposition of species 3a. Earlier we observed that decomposition of fluorinated
organozinc reagents is slowed down by dimethylformamide [8a], and, therefore, herein we used it
as a major solvent. Thus, a solution of 2a (2M in THF) was diluted with three volumes of DMF and
treated with 2 equiv of salt 1. The evolution of carbon dioxide proceeded at 50 °C leading, after
treatment with acetic acid, to 2,2-difluoroethylbenzene 4 in 62% yield determined by 19F NMR
analysis (entry 1). Increasing the amount of difluorocarbene source and performing the reaction at
longer period had virtually no increase in yield of 4, while providing more by-products along with
darkening of reaction mixture, which may be associated with side processes involving excessive
difluorocarbene. Furthermore, in these experiments we observed that the reaction rate decreases at
higher conversions. The latter phenomenon may be associated with the transformation of starting
benzylzinc bromide 2a into more Lewis acidic organozinc species 3a, which stronger interacts with
bromodifluoroacetate anion thus impeding decarboxylation. In an attempt to cope with decelerating
effect, the reaction was performed in the presence of nucleophilic acetate anion (entries 3 and 4).
Though in these cases there was no increase in yield, the reaction mixtures were notably cleaner
(19F NMR control). Finally, the use of tetraethylammonium bromide as an additive (0.5 equiv) was
found to be optimal, and the product 4 was formed in 70% yield within 45 minutes (entry 6). In a
preparative experiment carried out on 20 mmol scale of benzylzinc bromide 2a, volatile product 4
was isolated in 55 % yield after distillation.
2
Page 2 of 14

Table 1.
Reaction of benzylzinc bromide.
O
Br
OK
F
F
F
F
F
AcOH
1
Ph
ZnBr
Ph
Ph
ZnBr
F
rt, 20 h
DMF, 50 °C
2a
3a
4
Entry
Equiv of 1 Additive
Equiv
–
Time, mina Yield of 4, %b
1
2
3
4
5
6
7
8d
2
–
80
120
60
60
45
45
15
25
62
2.5
1.5
1.5
1.5
2
–
–
62
AcOK
Bu4NOAc
Et 4NBr
Et4NBr
Et 4NBr
Et 4NBr
0.5
1
53
55
0.5
0.5
2
60
70 (55c)
2
58
2
2
70
a Time for conversion 2a to 3a.
b Yield determined by 19F NMR using PhCF3 as internal standard.
c Isolated yield.
d Reaction of 2a with 1 was performed at 45 °C.
Under the optimized conditions, a variety of organozinc reagents 2 were reacted with potassium
bromodifluoroacetate (Table 2). The intermediate difluorinated organozincs 3 were quenched with
bromine or acetic acid or coupled with allylic electrophile [8b,9b]. The reaction was successfully
applied to benzyl and alkyl organozinc reagents furnishing products 5a-i in 45-85% yield. However,
reactions involving aromatic organozincs were unsuccessful.
3
Page 3 of 14

Table 2.
Reactions of organozinc reagents
BrCF2CO2K (2 equiv)
Et4NBr (0.5 equiv)
F
F
F F
E
R
ZnX
R
ZnX
R
E
DMF, 50 °C
2
3
5
E
Time, mina
Yield of 5, %a
2
5
Ph
Br
ZnBr
Ph
Br
CF2Br
Br2
Br2
60
60
60
56
2a
2b
5a
5b
ZnBr
CF2Br
Br
Br
Br
F
55
58
2c
5c
F
10% CuCN
ZnBr
OBz
OBz
CF2Br
Br2
50
40
51
45
2d
2e
5d
5e
ZnBr
Br2
ZnCl
CF2Br
EtO
EtO
Br2
80
80
67
65
2f
5f
ZnBr
CF2Br
EtO
EtO
P
P
O
O
O
O
2g
F
F
5g
Cl
ZnI
EtO
EtO
10% CuCN
F
BzO
ZnI
AcOH
60
50
60
85
2h
2i
5h
5i
BzO
BzO
F
BzO
ZnBr
CF2Br
Br2
a Time for conversion 2 to 3.
b Isolated yield.
Proposed reaction mechanism is shown in Scheme 2. First, bromodifluoroacetate anion binds to
a zinc of starting reagent 2 leading to ate complex 6. Its transformation into decarboxylated species
7 may proceed either through free difluorocarbene followed by trapping with bromide ion and
reagent 2 (upper path) [14] or in a concerted fashion (lower path). At the final step, zincate 7
undergoes loss of bromide with concomitant migration of R group from zinc to carbon affording
final organozinc species 3 [15]. Several other mechanisms cannot be excluded such as concerted
4
Page 4 of 14

insertion of difluorocarbene into C-Zn bond or intermediate formation of difluorocarben-zinc
complexes [16], they believed to be less likely.
O
O
X
R
RZnX (2)
Br
Br
OK
O Zn
F F
F F
6
1
Br , 2
– CO2, Br, 2
C
F
F
Br
F
X
F
F

Zn
O
R
ZnX
R
F
Br
F
F
3
7
O
– CO2
Zn
R X
Scheme 2. Proposed reaction mechanism.
In an attempt to trap difluorocarbene, the reaction of slight excess (1.5 equiv) of benzylzinc
bromide 2a with potassium bromodifluoroacetate was performed in the presence of 1,2-
19
diphenylethylene (Scheme 3). Analysis of reaction mixture by F NMR spectroscopy showed the
formation organozinc species 3a, while difluorocyclopropane 8 was not detected. This experiment
suggests that either the decarboxylation proceeds in a concerted fashion or difluorocarbene interacts
with bromide ion faster than with 1,2-difluoroethylene.
O
Br
OK
F
F
F
F
F F
Ph
Ph
Ph
(1 equiv)
Ph
ZnBr
Ph
+
+
ZnBr
50 °C, 1 h
Ph
2a
1.5 equiv
3a
8
1 equiv
45%
not detected
Scheme 3. Attempted trapping experiment.
3. Conclusions
In summary, a convenient protocol for the synthesis of gem-difluorinated compounds from
oranozinc reagents and potassium bromodifluoroacetate and a suitable electrophile is described.
Though the method provides
a
bit lower yields compared to that involving
(bromodifluoromethyl)trimethylsilane, the procedure is practical, being suitable for multi-gram
reactions, and employs a cheaper source of difluoromethylene fragment.
5
Page 5 of 14

4. Experimental
4.1 General Experimental Procedures
All reactions were performed under an argon atmosphere. DMF was distilled under vacuum from
P2O5 and stored over MS 4Å. NMR spectra were recorded on a Bruker AM-300 instrument.
Microanalyses were performed on KarloErba 1106 instrument. Organozinc reagents 2a-h were
prepared in THF from corresponding bromides or iodides according to a literature procedure [8a].
Organozinc reagent 2i was obtained from 3-bromobutyl benzoate using typical procedure [8a] (for
the preparation of 3-bromobutyl benzoate see section 4.2.).
4.2. 3-Bromobutyl benzoate.
A solution of Ph3P (29.2 mmol, 7.65 g) and imidazole (29.2 mmol, 1.99 g) in dry CH2Cl2 (40
mL) was cooled to 0 °C and then bromine (29.2 mmol, 1.5 mL) was added dropwise. To the
resulting orange suspension, 3-hydroxybutyl benzoate [17] (24.3 mmol, 4.72 g) was added, the
reaction was allowed to warm to a room temperature and stirred for 20 hours. Solvent was
evaporated under vacuum and the residue was diluted with hexane (50 mL). The resulting white
precipitate was filtered and washed with hexane (3×10 mL). The combined organic phases were
concentrated under vacuum, and the residue was chromatographed on silica gel (hexane/EtOAc,
1
12/1, Rf 0.37) affording 5.5 g (88% yield) of 3-bromobutyl benzoate as a colorless oil. H NMR
(300 MHz, CDCl3), δ: 1.78 (d, 3H, J = 6.6 Hz), 2.16–2.24 (m, 1H), 2.24–2.33 (m, 1H), 4.30 (qdd,
1H, J = 6.7, 6.6, 2.1 Hz), 4.38–4.49 (m, 1H), 4.49–4.58 (m, 1H), 7.43 (dd, 2H, J = 7.6, 7.5 Hz), 7.56
(t, 1H, J = 7.5 Hz), 8.03 (d, 2H, J = 7.6 Hz). 13C NMR (75 MHz, CDCl3), δ: 26.6, 39.9, 47.0, 63.1,
128.5, 129.7, 130.2, 133.1, 166.4. HRMS (ESI): Calcd for C11H13BrO2Na [M + Na]+: 278.9991.
Found: 278.9993.
4.3. Synthesis of products 4 and 5a.
To a solution of benzylzinc bromide (20 mmol, 10 mL, 2M in THF) were successively added
DMF (30 mL), Et4NBr (2.10 g, 10 mmol) and BrCF2CO2K (8.52 g, 40 mmol) at room temperature.
The mixture was vigorously stirred for 45 min at 50 °C, then cooled to room temperature affording
a solution of reagent 3a.
4.3.1. (2,2-Difluoroethyl)benzene (4) [18].
6
Page 6 of 14

From a solution of reagent 3a, tetrahydrofuran was evaporated under vacuum (1 Torr) at room
temperature. Then, the reaction flask containing a solution of 3a was immersed in an ice/water bath
followed by addition of AcOH (3.43 mL, 60 mmol). The cooling bath was removed, and the
mixture was stored for 20 hours at room temperature. The mixture was diluted with water (60 mL)
and extracted with pentane (3×10 mL). The combined organic phases were washed with 5M HCl (5
mL), filtered through Na2SO4. The solvent was evaporated at atmospheric pressure, and the residue
was distilled under vacuum affording 1.56 g (55%) of 4 as colorless liquid. Bp 62–64 °C/40 Torr.
4.3.2. (2-Bromo-2,2-difluoroethyl)benzene (5a).
A solution of 3a was cooled to –20°C, and bromine (22 mmol 1.15 mL) was added. The cooling
bath was removed, and the mixture was stirred for 1 hour at room temperature. Then, a solution of
Na2S2O3·5H2O (5.0 g) in water (15 mL), water (30 mL), and 2M HCl (10 mL) were successively
added with stirring. The mixture was extracted with pentane (15 mL and 2×10 mL), the combined
organic phases were concentrated at atmospheric pressure, and the residue was fractionally distilled
1
under vacuum. Yield 5.65 g (60%). Colorless liquid. Bp 78–81 °C/20 Torr. H NMR (300 MHz,
13
CDCl3) δ: 3.67 (t, 2H, J = 14.3 Hz), 7.28 (m, 5H). C NMR (75 MHz, CDCl3) δ: 50.4 (t, J = 22.5
Hz), 121.8 (t, J = 306.0 Hz), 128.3, 128.7, 130.7, 131.5 (t, J = 3.2 Hz). 19F NMR (282 MHz, CDCl3)
δ: –45.4 (t, J = 14.3 Hz). Anal. calcd for C12H9BrF2: C, 43.47; H, 3.19; found: C, 43.25; H, 3.41.
4.4. Preparation of 5b-i (General procedure)
A tetrahydrofuran solution of RZnX (1.5 mmol) was concentrated under vacuum to a viscous oil.
Then to the residue DMF (2.3 mL), Et4NBr (158 mg, 0.75 mmol) and BrCF2CO2K (639 mg, 3.0
mmol) were successively added. The mixture was vigorously stirred at 50°C during the time
indicated in Table 2. The resulting mixture, containing difluorinated reagent 3, was reacted with an
electrophile as described below.
Protonation. The reaction flask was immersed in an ice/water bath. AcOH (257 µL, 4.5 mmol)
was added, the cooling bath was removed, and the mixture was stored for 20 hours at room
temperature. The mixture was diluted with water (12 mL) and extracted with hexane (3×5 mL). The
combined organic phases were washed were filtered through Na2SO4, concentrated under vacuum,
and the residue was chromatographed on silica gel.
Bromination. The reaction flask was immersed in an ice/water bath and bromine (1.65 mmol, 85
µL) was added. Cooling bath was removed and the mixture was stirred for 1 hour at room
temperature, then diluted with 0.5M solution of Na2S2O3 and extracted with hexane (3×5 mL). The
combined organic phases were filtered through Na2SO4, concentrated either under vacuum, and the
residue was chromatographed on silica gel.
7
Page 7 of 14

Allylation. The reaction flask was immersed in an ice/water bath and allyl bromide or methallyl
chloride (3 mmol) and CuCN (13.4 mg, 0.15 mmol) were added. The resulting suspension was
stirred for 1 hour, then the cooling bath was removed and stirring was continued for 16 hours. The
mixture was diluted with water (12 mL) and extracted with hexane (3×5 mL). The combined
organic phases were filtered through Na2SO4, concentrated under vacuum, and the residue was
chromatographed on silica gel.
4.4.1. 1-Bromo-4-(2-bromo-2,2-difluoroethyl)benzene (5b)
Yield 252 mg (56%). Colorless liquid. Rf 0.34 (hexane). 1H NMR (300 MHz, CDCl3), δ: 3.60 (t,
2H, J = 14.4 Hz), 7.18 (d, 2H, J = 8.2 Hz), 7.50 (d, 2H, J = 8.2 Hz). 13C NMR (75 MHz, CDCl3), δ:
19
49.7 (t, J = 23.0 Hz), 121.1 (t, J = 306.0 Hz), 122.6, 130.3 (t, J = 2.9 Hz), 131.8, 132.2. F (282
MHz, CDCl3), δ: –45.8 (t, J = 14.4 Hz). Anal. calcd for C8H6Br2F2: C, 32.04, H, 2.02; found: C,
32.13; H, 2.14.
4.4.2. 1-Bromo-2-(2,2-difluoropent-4-en-1-yl)benzene (5c).
1
Yield 221 mg (58%). Colorless liquid. Rf 0.38 (hexane). H NMR (300 MHz, CDCl3), δ: 2.66
(td, 2H, J = 16.2, 7.0 Hz), 3.40 (t, 2H, J = 16.3 Hz), 5.22 (dd, 1H, J = 17.8, 1.2 Hz), 5.25 (dd, 1H, J
= 8.8, 1.2 Hz), 5.87 (ddt, 1H, J = 17.8, 8.8, 7.0 Hz), 7.15 (ddd, 1H, J = 8.1, 8.0, 1.8 Hz), 7.28 (ddd,
13
1H, J = 8.0, 7.3, 1.8 Hz), 7.39 (d, 1H, J = 7.3 Hz), 7.59 (dd, 1H, J = 8.1 Hz). C NMR (75 MHz,
CDCl3), δ: 41.1 (t, J = 25.3 Hz), 41.9 (t, J = 25.9 Hz), 120.5, 123.0 (t, J = 244.0 Hz), 125.9, 127.5,
129.1, 129.3 (t, J = 5.5 Hz), 132.4 (t, J = 1.5 Hz), 133.1, 133.2 (t, J = 4.0 Hz). 19F (282 MHz,
CDCl3), δ: –96.6 (tt, J = 16.3, 16.2 Hz). Anal. calcd for C11H11BrF2: C, 50.60, H, 4.25; found: C,
50.64; H, 4.41.
4.4.3. 2-(2-Bromo-2,2-difluoroethyl)phenyl benzoate (5d).
1
Yield 260 mg (51%). Colorless crystals. Mp 39–40°C Rf 0.28 (hexane/EtOAc, 15/1). H NMR
(300 MHz, CDCl3) δ: 3.75 (t, 2H, J = 13.9 Hz), 7.26–7.36 (m, 2H Hz), 7.46 (t, 2H, J = 7.2 Hz),
7.50–7.60 (m, 2H), 7.68 (t, 1H, J = 7.4 Hz), 8.26 (d, 2H, J = 7.4 Hz). 13C NMR (75 MHz, CDCl3) δ:
44.6 (t, J = 23.6 Hz), 121.0 (t, J = 306.6 Hz), 123.1, 123.7 (t, J = 2. Hz 9), 126.1, 128.7, 129.2,
19
129.7, 130.2, 132.5, 133.9, 149.9, 164.6. F NMR (282 MHz, CDCl3) δ: –44.9 (t, J = 13.9 Hz).
Anal. calcd for C15H11BrF2: C, 52.81; H, 3.25; found: C, 52.84; H, 3.29.
4.4.4. 1-(2-Bromo-2,2-difluoroethyl)naphthalene (5e).
Yield 182 mg (45%). Colorless oil. Rf 0.34 (hexane). 1H NMR (300 MHz, CDCl3) δ: 4.22 (t, 2H,
J = 14.6 Hz), 7.46–7.67 (m, 4H), 7.86–7.98 (m, 2H); 8.08 (d, 1H, J = 8.1 Hz). 13C NMR (75 MHz,
8
Page 8 of 14

CDCl3) δ: 46.9 (t, J = 22.5 Hz), 121.8 (t, J = 307.2 Hz), 123.9 (t, J = 1.8 Hz), 125.3, 125.9, 126.6,
127.6 (t, J = 2.4 Hz), 128.9, 129.3, 130.1, 132.5, 134.0. 19F NMR (282 MHz, CDCl3) δ: –44.0 (t, J =
14.6 Hz). Anal. calcd for C12H9BrF2: C, 53.16; H, 3.35; found: C, 53.19; H, 3.37.
4.4.5. Diethyl (3-bromo-3,3-difluoropropyl)phosphonate (5f).
1
Yield 296 mg (67%). Pale-yellow liquid. Rf 0.28 (hexane/EtOAc, 1/1). H NMR (300 MHz,
CDCl3), δ: 1.20 (t, 6H, J = 7.0 Hz), 1.78–1.97 (m, 2H), 2.38–2.60 (m, 2H), 3.89–4.10 (m, 4H). 13C
NMR (75 MHz, CDCl3), δ: 16.2 (d, J = 5.8 Hz), 20.7 (d, J = 146.3 Hz), 38.0 (td, J = 23.6, 1.5 Hz),
19
62.0 (d, J = 6.3 Hz), 121.7 (td, J = 305.2, 25.9 Hz). F (282 MHz, CDCl3), δ: –46.9 (t, J = 12.7
Hz). HRMS (ESI): Calcd for C17H14BrF2O3PNa [M + Na]+: 316.9724. Found: 316.9733.
4.4.6. Ethyl 5,5-difluoro-7-methyloct-7-enoate (5g).
Yield 214 mg (65%). Colorless oil. Rf 0.18 (hexane/CH2Cl2, 2/1). 1H NMR (300 MHz, CDCl3),
δ: 1.21 (t, 3H, J = 7.2 Hz), 1.68–1.93 (m, 2H), 2.31 (t, 2H, J = 6.8 Hz), 2.52 (t, 2H, J = 16.3 Hz),
4.09 (q, 2H, J = 7.2 Hz), 4.81 (s, 1H), 4.92 (s, 1H). 13C NMR (75 MHz, CDCl3), δ: 14.2, 17.8 (t, J =
4.9 Hz), 23.2 (t, J = 1.8 Hz), 33.7, 35.2 (t, J = 25.3 Hz), 44.7 (t, J = 25.3 Hz), 60.4, 116.5, 124.3 (t, J
19
= 242.7 Hz), 138.4 (t, J = 4.0 Hz), 173.0. F (282 MHz, CDCl3), δ: –96.3 (quint, J = 16.5 Hz).
HRMS (ESI): Calcd for C11H18F2O2Na [M + Na]+: 243.1167. Found: 243.1167.
4.4.7. 4,4-Difluorobutyl benzoate (5h).
Yield 192 mg (60%). Colorless oil, Rf 0.20 (hexane/EtOAc, 15/1). 1H NMR (300 MHz, CDCl3)
δ: 1.87–2.12 (m, 4H), 4.36 (t, 2H, J = 5.9 Hz), 5.89 (tt, J = 55.7, 3.9 Hz), 7.43 (t, 2H, J = 7.5 Hz),
13
7.55 (t, 1H, J = 7.3 Hz), 8.03 (d, 2H, J = 7.3 Hz). C NMR (75 MHz, CDCl3) δ: 21.6 (t, J = 5.5
Hz), 31.0 (t, J = 21.3 Hz), 63.9, 116.8 (t, J = 239.0 Hz), 128.4, 129.5, 130.1, 133.0, 166.4. 19F NMR
(282 MHz, CDCl3) δ: –117.1 (dt, J = 55.7, 17.0 Hz). Anal. calcd for C11H12F2O2: C, 61.68; H, 5.65;
found: C, 61.67; H, 5.70.
4.4.8. 4-Bromo-4,4-difluoro-3-methylbutyl benzoate (5i).
Yield 420 mg (85%). Colorless oil. Rf 0.27 (hexane/EtOAc, 20/1). 1H NMR (300 MHz, CDCl3),
δ: 1.23 (d, 3H, J = 6.6 Hz), 1.68–1.82 (m, 1H), 2.20–2.25 (m, 1H), 2.36–2.50 (m, 1H), 4.36–4.46
(m, 2H), 7.45 (dd, 2H, J = 7.4, 7.3 Hz), 7.57 (t, 1H, J = 7.4 Hz), 8.04 (d, 2H, J = 7.3 Hz). 13C NMR
(75 MHz, CDCl3), δ: 14.7 (dd, J = 4.0, 2.3 Hz), 30.7 (dd, J = 3.7, 2.3 Hz), 43.5 (t, J = 19.9 Hz),
19
61.8, 127.6 (t, J = 307.5 Hz), 128.5, 129.6, 130.0, 133.2, 166.4. F (282 MHz, CDCl3), δ: –49.3
(dd, 1F, J = 156.6, 8.5 Hz), –48.5 (dd, 1F, J = 156.6, 9.4 Hz). HRMS (ESI): Calcd for
C12H13BrF2O2Na [M + Na]+: 328.9959. Found: 328.9963.
9
Page 9 of 14

Acknowledgments
This work was supported by the Russian Science Foundation (project 14-23-00150).
References and Notes
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Biology, John Wiley & Sons, Chichester, 2009.
[2] (a) F.-L. Qing, F. Zheng, Synlett (2011) 1052–1072. (b) E. Leclerc, X. Pannecoucke, M.
Ethève-Quelquejeu, M. Sollogoub, Chem. Soc. Rev. 42 (2013) 4270–4283.
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[7] W.R. Dolbier, M.A. Battiste, Chem. Rev. 103 (2003) 1071–1098.
[8] (a) V.V. Levin, A.A. Zemtsov, M.I. Struchkova, A.D. Dilman, Org. Lett. 15 (2013) 917–919.
(b) A.A. Zemtsov, N.S. Kondratyev, V.V. Levin, M.I. Struchkova, A.D. Dilman, J. Org.
Chem. 79 (2014) 818–822.
[9] For relevant results from our group, see: (a) M.D. Kosobokov, A.D. Dilman, V.V. Levin, M.I.
Struchkova, J. Org. Chem. 77 (2012) 5850–5855. (b) M.D. Kosobokov, V.V. Levin, A.A.
Zemtsov, M.I. Struchkova, A.A. Korlyukov, D.E. Arkhipov, A.D. Dilman, Org. Lett. 16
(2014) 1438–1441. (c) M.D. Kosobokov, V.V. Levin, M.I. Struchkova, A.D. Dilman, Org.
Lett. 16 (2014) 3784–3787. (d) A.V. Tsymbal, M.D. Kosobokov, V.V. Levin, M.I.
Struchkova, A.D. Dilman, J. Org. Chem. 79 (2014) ASAP, DOI: 10.1021/jo501644m.
[10] Earlier, a specific example of insertion of difluorocarbene into carbon-metal bond, the
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Burton, J. Am. Chem. Soc. 108 (1986) 832–834. (b) Z.Y. Yang, D.M. Wiemers, D.J. Burton,
J. Am. Chem. Soc. 114 (1992) 4402–4403. (c) M.M. Kremlev, W. Tyrra, A.I. Mushta, D.
Naumann, Y.L. Yagupolskii, J. Fluorine Chem. 131 (2010) 212–216. (d) H. Urata, T.
Fuchikami, Tetrahedron Lett. 32 (1991) 91–94. (e) A. Hafner, S. Bräse, Adv. Synth. Catal.
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Aikawa, K. Mikami, Beilstein J. Org. Chem. 9 (2013) 2404–2409.
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[11] (a) L. Li, F. Wang, C. Ni, J. Hu, Angew. Chem. Int. Ed. 52 (2013) 12390–12394. (b) F.
Wang, W. Zhang, J. Zhu, H. Li, K.-W. Huang, J. Hu, Chem. Commun. 47 (2011) 2411–2413.
[12] For reviews on synthetic applications of difluorocarbene, see: C. Ni, J. Hu, Synthesis. 46
(2014) 842–863.
[13] J. Zheng, J. Cai, J.-H. Lin, Y. Guo, J.-C. Xiao, Chem. Commun. 49 (2013) 7513–7515.
[14] (a) For proposed interaction of difluorocarbene with bromide and iodide anions, see ref. 9c.
(b) D.-B. Su, J.-X. Duan, Q.-Y. Chen, J. Chem. Soc., Chem. Commun. (1992) 807–808.
[15] For a discussion of similar pathways in difluoromethylation reactions using CF3ZnBr, see: W.
Tyrra, D. Naumann, J. Prakt. Chem. 338 (1996) 283–286.
[16] For examples of difluorocarbene complexes of transition metals, see: (a) M.A. García-
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[17] G.V.M. Sharma, P.S. Reddy, Eur. J. Org. Chem. (2012) 2414–2421.
[18] D.J. Burton, G.A. Hartgraves, J. Fluorine Chem. 128 (2007) 1198–1215.
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O
Br
OK
E
F F
R
ZnX
R
E
R ZnX
F
F
F F
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Reactions of organozinc reagents with potassium bromodifluoroacetate
Vitalij V. Levin, Artem A. Zemtsov, Marina I. Struchkova, Alexander D. Dilman*
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian
Federation, Fax: +7-499-1355328, E-mail: adil25@mail.ru
O
Br
OK
E
F
F
R
ZnX
R
E
R ZnX
F
F
F F
Assembling of gem-difluorinated compounds from organozinc reagents, potassium
bromodifluoroacetate and electrophiles is described.
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Synthesis of gem-difluorinated compounds.
Preparation and reactions of fluorinated organozinc reagents.
Reactions of potassium boromodifluoroacetate.
Page 14 of 14