Copper-mediated direct functionalization of unsaturated C-C bonds with ethyl bromo(difluoro)acetate: A straightforward access to highly valuable difluoromethylated alkenes

Article abstract of DOI:10.1055/s-0033-1338637

A copper-mediated fluorofunctionalization of alkenes and alkynes has been developed. This method provides ready access to trisubstituted difluoromethylated olefins (from dihydropyrans, glycal derivatives, or terminal alkynes) or to tetrasubstituted olefins (from disubstituted alkynes). The products were obtained in good to high yields with acceptable E/Z selectivities. Finally, a first direct route to difluoromethylated alkynes is reported, albeit with low yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1338637

SPECIAL TOPIC
▌1859
sCpeociapl tpopeicr-Mediated Direct Functionalization of Unsaturated C–C Bonds with
Ethyl Bromo(difluoro)acetate: A Straightforward Access to Highly Valuable
Difluoromethylated Alkenes
Copper-Mediated Difluoroacetylation
Marie-Charlotte Belhomme,1 Delphine Dru,1 Heng-Ying Xiong, Dominique Cahard, Tatiana Besset,*
Thomas Poisson,* Xavier Pannecoucke
Normandie Université, COBRA, UMR 6014 et FR 3038, Université de Rouen, INSA Rouen, CNRS, 1 rue Tesnière, 76821 Mont Saint-Aignan,
France
Fax +33(2)35522959; E-mail: tatiana.besset@insa-rouen.fr; E-mail: thomas.poisson@insa-rouen.fr
Received: 27.02.2014; Accepted after revision: 13.04.2014
tionalized fluorinated motifs remains in its infancy despite
Abstract: A copper-mediated fluorofunctionalization of alkenes
the considerable possibilities for post-functionalization.7
and alkynes has been developed. This method provides ready access
Surprisingly, the direct introduction of the ethoxy-
to trisubstituted difluoromethylated olefins (from dihydropyrans,
glycal derivatives, or terminal alkynes) or to tetrasubstituted olefins
carbonyl(difluoro)methyl moiety into non-prefunctional-
(from disubstituted alkynes). The products were obtained in good to ized substrates is underexplored.8 Indeed, the usual
high yields with acceptable E/Z selectivities. Finally, a first direct
route to difluoromethylated alkynes is reported, albeit with low
yields.
methods generally require the use of prefunctionalized
substrates. For instance, most of the well-established
methods rely on radical addition of halo or chalcogeno-
fluorinated reagents to alkenes,9 reductive coupling of
Key words: copper, fluorine, alkenes, alkynes, carbohydrates
aryl or vinyl iodides with halo or silylated ethoxycarbon-
yl(difluoro)methyl derivatives in the presence of copper
Transition-metal-promoted carbon–carbon or carbon–het- bronze,10 or transition-metal-catalyzed Suzuki or Negishi
eroatom (e.g., C–O or C–N) bond formation is well recog- cross couplings of halogenated ethoxycarbonyl(difluo-
nized as a powerful method for the functionalization of ro)methyl derivatives (Scheme 1).11
organic molecules.2 As a result, this field of research was
recognized by the award of the Nobel Prize in Chemistry
previous work:
X
CO2Et
hν
to Heck, Suzuki, and Negishi in 2010 for their develop-
ment of palladium-catalyzed cross-coupling reactions.
Among the transition metals, copper has particular appeal
for performing new transformations because of its high
abundance, low cost, and low toxicity compared with its
congeners. It is therefore not surprising that copper chem-
istry is a field showing tremendous expansion. Indeed,
since the discovery of the venerable Glaser and Ullman–
Goldberg reactions in 1869 and 1901, respectively, much
attention has been paid to developing new transformations
mediated or catalyzed by copper.3 These efforts have re-
sulted in several elegant and efficient processes to achieve
new transformations, permitting novel retrosynthetic dis-
connections.
F F
EDG
1)
CF2CO2Et
CF2CO2Et
EDG
X = I, SePh
Cu CO2Et
F F
I
2)
X
CO2Et
M
CF2CO2Et
F F
3)
X = I, Br
our approach:
H
H
CF2CO2Et
R
R
R
Fluorinated compounds are of great interest in medicinal
chemistry, materials, and agrochemical research.4 The de-
velopment of new and efficient methods for preparing
these compounds is therefore a relevant challenge. Sever-
al recent efforts have focused on the selective introduction
of fluorinated moieties, particularly by direct and selec-
tive C–H bond-functionalization reactions.5,6 Although
the introduction of the trifluoromethyl group has been
widely explored, the selective introduction of other func-
[Cu]
or
or
Br CO2Et
Br
F F
CF2CO2Et
R
Scheme 1 State-of-the-art methods for introducing ethoxycarbon-
yl(difluoro)methyl group
Therefore, as part of our ongoing research program devot-
ed to the design and synthesis of new fluorinated building
blocks,12 we were interested in the direct and selective in-
troduction of the ethoxycarbonyl(difluoro)methyl group
SYNTHESIS 2014, 46, 1859–1870
Advanced online publication: 28.05.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338637; Art ID: ss-2014-c0137-st
© Georg Thieme Verlag Stuttgart · New York

1860
M.-C. Belhomme et al.
SPECIAL TOPIC
by using copper as a promoter.8,13 Here, we report the di- groups. Pleasingly, the benzyl-protected 2-hydroxydihy-
rect copper-mediated functionalization of alkenes and al- dropyran 1b reacted smoothly to give the fluorinated ad-
kynes.
duct 2b in 72% yield. A pivaloyl protecting group was
also compatible, and the corresponding product 2c was
obtained in 60% isolated yield. We then turned our atten-
tion to amide derivatives. Treatment of dihydropyran 1b
with the 2-bromo-N,N-diethyl-2,2-difluoroacetamide un-
der slightly modified conditions (5 mol% of Cu2O with
Cs2CO3 as the base at 90 °C) gave the corresponding prod-
uct 2d in a modest 33% isolated yield. Similarly, treat-
ment of an N-morpholino derivative under our modified
conditions gave the coupling product 2e in 30% isolated
yield. These lower yields might be explained by the lower
electrophilicity of the intermediate copper complex (see
below) compared with the one derived from ethyl bro-
mo(difluoro)acetate. Finally, because of the importance
of fluorinated carbohydrates, we decided to apply our re-
action conditions to glycal derivatives. To our delight, af-
ter a slight modification of the reaction temperature and
the stoichiometry of ethyl bromo(difluoro)acetate, tri-O-
benzyl-D-glucal (1f) reacted smoothly to give the fluori-
At the outset of the project, we focused our attention on
the direct and selective introduction of the ethoxycarbon-
yl(difluoro)methyl moiety onto a dihydropyran back-
bone,8 and we examined the effects of various changes in
the reaction conditions. Under the optimized conditions,
the fluorinated product 2a was obtained in 73% isolated
yield by using copper(II) triflate as a catalyst (Table 1, en-
try 1). Although a palladium catalyst promoted the reac-
tion, the isolated yield was only 19% (entry 2); this result
highlights the efficiency of the copper catalyst in compar-
ison with a palladium catalyst. The base played a crucial
role in the outcome of the reaction. Indeed, the replace-
ment of potassium carbonate by an organic base (triethyl-
amine) had a marked effect on the reaction, affording
product 2a in only 21% yield (entry 3); another inorganic
base (cesium carbonate) also gave a lower yield (entry 4).
We found that two equivalents of base were required to
ensure a reasonable yield (entry 5). Pleasingly, the re-
placement of the copper(II) catalyst by a copper(I) cata-
lyst provided the fluorinated dihydropyran 2a in good
yield (entries 6 and 7). These two results suggested that
copper(I) species might be the real active catalytic species
in this transformation. Finally, control experiments
showed that no reaction occurred in the absence of a base
or a copper catalyst (entries 8 and 9).
O
O
BrCF2CO2Et
or
Cu(PF6).[MeCN]4 (10 mol%)
1,10-phenanthroline (12 mol%)
CF2COR
2a–h
K2CO3 (2 equiv)
DMF, 80 °C, 24 h, air
BrCF2CONR2
1a–h
O
O
O
BnO
PivO
Table 1 Optimization of the Reaction of 3,4-Dihydro-2H-pyran
CF2CO2Et
2a, 73%a
CF2CO2Et
2b, 72%
CF2CO2Et
Cu(OTf)2 (10 mol%)
O
O
1,10-phenanthroline (12 mol%)
BrCF2CO2Et
2c, 60%
K2CO3 (2 equiv)
DMF, 80 °C, 18 h, air
CF2CO2Et
4 equiv
1a
2a
O
O
BnO
O
BnO
O
Entry
Deviations from standard conditions
Yielda (%)
Et
N
N
F
F
F
F
Et
O
1
2
3
4
5
6
7
8
9
none
73
2d, 33%b
2e, 30%b
Pd(PPh3)4 instead of Cu(OTf)2
Et3N instead of K2CO3
Cs2CO3 instead of K2CO3
K2CO3 (1 equiv)
19
21b
47
O
O
BnO
BnO
AcO
AcO
CF2CO2Et
CF2CO2Et
18b
70
OBn
OAc
2f, 62%c
2g, 65%c
CuI instead of Cu(OTf)2
[Cu(OTf)]2·C6H6 instead of Cu(OTf)2
no base
O
62b
NRb,c
NRb,c
BnO
BnO
CF2CO2Et
OBn
no metal
2h, 49%c
a Isolated yield.
b Determined by 19F NMR using PhCF3 as an internal standard.
c NR = no reaction.
Scheme 2 Difluoromethylation reactions of dihydropyrans and
glycal derivatives. Reagents and conditions: 1 (0.24 mmol),
BrCF2CO2Et or BrCF2CONR2 (NR2 = NEt2 or morpholino) (4 equiv),
Cu(PF6)·[MeCN]4 (0.024 mmol), 1,10-phenanthroline (0.029 mmol),
a
b
We then applied our optimized reaction conditions to oth-
er dihydropyran derivatives and to several carbohydrate
derivatives (Scheme 2). First, we extended the reaction to
dihydropyrans 1b and 1c containing different protecting
K2CO3 (0.48 mmol), DMF (1.2 mL), 80 °C. Cu(OTf)2 was used.
The reaction was performed at 90 °C with 5 mol% of Cu2O and with
Cs2CO3 as the base. c Reaction was performed at 110 °C with 8 equiv
of BrCF2CO2Et.
Synthesis 2014, 46, 1859–1870
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Copper-Mediated Difluoromethylation
1861
nated carbohydrate 2f in 62% yield, and D-glucal triace- and alkenes are suitable reaction partners for a highly
tate (1g) gave a similar yield (65%) of the corresponding electrophilic species (an iodonium salt) in the presence of
product. When tri-O-benzyl-D-galalactal (1h) reacted un- a copper catalyst. Accordingly, the copper(III) species A
der the same conditions, the corresponding product 2h might form a copper π-complex D, which would then per-
was isolated in 49% yield.
forms an electrophilic carbofluorofunctionalization, gen-
erating a new copper(III) species E. The latter would
undergo a reductive elimination to release the bromofluo-
rinated alkene 4 with regeneration of the copper species
(Scheme 4).
We were intrigued by the mechanism of this new transfor-
mation, so we performed some mechanistic experiments
and, as a result, we proposed the following catalytic cycle
(Scheme 3). To elucidate the reaction pathway, we carried
out the reaction in the presence of radical inhibitors or rad-
ical scavengers.14 The addition of (2,2,6,6-tetramethylpi-
peridin-1-yl)oxyl (TEMPO) did not have any marked
effect on the transformation, and the corresponding prod-
uct 2b was obtained in a similar yield. On the basis of
these results, we proposed a mechanism involving a high-
ly electrophilic copper(III) species.15 First, the copper(I)
catalyst undergoes an oxidative addition to the C–Br bond
of ethyl bromo(difluoro)acetate to give the copper(III) in-
termediate A. A nucleophilic attack of the dihydropyran
derivative 1 then generates the oxonium species B, which
is released as the enol ether C by the base. Finally, reduc-
tive elimination regenerates the catalyst and delivers the
desired product 2.16
Br
CF2CO2Et
R
CuIX
4
BrCF2CO2Et
reductive
elimination
III
Cu
Br
X
Br
X
CF2CO2Et
CuIII CF2CO2Et
R
E
A
X
CuIII CF2CO2Et
electrophilic
carbo-
fluorofunctionalization
Br
R
3
R
D
Scheme 4 Proposed reaction pathway for the functionalization of al-
kynes
O
O
standard conditions
BnO
BnO
CO2Et
Because of the importance of fluorinated alkenes, the de-
sign of innovative and straightforward synthetic pathways
to these highly valuable compounds is an interesting chal-
lenge that has recently attracted growing interest from
several research groups.18 The application of the strategy
described above to the functionalization of alkynes should
give the corresponding difluoromethylated alkenes, com-
pounds that are usually obtained by radical addition of
iodo- or seleno-substituted difluoroacetates.9,19 If our
strategy proved successful, the resulting difluoromethyl-
ated vinyl bromides would constitute highly valuable tri-
substituted olefin building blocks, capable of undergoing
further synthetic transformations.
1b
2b
F
F
yield (%)
no additive
73
68
TEMPO (20 mol%)
TEMPO (100 mol%)
66 (36 h)
CF2CO2Et
CuIX
O
2
BrCF2CO2Et
O
Br
CuIII CF2CO2Et
CF2CO2Et
Cu
Br
X
A
C
We began by studying the reaction of ethyl bromodifluo-
roacetate with phenylacetylene (3a) as a model substrate
(Table 2). After extensive investigations, we were pleased
to discover that alkene 4a could be obtained in the pres-
ence of a catalytic amount of copper(II) triflate in N,N-di-
methylformamide under air at 120 °C (Table 2, entry 1).
Although (E)-4a was obtained in low yield, this prelimi-
nary result demonstrated the potential of the approach.
Encouraged by this observation, we decided to pursue our
investigations by using a stoichiometric amount of the
copper salt to improve the conversion of alkyne 3a into
the corresponding alkene 4a. For this purpose, several
copper sources were examined with a shorter reaction
time at 140 °C (entries 2–4). Both copper(II) and cop-
per(I) salts provided the expected alkene 4a, but the cop-
per(II) complexes were far more efficient. In particular,
when the reaction was performed with copper(II) triflate,
alkene 4a was obtained in a high yield as an inseparable
O
X
O
base·HX
1
CF2CO2Et
base
Cu
Br
B
Scheme 3 Mechanistic study and proposed mechanism. Reagents
and conditions: 1b (0.24 mmol), BrCF2CO2Et (4 equiv),
Cu(PF6)·[MeCN]4 (0.024 mmol), 1,10-phenanthroline (0.029 mmol),
K2CO3 (0.48 mmol), DMF (1.2 mL), 80 °C.
On the basis of this proposed mechanism, which involves
an electrophilic copper(III) species, we wondered if such
process might be further applied in the direct functional-
ization of another important class of versatile compounds:
the alkynes. Indeed, this hypothesis was supported by re-
cent report from Gaunt’s group,17 who found that alkynes
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1859–1870

1862
M.-C. Belhomme et al.
SPECIAL TOPIC
68:32 mixture of the E- and Z-diastereoisomers (entry 3). Notably, even a bromine atom on the aryl group was tol-
The geometry of the double bond was established un- erated, thereby providing the dibromo derivative 4f,
equivocally by means of NOESY experiments.19 Decreas- which offers new possibilities for further functionaliza-
ing the temperature to 120 °C (entry 5) had a beneficial tion, for example, by cross-coupling reactions. Aryl-
effect on the reactivity while the selectivity remained un- alkynes with various substitution patterns, such as meta-
changed (E/Z 68:32). In contrast, the use of another base or ortho-substitution (3g, 3h and 3i), were also efficiently
(sodium acetate) did not have a significant effect on the converted into the corresponding difluoromethylated ole-
outcome of the reaction (entry 6; E/Z 74:26), whereas the fins (4g, 4h and 4i). Steric hindrance on the aromatic ring
use of bathophenanthroline as a ligand gave a lower yield had no effect on the outcome of the reaction, except in the
of 4a (entry 7). Finally, control experiments revealed that case of the o-methoxy-substituted derivative 4h. Pleasing-
the fluorinated containing olefin 4a was not obtained in ly, the reaction was also compatible with hetaryl groups
the absence of a copper salt or of a base.20
such as 3-thienyl (3j) or 2-pyridyl (3k). These results
highlight the broad scope of this transformation. Note that
in the case of the pyridyl compound 4k, a reverse selectiv-
ity was observed (E/Z ratio of 41:59), probably as a result
of coordination of the pyridine ring to the copper species.
The benzylic-substituted alkyne 3l was functionalized
with a moderate yield of 23% and with loss of diastereose-
lectivity. Finally, to assess the effectiveness of our reac-
tion, more-challenging disubstituted alkynes, such as 3m
and 3n, were also tested. Gratifyingly, under the standard
conditions, 1-phenylbutyne and diphenylacetylene gave
Next, we examined the scope of the reaction for the syn-
thesis of alkenes 4 from terminal and internal alkynes 3.
The desired products were generally isolated in high
yields and in moderate to good E/Z ratios (Scheme 5). Ini-
tially, we tested aryl-substituted terminal alkynes, which
gave the corresponding trisubstituted alkenes. We were
delighted to find that the reaction proceeded with a broad
tolerance to various functional groups. Electron-rich (3b
and 3c) and electron-deficient (3d, 3e, and 3f) arylacety-
lene derivatives were suitable substrates for this reaction.
Table 2 Optimization Study for the Preparation of Fluoroalkene 4aa
Br
Br
copper salt (x mol%)
1,10-phenanthroline
H
CF2CO2Et
BrCF2CO2Et
+
CF2CO2Et
+
+
base, additive, DMF
T (°C), air
CF2CO2Et
H
(Z)-4a
5a
3a
(E)-4a
Entry
Copper salt
x mol%
Base
Additive
Yieldb of 4a (%) E/Z ratioc
Yieldb of 5a (%)
1d,e
2f
Cu(OTf)2
CuCl2
10
100
100
100
100
100
100
100
10
KF
–
12
–
–
KF
–
55
73:27
68:32
90:10
69:31
74:26
63:37
69:31
–
–
3f
Cu(OTf)2
CuBr
KF
–
76
–
4f
KF
–
30
–
5d,g
6d,g
7d,g,i
8d,g
9j
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
–
KF
–
94 (78)h
–
NaOAc
KF
–
84
62
52
–
–
–
–
KF
–
3
KF
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
18
28
29
3
10j
11j
12j
10
CsOPiv
NaOAc
KF
–
–
10
–
–
–
–
–
a Reaction conditions: 3a (1 equiv), BrCF2CO2Et (5 equiv), 1,10-phenanthroline (1.1x mol%), base (2.1 equiv), additive (1.5 equiv),
[DMF] = 0.125 mol/L, air.
b Yields determined by 19F NMR with PhCOCF3 as internal standard.
c Determined by 19F NMR spectroscopy on the crude reaction mixture.
d At 120 °C.
e 16 h.
f 140 °C for 2 h.
g 2 h.
h Isolated yield.
i Bathophenanthroline was used instead of 1,10-phenanthroline.
j 100 °C for 16 h, [DMF] = 0.1 mol/L.
Synthesis 2014, 46, 1859–1870
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Copper-Mediated Difluoromethylation
1863
the otherwise relatively inaccessible tetrasubstituted ole- is an ozone-depleting substance that presents difficulties
fins 4m and 4n, with good E/Z selectivity (83:17) in the in handling.23
case of 4m.
Consequently, we sought to optimize the reaction condi-
Surprisingly, during the course of our optimization study, tions to give difluoromethylated alkyne 5a selectively.
we observed that when the reaction was mediated by Pleasingly, when we performed the reaction with a cata-
bis(acetylacetonate)copper, traces (3%) of the difluoro- lytic amount of bis(acetylacetonato)copper (10 mol%) in
methylated alkyne 5a were obtained (Table 2, entry 8). the presence of copper(II) acetate at 100 °C, the desired
The direct fluorination of terminal alkynes with trifluoro- alkyne 5a was obtained in 18% yield (Table 2, entry 9).
methyl, (trifluoromethyl)sulfide or fluoro groups is chal- Note that the presence of copper(II) acetate as an additive
lenging, and the development of such transformations is was required to ensure the formation of alkyne 5a.24 Fur-
of considerable interest.21 Furthermore, there is no report ther experiments with various bases showed that the use
of a direct route to difluoromethylated terminal alkynes. of cesium pivalate or sodium acetate gave 5a with slightly
Therefore, a straightforward synthesis of fluorinated scaf- improved yields (28% and 29%, respectively; entries 10
folds such as 5 would be extremely valuable because of and 11). Finally, we performed a control experiment with-
their potential use in various transformations.22 Such com- out bis(acetylacetonate)copper (entry 12), and this gave
pounds are normally prepared by multistep syntheses in- traces of the desired product 5a, suggesting that copper(II)
volving the use of difluoropropargyl bromide derivatives. acetate is not the active catalytic species. Although its role
These derivatives are usually obtained by the addition of has not yet been clearly defined, our observations high-
phenylacetylene to dibromodifluoromethane in the pres- light the fact that copper(II) acetate is a key additive for
ence of butyllithium; however, dibromodifluoromethane the success of this transformation.25
Cu(OTf)2 (100 mol%)
Br
1,10-phenanthroline (110 mol%)
KF (2.1 equiv)
BrCF2CO2Et
R
R
DMF, air, 120 °C, 2 h
Br
CF2CO2Et
3
4
Br
Br
CF2CO2Et
CF2CO2Et
CF2CO2Et
t-Bu
MeO
4a, 78%
E/Z = 69:31
4b, 81%
E/Z = 68:32
4c, 79%
E/Z = 68:32
Br
Br
Br
CF2CO2Et
CF2CO2Et
CF2CO2Et
Br
F3C
F
4d, 88%
4e,a 78%
4f, 85%
E/Z = 71:29
E/Z = 70:30
E/Z = 72:28
F
Br
OMe Br
Br
CF2CO2Et
CF2CO2Et
CF2CO2Et
F
4g, 75%
E/Z = 70:30
4h, 81%
E/Z = 58:42
4i,a 84%
E/Z = 89:11
Br
Br
Br
CF2CO2Et
N
CF2CO2Et
S
CF2CO2Et
4k,a 44%
E/Z = 41:59
4j, 53%
E/Z = 68:32
4l, 23%
E/Z = 53:47
Br
Br
CF2CO2Et
CF2CO2Et
4n, 36%
E/Z = 75:25
4m, 49%
E/Z = 83:17
Scheme 5 Difluoromethylation of alkynes 3 to give alkenes 4. Reagents and conditions: 3 (0.4 mmol, 1 equiv), BrCF2CO2Et (5 equiv),
Cu(OTf)2 (100 mol%), 1,10-phenanthroline (110 mol%), KF (2.1 equiv), [DMF] = 0.125 mol/L, air, 120 °C, 2 h. The major isomers are shown,
and the isolated yields for the two stereoisomers are reported. The E/Z ratios were determined by 19F NMR spectroscopy of the crude mixture.
a This compound and its isomer were isolated together with an inseparable impurity.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1859–1870

1864
M.-C. Belhomme et al.
SPECIAL TOPIC
Cu(acac)2 (10 mol%)
1,10-phenanthroline (11 mol%)
NaOAc (2.1 equiv)
BrCF2CO2Et
R
CF2CO2Et
R
Cu(OAc)2 (1.5 equiv), DMF
air, 100 °C, 16 h
5
3
CF2CO2Et
F3C
CF2CO2Et
5a, 29%
5b, 22%
NC
CF2CO2Et
5c, 18%
Scheme 6 Difluoromethylation of alkynes 3 to give alkynes 5. Reagents and conditions: 3 (0.2 mmol, 1 equiv), BrCF2CO2Et (5 equiv),
Cu(acac)2 (10 mol%), 1,10-phenanthroline (11 mol%), NaOAc (2.1 equiv), Cu(OAc)2 (1.5 equiv), [DMF] = 0.1 mol/L, air, 100 °C, 16 h. Yields
were determined by 19F NMR with PhCOCF3 as internal standard.
Next, we focused on the scope of the reaction toward the highly valuable functionalized fluorinated olefins and al-
synthesis of alkynes 5 from three terminal alkynes 3 kynes. Indeed, these substrates might easily be engaged in
(Scheme 6). In general, yields were quite moderate, prob- further post-functionalizations on the bromine atom or the
ably due to competition from the homocoupling reac- ester moiety to give more-complex fluorinated molecules.
tion.26 The reaction was compatible with electron-
withdrawing substituents, such as the trifluoromethyl (5b)
All reactions were carried out using oven-dried glassware with
or nitrile group (5c); electron-rich groups, such as meth-
oxy, gave poorer results. Although alkynes 5 were ob-
tained in low yields, these examples showcase the
potential of this strategy and constitute the first example
of the direct introduction of an ethoxycarbonyl(difluo-
ro)methyl group onto alkynes.
magnetic stirring under an atmosphere of air unless otherwise stat-
ed. Flash chromatography was performed on silica gel (0.040–0.060
nm or 0.060–0.200 nm) unless otherwise stated. Analytical TLC
was performed on silica gel coated aluminum plates with F-254 in-
dicator with visualization by UV irradiation (254 nm) and/or chem-
ical staining with KMnO4 solution. 1H NMR spectra were recorded
on a Bruker DXP 300 spectrometer; 13C NMR spectra were record-
ed at 75 MHz, and 19F NMR spectra at 282 MHz. Chemical shifts
(δ) are quoted in ppm relative to the residual solvent (CHCl3:
δ = 7.26 for 1H, δ = 77.0 for 13C) or to external (CFCl3; δ = 0 ppm).
High-resolution mass spectra were recorded on a Waters LCT Pre-
mier spectrometer. IR spectra were recorded on a Perkin-Elmer
Spectrum 100. Optical rotations were measured in CHCl3 on a
Perkin-Elmer 341 polarimeter with a 1 cm cell. Melting points are
uncorrected. All anhydrous solvents were dried by standard tech-
niques. Dry DMF (sealed bottles) was purchased from Acros Or-
ganics. Dihydropyran and ethyl bromodifluoroacetate were distilled
before use. 3,4,6-Tri-O-benzyl-D-glucal28 and 3,4,6- tri-O-benzyl-
D-galactal,29 were prepared by known procedures. All the solid bas-
es (KF, CsOPiv, Cs2CO3, and NaOAc) were dried over P2O5 under
vacuum before use.
Finally, to gain further insight into the mechanism of the
formation of the bromodifluoromethylated olefin, we car-
ried out the reaction in the presence of one equivalent of
TEMPO. No effect on either the reactivity or the selectiv-
ity was observed, thereby ruling out a plausible radical
pathway. Consequently, in agreement with previous re-
ports,17 we assume that our initial hypothesis of a mecha-
nism involving an electrophilic copper(III) intermediate is
plausible (Scheme 4). With respect to the mechanism for
the synthesis of the difluoromethylated alkyne, we assume
that the reaction proceeds through another pathway, be-
cause 4a is not an intermediate for the formation of alkyne
5a.27
Ethyl 3,4-Dihydro-2H-pyran-5-yl(difluoro)acetates 2a–e; Gen-
eral Procedure
In conclusion, we have developed a copper-mediated di-
rect fluorofunctionalization of unsaturated derivatives by
using commercially available ethyl bromo(difluoro)ace-
tate. By this method, we obtained a panel of trisubstituted
difluoromethylated olefins, including dihydropyrans, gly-
cal derivatives, and tetrasubstituted olefins, in good to
high yields. Because various functional groups are toler-
ated, this copper-promoted transformation has consider-
able synthetic potential and constitutes a versatile method
for the direct introduction of difluoro moieties onto non-
prefunctionalized alkenes or alkynes. Moreover, we de-
veloped a new route to difluoroacetylated alkynes. Al-
though the fluorinated alkynes were obtained in modest
yields, this method represents the first direct access to eth-
oxycarbonyl(difluoro)methyl-substituted alkynes. Final-
ly, both these strategies pave the way for the synthesis of
The appropriate Cu complex (0.036 mmol), 1,10-phenanthroline
(0.043 mmol), and K2CO3 (0.72 mmol) were dissolved in DMF (1.8
mL) under air. Enol ether 1 (0.36 mmol) and BrCF2CO2Et or
BrCF2CONR2 (NR2 = NEt2, morpholino; 1.44 mmol) were added,
and the tube was sealed. The mixture was heated at 80 or 90 °C for
18 h. The solution was then cooled and extracted with Et2O (3 × 10
mL). The organic layer was washed successively with H2O (2 × 10
mL) and brine (2 × 10 mL) then dried (MgSO4). The solvent was re-
moved under vacuum and the residue was purified by flash chroma-
tography.
Ethyl 3,4-Dihydro-2H-pyran-5-yl(difluoro)acetate (2a)
Prepared by following the general procedure from dihydropyran 1a
and BrCF2CO2Et on a 0.36 mmol scale with Cu(OTf)2 (13 mg,
0.036 mmol) as catalyst. Flash chromatography (silica gel) gave a
colorless oil (Caution: highly volatile); yield: 0.054 g (73%);
Rf = 0.34 (pentane–Et2O, 19:1).
IR (neat): 2941, 1760, 1662, 1256, 1009 cm–1.
Synthesis 2014, 46, 1859–1870
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Copper-Mediated Difluoromethylation
1865
1H NMR (300 MHz, CDCl3): δ = 6.84 (br s, 1 H), 4.33 (q, JH,H = 7.1
Hz, 2 H), 4.00 (dd, JH,H = 5.3, 5.1 Hz, 2 H), 2.14 (dt, JH,H = 6.3, 1.1
Hz, 2 H), 1.93–1.85 (m, 2 H), 1.35 (t, JH,H = 7.1 Hz, 3 H).
3.33 (m, 4 H), 2.23–2.21 (m, 2 H), 2.00–1.92 (m, 1 H), 1.80–1.67
(m, 1 H), 1.21–1.14 (m, 6 H).
13C NMR (75 MHz, CDCl3): δ = 162.4 (t, JC,F = 29.7 Hz), 145.6 (t,
JC,F = 10.5 Hz), 137.7, 128.4 (2 C), 127.8, 127.7 (2 C), 116.6 (t,
13C NMR (75 MHz, CDCl3): δ = 164.0 (t, JC,F = 35.8 Hz), 146.3 (t,
JC,F = 11.0 Hz), 114.3 (t, JC,F = 248.1 Hz), 105.9 (t, JC,F = 24.8 Hz),
JC,F = 243.7 Hz), 107.3 (t, JC,F = 25.9 Hz), 74.9, 73.5, 71.7, 42.4,
66.0, 62.8, 21.0, 17.8 (t, JC,F = 2.8 Hz), 13.9.
41.3, 23.1, 17.3, 14.0, 12.2.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –105.3 (s, 2 F).
HRMS (AP+): m/z calcd for [M + H]+ C9H13F2O3: 207.0833; found:
19F NMR (282 MHz, CDCl3, CFCl3): δ = –96.5 (d, JF,F = 265.7 Hz),
–97.7 (d, JF,F = 265.7 Hz).
HRMS (ESI+): m/z [M + H]+ calcd for C19H26F2NO3: 354.1881;
207.0827 (–2.9 ppm).
found: 354.1881 (0 ppm).
Ethyl {2-[(Benzyloxy)methyl]-3,4-dihydro-2H-pyran-5-yl}(di-
fluoro)acetate (2b)
4-[{2-[(Benzyloxy)methyl]-3,4-dihydro-2H-pyran-5-yl}(difluo-
ro)acetyl]morpholine (2e)
Prepared by following the general procedure from 2-(benzyloxy-
methyl)-3,4-dihydro-2H-pyran (1b) and BrCF2CO2Et on a 0.24
mmol scale with Cu(MeCN)4PF6 (9 mg, 0.024 mmol) as catalyst.
Flash chromatography (silica gel) gave a colorless oil; yield: 0.056
g (72%); Rf = 0.37 (pentane–Et2O, 19:1).
Prepared by following the general procedure from 2-(benzyloxy-
methyl)-3,4-dihydro-2H-pyran (1b) and 4-[bromo(difluoro)ace-
tyl]morpholine at 90 °C on a 0.24 mmol scale with Cu2O (2 mg,
0.012 mmol) as catalyst. Flash chromatography (silica gel) gave a
colorless oil; yield: 0.026 g (30%); Rf = 0.30 (PE–EtOAc, 3:1).
IR (neat): 2859, 1760, 1662, 1271, 1198, 1089 cm−1.
IR (neat): 2860, 1663, 1254, 1101, 1022 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.40–7.28 (m, 5 H), 6.88 (br s, 1
H), 4.64–4.55 (m, 2 H), 4.33 (q, JH,H = 7.2 Hz, 2 H), 4.10–4.03 (m,
1 H), 3.62 (dd, JH,H = 10.2, 5.7 Hz, 1 H), 3.56 (dd, JH,H = 10.2, 4.5
Hz, 1 H), 2.21–2.16 (m, 2 H), 2.00–1.92 (m, 1 H), 1.80–1.66 (m, 1
H), 1.35 (t, JH,H = 7.2 Hz, 3 H).
1H NMR (300 MHz, CDCl3): δ = 7.37–7.30 (m, 5 H), 6.81 (s, 1 H),
4.63–4.55 (m, 2 H), 4.13–4.06 (m, 1 H), 3.71–3.59 (m, 10 H), 2.22–
2.20 (m, 2 H), 2.01–1.93 (m, 1 H), 1.81–1.68 (m, 1 H).
13C NMR (75 MHz, CDCl3): δ = 161.8 (t, JC,F = 30.3 Hz), 145.7 (t,
JC,F = 11.0 Hz), 137.7, 128.4 (2 C), 127.8, 127.7 (2 C), 116.6 (t,
13C NMR (75 MHz, CDCl3): δ = 164.0 (t, JC,F = 35.8 Hz), 146.0 (t,
JC,F = 11.0 Hz), 137.8, 128.4, 127.8 (2 C), 127.7 (2 C), 114.2 (dd,
JC,F = 245.4 Hz), 106.9 (t, JC,F = 24.8 Hz), 75.0, 73.5, 71.6, 66.7,
JC,F = 248.7, 248.7 Hz), 105.8 (t, JC,F = 25.3 Hz), 74.9, 73.5, 71.6,
66.5, 46.9, 43.3, 23.0, 17.5 (t, JC,F = 2.2 Hz).
62.8, 23.0, 17.7 (t, JC,F = 2.8 Hz), 14.0.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –104.5 (d, JF,F = 253.4
Hz), –105.9 (d, JF,F = 253.4 Hz).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –96.3 (d, JF,F = 268.7 Hz),
–97.3 (d, JF,F = 268.7 Hz).
HRMS (AP+): m/z [M + H]+ calcd for C19H24F2NO4: 368.1673;
HRMS (AP+): m/z [M + H]+ calcd for C17H21F2O4: 327.1408;
found: 368.1661 (–3.3 ppm).
found: 327.1401 (–2.1 ppm).
Glycal Derivatives 2f–h; General Procedure
Cu[MeCN]4PF6 (9 mg, 0.024 mmol), 1,10-phenanthroline (5 mg,
0.029 mmol), and K2CO3 (66 mg, 0.48 mmol) were dissolved in
DMF (1.2 mL) under air . The appropriate glycal derivative (0.24
mmol) and BrCF2CO2Et (0.25 mL, 1.92 mmol) were added, the tube
was sealed, and the mixture was heated at 110 °C for 24 h. The so-
lution was then cooled and extracted with Et2O (3 × 8 mL). The or-
ganic layer was washed successively with H2O (2 × 8 mL) and brine
(2 × 8 mL) then dried (MgSO4). The solvent was removed under
vacuum and the residue was purified by flash chromatography (sil-
ica gel, pentane–Et2O).
[5-(2-Ethoxy-1,1-difluoro-2-oxoethyl)-3,4-dihydro-2H-pyran-
2-yl]methyl Pivalate (2c)
Prepared by following the general procedure from 2-(pivaloyloxy-
methyl)-3,4-dihydro-2H-pyran (1b) and BrCF2CO2Et on a 0.24
mmol scale with Cu(MeCN)4PF6 (9 mg, 0.024 mmol) as catalyst.
Flash chromatography [silica gel, pentane–Et2O (9:1)] gave a color-
less oil; yield: 0.046 g (60%); Rf = 0.34 (pentane–Et2O, 9:1).
IR (neat): 2971, 1755, 1737, 1659, 1283, 1156, 1096 cm−1.
1H NMR (300 MHz, CDCl3): δ = 6.86 (br s, 1 H), 4.33 (q, JH,H = 7.2
Hz, 2 H), 4.22 (dd, JH,H = 11.7, 4.7 Hz, 1 H), 4.17 (dd, JH,H = 11.7,
5.3 Hz, 1 H), 4.12–4.04 (m, 1 H), 2.23–2.19 (m, 2 H), 2.00–1.92 (m,
1 H), 1.77–1.67 (m, 1 H), 1.36 (t, JH,H = 7.2 Hz, 3 H), 1.22 (s, 9 H).
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-[ethoxycarbon-
yl(difluoro)methyl]-D-arabino-hex-1-enitol (2f)
Prepared by following the general procedure from 3,4,6-tri-O-ben-
zyl-D-glucal (1f) as a colorless oil; yield: 0.080 g (62%); [α]D20 –9.2
(c 0.25, CHCl3); Rf = 0.30 (pentane–Et2O, 4:1).
IR (neat): 2928, 2869, 1762, 1291, 1202, 1088, 1068 cm−1.
13C NMR (75 MHz, CDCl3): δ = 178.2, 163.9 (t, JC,F = 35.8 Hz),
145.8 (dd, JC,F = 11.0, 11.0 Hz), 114.1 (dd, JC,F = 248.7, 248.7 Hz),
105.9 (t, JC,F = 24.8 Hz), 73.5, 65.1, 62.9, 38.8, 27.1 (3 C), 22.8,
17.6 (t, JC,F = 2.8 Hz), 13.9.
1H NMR (300 MHz, CDCl3): δ = 7.37–7.19 (m, 15 H), 6.97 (d,
19F NMR (282 MHz, CDCl3, CFCl3): δ = –103.9 (d, JF,F = 253.4
Hz), –105.6 (d, JF,F = 253.4 Hz).
HRMS (AP+): m/z [M + H]+ calcd for C15H23F2O5: 321.1514;
J
H,F = 2.6 Hz, 1 H), 4.61–4.60 (m, 2 H), 4.50–4.49 (m, 4 H), 4.45–
4.40 (m, 1 H), 4.14–4.01 (m, 3 H), 3.89–3.86 (m, 1 H), 3.78 (dd,
JH,H = 10.6, 6.4 Hz, 1 H), 3.66 (dd, JH,H = 10.6, 4.5 Hz, 1 H), 1.15 (t,
found: 321.1520 (+1.9 ppm).
J
H,H = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 163.9 (dd, JC,F = 37.9, 33.6 Hz),
146.6 (dd, JC,F = 12.7, 9.4 Hz), 137.6, 137.5, 137.3, 128.5 (2 C),
128.4 (2 C), 128.2 (2 C), 128.0, 127.8 (2 C), 127.73 (2 C), 127.69
(2 C), 127.63 (2 C), 113.4 (t, JC,F = 250.3 Hz), 105.7 (dd,
2-{2-[(Benzyloxy)methyl]-3,4-dihydro-2H-pyran-5-yl}-N,N-di-
ethyl-2,2-difluoroacetamide (2d)
Prepared by following the general procedure from 2-(benzyloxy-
methyl)-3,4-dihydro-2H-pyran (1b) and BrCF2CONEt2 at 90 °C on
a 0.24 mmol scale with Cu2O (2 mg, 0.012 mmol) as catalyst. Flash
chromatography [silica gel, PE–EtOAc (4:1)] gave a colorless oil;
yield: 0.028 g (33%); Rf = 0.25 (PE–EtOAc, 4:1).
J
C,F = 26.4, 22.0 Hz), 76.3, 73.3, 72.5, 72.2, 71.9, 70.0 (d, JC,F = 3.9
Hz), 67.6, 62.6, 13.7.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –103.2 (d, JF,F = 256.5
Hz), –109.4 (d, JF,F = 256.5 Hz).
HRMS (ESI+): m/z [M + Na]+ calcd for C31H32F2O6Na: 561.2065;
found: 561.2063 (–0.4 ppm).
IR (neat): 2856, 1660, 1264, 1103, 1069 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.34–7.30 (m, 5 H), 6.75 (s, 1 H),
4.63–4.54 (m, 2 H), 4.11–4.04 (m, 1 H), 3.64–3.54 (m, 2 H), 3.45–
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1859–1870

1866
M.-C. Belhomme et al.
SPECIAL TOPIC
1,5-Anhydro-3,4,6-tri-O-acetyl-2-deoxy-2-[ethoxycarbon-
yl(difluoro)methyl]-D-arabino-hex-1-enitol (2g)
Prepared by following the general procedure from 3,4,6-tri-O-ace-
tyl-D-glucal (1g) as a colorless oil; yield: 0.062 g (65%);
[α]D20 +31.2 (c 0.25, CHCl3); Rf = 0.22 (pentane–Et2O, 3:2).
4.39 (q, JH,H = 7.2 Hz, 1.14 H, Z), 3.97 (q, JH,H = 7.2 Hz, 2 H, E),
1.38 (t, JH,H = 7.2 Hz, 1.76 H, Z), 1.19 (t, JH,H = 7.2 Hz, 3 H, E).
13C NMR (75 MHz, CDCl3): δ = 162.7 (t, JC,F = 33.8 Hz, Z), 162.4
(t, JC,F = 33.2 Hz, E), 137.8 (Z), 137.1 (E), 133.5 (t, JC,F = 10.1 Hz,
E), 132.9 (t, JC,F = 10.4 Hz, Z), 130.4 (Z), 129.9 (E), 128.5 (Z), 128.4
(t, JC,F = 2.2 Hz, E), 128.1 (E), 127.6 (Z), 125.0 (t, JC,F = 28.5 Hz,
E), 123.3 (t, JC,F = 30.0 Hz, Z), 112.0 (t, JC,F = 246.0 Hz, Z), 111.0
(t, JC,F = 247.5 Hz, E), 63.3 (Z), 63.1 (E), 13.8 (Z), 13.6 (E).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –93.6 (d, JFH = 11.1 Hz,
CF2, E), –97.6 (d, JFH = 11.1 Hz, CF2, Z).
MS (EI): m/z = 306 [M+].
IR (neat): 2990, 1743, 1661, 1369, 1216, 1198, 1021 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.08 (br s, 1 H), 5.61 (d, JH,H = 4.3
Hz, 1 H), 5.16 (t, JH,H = 4.3 Hz, 1 H), 4.47–4.18 (m, 5 H), 2.10 (s, 3
H), 2.09 (s, 3 H), 2.03 (s, 3 H), 1.36 (t, JH,H = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 170.3, 169.4, 169.3, 163.3 (dd,
JC,F = 35.8, 35.8 Hz), 148.7 (t, JC,F = 10.5 Hz), 112.6 (dd,
JC,F = 250.9, 250.9 Hz), 104.0 (t, JC,F = 24.8 Hz), 74.1, 66.1, 63.1,
HRMS (EI): m/z [M – CO2Et]+ calcd for C9H6BrF2: 232.9600;
found: 232.9607 (+2.7 ppm).
62.8 (dd, JC,F = 3.3, 2.2 Hz), 60.8, 20.7, 20.6, 20.5, 13.7.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –104.3 (d, JF,F = 262.6
Hz), –105.4 (d, JF,F = 262.6 Hz).
HRMS (ESI+): m/z [M + Na]+ calcd for C16H20F2O9Na: 417.0980;
found: 417.0973 (–1.7 ppm).
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-(4-methoxyphe-
nyl)but-3-enoate (4b)
Prepared by following the general procedure from 4-ethynylanisole
(3b; 0.394 mmol) as a mixture of stereoisomers in an E/Z ratio of
68:32. The crude mixture was purified by column chromatography
(silica gel) to give a yellow oil; yield: 0.106 g (81%); Rf = 0.36 (pen-
tane–Et2O, 9:1).
1,5-Anhydro-3,4,6-tri-O-benzyl-2-deoxy-2-[ethoxycarbon-
yl(difluoro)methyl]-D-lyxo-hex-1-enitol (2h)
Prepared following the general procedure from 3,4,6-tri-O-benzyl-
D-galactal (1h) as a colorless oil; yield: 0.063 g (49%); [α]D20 –11.5
(c 0.4, CHCl3); Rf = 0.29 (pentane–Et2O, 9:1).
IR (neat): 2923, 2863, 1761, 1296, 1211, 1096 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.37–7.28 (m, 15 H), 6.89 (d,
IR (neat): 2988, 2843, 1768, 1604, 1508, 1294, 1253, 1178, 1067,
1029, 833 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.58–7.50 (m, 0.93 H, Z), 7.35–
7.29 (m, 2 H, E), 6.93–6.82 (m, 3.09 H, E and Z), 6.57 (t, JH,F = 11.3
Hz, 0.46 H, Z), 6.44 (t, JH,F = 11.3 Hz, 1 H, E), 4.38 (q, JH,H = 7.2
Hz, 1.20 H, Z), 3.99 (q, JH,H = 7.2 Hz, 2 H, E), 3.84 (s, 1.48 H, Z),
3.81 (s, 3 H, E), 1.37 (t, JH,H = 7.2 Hz, 1.68 H, Z), 1.19 (t, JH,H = 7.2
Hz, 3 H, E).
JH,F = 2.8 Hz, 1 H), 4.79–4.39 (m, 7 H), 4.33–4.32 (m, 1 H), 4.04 (q,
JH,H = 7.2 Hz, 2 H), 4.00–3.97 (m, 1 H), 3.73 (dd, JH,H = 10.6, 6.6
Hz, 1 H), 3.60 (dd, JH,H = 10.6, 4.5 Hz, 1 H), 1.09 (t, JH,H = 7.2 Hz,
3 H).
13C NMR (75 MHz, CDCl3): δ = 162.9 (t, JC,F = 33.8 Hz, Z), 162.6
(t, JC,F = 33.2 Hz, E), 161.3 (Z), 160.8 (E), 133.9 (t, JC,F = 10.4 Hz,
E), 132.7 (t, JC,F = 10.6 Hz, Z), 130.3 (t, JC,F = 2.0 Hz, E), 130.1 (Z),
129.4 (t, JC,F = 28.5 Hz, Z), 129.2 (t, JC,F = 30.0 Hz, E), 124.3 (t,
13C NMR (75 MHz, CDCl3): δ = 163.8 (dd, JC,F = 38.5, 33.0 Hz),
146.2 (dd, JC,F = 13.2, 9.4 Hz), 137.9, 137.8, 137.7, 128.48 (2 C),
128.45 (2 C), 128.2 (2 C), 128.0 (2 C), 127.94, 127.92 (2 C), 127.8,
127.73 (2 C), 127.67, 113.3 (dd, JC,F = 249.8, 248.1 Hz), 106.7 (dd,
J
C,F = 28.5 Hz, E), 121.2 (t, JC,F = 30.0 Hz, Z), 113.8 (Z), 113.4 (E),
JC,F = 26.4, 20.4 Hz), 76.1, 73.9, 73.5, 72.9, 72.1, 69.5, 67.8, 62.6,
112.2 (t, JC,F = 245.3 Hz, Z), 111.2 (t, JC,F = 246.8 Hz, E), 63.3 (Z),
13.7.
63.1 (E), 55.4 (Z), 55.3 (E), 13.9 (Z), 13.7 (E).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –93.6 (d, JFH = 11.3 Hz,
CF2, E), –97.5 (d, JFH = 11.3 Hz, CF2, Z).
HRMS (EI): m/z [M+] calcd for C13H13BrF2O3: 335.9996; found:
335.9993 (–0.9 ppm).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –101.9 (d, JF,F = 257.5
Hz), –109.8 (d, JF,F = 257.5 Hz).
HRMS (ESI+): m/z [M + NH4]+ calcd for C31H36F2NO6: 556.2511;
found: 556.2527 (+2.9 ppm).
Difluoromethylated Vinyl Bromides 4a–n: General Procedure
Cu(OTf)2 (1 equiv), 1,10-phenanthroline (1.1 equiv), and KF (2.1
equiv) were dissolved in DMF (3.2 mL) under air, BrCF2CO2Et (5
equiv) was added, and the tube was sealed. The mixture was stirred
for 15 min at 120 °C in a preheated oil bath then cooled (~15 min).
Alkyne 3 (0.4 mmol, 1 equiv) was added and the mixture was heated
at 120 °C for 2 h. The tube was then cooled to r.t. and the mixture
was diluted with Et2O (15 mL) and H2O (15 mL). The organic layer
was washed successively with H2O (2 × 20 mL) and brine (2 × 20
mL) then extracted with Et2O (2 × 20 mL). The organic layer was
dried (MgSO4) and carefully concentrated under vacuum (Caution:
the products are highly volatile) to give a residue that was purified
by column chromatography. The E/Z ratio was determined by 19F
NMR spectrometric analysis of the crude reaction mixture.
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-(4-tert-butylphe-
nyl)but-3-enoate (4c)
Prepared by following the general procedure from (4-tert-butylphe-
nyl)acetylene (3c) as a mixture of stereoisomers in an E/Z ratio of
68:32. The crude mixture was purified by flash chromatography
(silica gel) to give a colorless oil; yield: 0.114 g (79%); Rf = 0.58
(pentane–Et2O, 19:1).
IR (neat): 2964, 1771, 1641, 1298, 1192, 1068, 686 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.57–7.31 (m, 6.38 H, E and Z),
6.66 (t, JH,F = 11.3 Hz, 0.49 H, Z), 6.49 (t, JH,F = 11.0 Hz, 1 H, E),
4.40 (q, JH,H = 7.2 Hz, 1.03 H, Z), 3.93 (q, JH,H = 7.2 Hz, 2 H, E),
1.38 (t, JH,H = 7.2 Hz, 1.67 H, Z), 1.35–1.33 (m, 13.54 H, E and Z),
1.16 (t, JH,H = 7.2 Hz, 3 H, E).
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-phenylbut-3-eno-
ate (4a)
13C NMR (75 MHz, CDCl3): δ = 162.8 (t, JC,F = 34.1 Hz, Z), 162.5
(t, JC,F = 33.6 Hz, E), 153.9 (Z), 153.3 (E), 134.9 (t, JC,F = 1.1 Hz,
Z), 134.2 (t, JC,F = 1.1 Hz, E), 133.9 (t, JC,F = 11.0 Hz, E), 132.9 (t,
Prepared by following the general procedure from phenylacetylene
(3a) as a mixture of stereoisomers in an E/Z ratio of 69:31. The
crude mixture was purified by column chromatography (silica gel)
to give a colorless oil; yield: 0.119 g (78%); Rf = 0.37 (pentane–
Et2O, 9:1).
J
C,F = 10.5 Hz, Z), 128.4 (t, JC,F = 2.2 Hz, 2 C, E), 127.4 (2 C, Z),
125.3 (2 C, Z), 125.0 (2 C, E), 124.6 (t, JC,F = 28.6 Hz, E), 122.4 (t,
J
J
C,F = 30.3 Hz, Z), 112.1 (t, JC,F = 247.0 Hz, Z), 114.1 (t,
C,F = 248.7 Hz, E), 63.2 (Z), 63.0 (E), 34.8 (Z), 34.7 (E), 31.11 (3
IR (neat): 2988, 1769, 1641, 1446, 1299, 1193, 1067 cm−1.
C, Z), 31.08 (3 C, E), 13.9 (Z), 13.6 (E).
1H NMR (300 MHz, CDCl3): δ = 7.63–7.33 (m, 7.87 H, E and Z),
6.67 (t, JH,F = 11.1 Hz, 0.45 H, Z), 6.51 (t, JH,F = 11.1 Hz, 1 H, E),
19F NMR (282 MHz, CDCl3, CFCl3): δ = –93.2 (d, JFH = 11.0 Hz,
CF2, E), –97.7 (d, JFH = 11.3 Hz, CF2, Z).
Synthesis 2014, 46, 1859–1870
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Copper-Mediated Difluoromethylation
1867
HRMS (EI): m/z [M+] calcd for C16H19BrF2O2: 362.0516; found:
362.0518 (+0.6 ppm).
IR (neat): 2988, 1767, 1680, 1591, 1485, 1300, 1097, 1068, 821
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.54–7.10 (m, 6.56 H, E and Z),
6.58 (t, JH,F = 11.1 Hz, 0.38 H, Z), 6.42 (t, JH,F = 11.5 Hz, 1 H, E),
4.42–4.26 (m, 1.21 H, Z), 4.00 (q, JH,H = 7.2 Hz, 2 H, E), 1.37–1.25
(m, 2.03 H, Z), 1.16 (t, JH,H = 7.2 Hz, 3 H, E).
13C NMR (75 MHz, CDCl3): δ = 162.5 (t, JC,F = 33.3 Hz, Z), 162.4
(t, JC,F = 33.1 Hz, E), 136.8 (Z), 136.1 (E), 133.7 (Z), 132.1 (t,
JC,F = 9.3 Hz, E), 131.8 (Z), 131.4 (E), 130.0 (t, JC,F = 1.9 Hz, E),
129.1 (Z), 125.4 (t, JC,F = 27.8 Hz, E), 124.8 (Z), 124.3 (E), 123.7 (t,
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-(4-fluorophe-
nyl)but-3-enoate (4d)
Prepared by following the general procedure from 1-ethynyl-4-flu-
orobenzene (3d) as a mixture of stereoisomers in an E/Z ratio of
71:29. The crude mixture was purified by flash chromatography
(silica gel) to give a colorless oil; yield: 0.114 g (88%); Rf = 0.67
(pentane–Et2O, 19:1).
IR (neat): 2988, 1769, 1600, 1505, 1299, 1161, 1069, 730 cm−1.
J
C,F = 30.2 Hz, Z), 111.8 (t, JC,F = 246.2 Hz, Z), 110.9 (t,
1H NMR (300 MHz, CDCl3): δ = 7.62–7.57 (m, 0.98 H, E and Z),
7.40–7.36 (m, 2.06 H, E and Z), 7.12–7.02 (m, 3.15 H, E and Z),
6.62 (t, JH,F = 11.0 Hz, 0.46 H, Z), 6.50 (t, JH,F = 11.3 Hz, 1 H, E),
4.40 (q, JH,H = 7.2 Hz, 1.10 H, Z), 4.08 (q, JH,H = 7.2 Hz, 2 H, E),
1.38 (t, JH,H = 7.2 Hz, 1.51 H, Z), 1.24 (t, JH,H = 7.2 Hz, 3 H, E).
JC,F = 248.6 Hz, E), 63.4 (Z), 63.3 (E), 13.9 (Z), 13.7 (E).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –94.8 (d, JFH = 11.5 Hz,
CF2, E), –97.9 (d, JFH = 11.0 Hz, CF2, Z).
HRMS (EI): m/z [M+] calcd for C12H10Br2F2O2: 383.8995; found:
13C NMR (75 MHz, CDCl3): δ = 163.9 (d, JC,F = 252.0 Hz, Z), 163.3
(d, JC,F = 251.4 Hz, E), 162.6 (t, JC,F = 34.1 Hz, Z), 162.5 (t,
383.8988 (–2.0 ppm).
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-(3-methylphe-
nyl)but-3-enoate (4g)
JC,F = 33.0 Hz, E), 134.1 (d, JC,F = 3.9 Hz, Z), 133.3 (t, JC,F = 4.4 Hz,
E), 132.4 (t, JC,F = 9.9 Hz, E), 131.6 (t, JC,F = 10.5 Hz, Z), 130.7 (dt,
JC,F = 8.8, 2.2 Hz, 2 C, E), 129.7 (dt, JC,F = 8.8, 1.1 Hz, 2 C, Z),
125.3 (t, JC,F = 28.1 Hz, E), 123.3 (t, JC,F = 30.3 Hz, Z), 115.6 (d,
Prepared by following the general procedure from 3-ethynyltoluene
(3g) as a mixture of stereoisomers in an E/Z ratio of 70:30. The
crude mixture was purified by column chromatography (silica gel)
to give a light-yellow oil; yield: 0.095 g (75%); Rf = 0.62 (pentane–
Et2O, 9:1).
JC,F = 22.0 Hz, 2 C, Z), 115.3 (d, JC,F = 22.0 Hz, 2 C, E), 111.9 (t,
JC,F = 247.6 Hz, Z), 111.0 (t, JC,F = 249.8 Hz, E), 63.4 (Z), 63.3 (E),
13.9 (Z), 13.7 (E).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –94.8 (d, JFH = 11.3 Hz,
CF2, E), –98.0 (d, JFH = 11.0 Hz, CF2, Z), –110.4 (m, F, E), –110.5
(m, F, Z).
HRMS (EI): m/z [M+] calcd for C12H10BrF3O2: 323.9796; found:
323.9799 (+1.3 ppm).
IR (neat): 2986, 1771, 1640, 1448, 1300, 1189, 1101, 1071, 783
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.48–7.07 (m, 6.70 H, E and Z),
6.65 (t, JH,F = 11.1 Hz, 0.43 H, Z), 6.48 (t, JH,F = 11.1 Hz, 1 H, E),
4.39 (q, JH,H = 7.2 Hz, 1.01 H, Z), 3.96 (q, JH,H = 7.2 Hz, 2 H, E),
2.39 (s, 1.35 H, Z), 2.36 (s, 3 H, E), 1.38 (t, JH,H = 7.2 Hz, 1.63 H,
Z), 1.19 (t, JH,H = 7.2 Hz, 3 H, E).
13C NMR (75 MHz, CDCl3): δ = 162.7 (t, JC,F = 33.8 Hz, Z), 162.4
(t, JC,F = 33.0 Hz, E), 138.4 (Z), 137.9 (E), 137.8 (Z), 137.0 (E),
133.8 (t, JC,F = 10.4 Hz, E), 133.1 (t, JC,F = 10.4 Hz, Z), 131.1 (Z),
130.7 (E), 129.0 (t, JC,F = 1.9 Hz, E), 128.4 (Z), 128.2 (Z), 128.0 (E),
125.6 (t, JC,F = 1.9 Hz, E), 124.84 (t, JC,F = 28.5 Hz, E), 124.82 (Z),
123.0 (t, JC,F = 30.2 Hz, Z), 112.0 (t, JC,F = 245.6 Hz, Z), 111.1 (t,
JC,F = 246.9 Hz, E), 63.3 (Z), 63.0 (E), 21.3 (Z), 21.2 (E), 13.9 (Z),
13.6 (E).
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-[4-(trifluorometh-
yl)phenyl]but-3-enoate (4e)
Prepared by following the general procedure from 1-ethynyl-4-(tri-
fluoromethyl)benzene (3e) as a mixture of stereoisomers in an E/Z
ratio of 72:28. The crude mixture was purified by column chroma-
tography (silica gel) to give a light-yellow oil. This compound and
its isomer were isolated together with an inseparable impurity;
yield: 0.116 g (78%); Rf = 0.66 (pentane–Et2O, 9:1).
IR (neat): 2988, 1769, 1652, 1408, 1322, 1169, 1128, 1066, 835
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.77–7.43 (m, 8.02 H, E and Z),
6.73 (t, JH,F = 10.7 Hz, 0.51 H, Z), 6.55 (t, JH,F = 11.8 Hz, 1 H, E),
4.46–4.31 (m, 1.85 H, Z), 4.11 (q, JH,H = 7.2 Hz, 2 H, E), 1.44–1.33
(m, 2.69 H, Z), 1.24 (t, JH,H = 7.2 Hz, 3 H, E).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –93.9 (d, JFH = 11.1 Hz,
CF2, E), –98.0 (d, JFH = 11.1 Hz, CF2, Z).
HRMS (EI): m/z [M+] calcd for C13H13BrF2O2: 318.0067; found:
318.0072 (+1.6 ppm).
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-(2-methoxyphe-
nyl)but-3-enoate (4h)
13C NMR (75 MHz, CDCl3): δ = 163.6 (t, JC,F = 34.3 Hz, Z), 162.4
(t, JC,F = 33.2 Hz, E), 141.3 (Z), 140.8 (E), 131.8 (q, JC,F = 32.9 Hz,
Z), 131.7 (q, JC,F = 32.5 Hz, E), 131.4 (t, JC,F = 9.0 Hz, E), 131.0 (t,
Prepared by following the general procedure from 2-ethynylanisole
(3h) as a mixture of stereoisomers in an E/Z ratio of 58:42. The
crude mixture was purified by column chromatography (silica gel)
to give a light-yellow oil; yield: 0.109 g (81%); Rf = 0.34 (pentane–
Et2O, 9:1).
JC,F = 10.5 Hz, Z), 128.8 (t, JC,F = 2.3 Hz, E), 128.1 (Z), 125.9 (t,
J
C,F = 27.5 Hz, E), 125.8 (q, JC,F = 3.6 Hz, Z), 125.2 (q, JC,F = 3.8
Hz, E), 123.6 (q, JC,F = 270.8 Hz, E), 121.5 (t, JC,F = 24.8 Hz, Z),
111.7 (t, JC,F = 246.8 Hz, Z), 110.9 (t, JC,F = 249.4 Hz, E), 63.5 (Z),
63.4 (E), 13.9 (Z), 13.7 (E). One carbon of the minor isomer was
overlapped.
IR (neat): 2977, 1770, 1652, 1597, 1490, 1282, 1251, 1067, 752
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.30 (m, 2.34 H, E and Z),
7.24–7.16 (m, 0.94 H, E and Z), 7.04–6.83 (m, 3.40 H, E and Z),
6.61 (t, JH,F = 11.4 Hz, 0.72 H, Z), 6.52 (t, JH,F = 11.4 Hz, 1 H, E),
4.40 (q, JH,H = 7.2 Hz, 1.41 H, Z), 4.05 (q, JH,H = 7.2 Hz, 2 H, E),
3.87 (s, 2.17 H, Z), 3.84 (s, 3 H, E), 1.40 (t, JH,H = 7.2 Hz, 2.10 H,
Z), 1.25 (t, JH,H = 7.2 Hz, 3 H, E).
13C NMR (75 MHz, CDCl3): δ = 162.8 (t, JC,F = 33.9 Hz, Z), 162.5
(t, JC,F = 33.5 Hz, E), 156.3 (Z), 155.8 (E), 131.4 (E), 131.2 (Z),
130.4 (Z), 129.9 (E), 129.4 (t, JC,F = 9.7 Hz, E), 128.2 (t, JC,F = 11.1
Hz, Z), 127.7 (Z), 126.6 (t, JC,F = 30.0 Hz, Z), 126.3 (t, JC,F = 28.5
Hz, E), 125.9 (E), 120.4 (Z), 120.1 (E), 111.9 (t, JC,F = 246.0 Hz, Z),
19F NMR (282 MHz, CDCl3, CFCl3): δ = –63.4 (s, CF3, Z), –63.5 (s,
CF3, E), –95.8 (d, JFH = 11.8 Hz, CF2, E), –98.6 (d, JFH = 10.7 Hz,
CF2, Z).
MS (EI): m/z = 354 [M – F]+.
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-(4-bromophe-
nyl)but-3-enoate (4f)
Prepared by following the general procedure from 4-bromophenyl-
acetylene 3f as a mixture of stereoisomers in an E/Z ratio of 70:30.
The crude mixture was purified by column chromatography (silica
gel) to give a yellow oil; yield: 0.131 g (85%); Rf = 0.82 (pentane–
Et2O, 9:1)
© Georg Thieme Verlag Stuttgart · New York
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1868
M.-C. Belhomme et al.
SPECIAL TOPIC
111.4 (Z), 111.0 (t, JC,F = 246.8 Hz, E), 111.0 (E), 63.2 (Z), 62.9 (E),
55.7 (Z), 55.6 (E), 13.9 (Z), 13.7 (E).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –97.8 (br s, CF2, E), –98.5
(d, JFH = 11.4 Hz, CF2, Z).
(SiO2) to give a colorless oil. This compound and its isomer were
isolated together with an inseparable impurity; yield: 0.054 g
(44%); Rf = 0.46 (pentane–Et2O, 4:1).
IR (neat): 2927, 1770, 1635, 1294, 1071, 774 cm−1.
HRMS (EI): m/z [M+] calcd for C13H13BrF2O3: 335.9996; found:
335.9991 (–1.2 ppm).
1H NMR (300 MHz, CDCl3): δ = 8.63–8.61 (m, Z), 8.48–8.47 (m,
0.71 H, E), 7.87–7.71 (m, 3.75 H, E and Z), 7.63 (t, JH,F = 12.3 Hz,
1 H, Z), 7.34–7.30 (m, 1.50 H, E and Z), 6.63 (t, JH,F = 12.3 Hz, 0.73
H, E), 4.39 (q, JH,H = 7.2 Hz, 2 H, Z), 4.22 (q, JH,H = 7.2 Hz, 1.51 H,
E), 1.37 (t, JH,H = 7.2 Hz, 3 H, Z), 1.24 (t, JH,H = 7.2 Hz, 3H, E).
13C NMR (75 MHz, CDCl3): δ = 162.63 (t, JC,F = 33.6 Hz, Z),
162.55 (t, JC,F = 34.1 Hz, E), 152.7 (Z), 152.5 (E), 149.2 (Z), 147.5
(E), 137.2 (Z), 137.1 (E), 130.6 (t, JC,F = 9.9 Hz, Z), 129.9 (t,
Ethyl (3E)- and (3Z)-4-Bromo-4-(2,4-difluorophenyl)-2,2-di-
fluorobut-3-enoate (4i)
Prepared by following the general procedure from 1-ethynyl-2,4-
difluorobenzene (3i) as a mixture of stereoisomers in an E/Z ratio of
89:11. The crude mixture was purified by column chromatography
(silica gel) to give a light-yellow oil. This compound and its isomer
were isolated together with an inseparable impurity; yield: 0.115 g
(84%); Rf = 0.57 (pentane–Et2O, 9:1).
J
C,F = 10.5 Hz, E), 128.4 (t, JC,F = 30.8 Hz, E), 125.6 (t,
JC,F = 30.3 Hz, Z), 124.5 (Z), 124.1 (E), 124.0 (E), 122.7 (Z), 112.3
(t, JC,F = 247.6 Hz, Z), 111.6 (t, JC,F = 245.4 Hz, E), 63.3 (Z), 62.5
(E), 13.9 (Z), 13.8 (E).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –94.6 (d, JFH = 12.3 Hz,
CF2, E), –98.3 (d, JFH = 12.3 Hz, CF2, Z).
HRMS (ESI+): m/z [M + H]+ calcd for C11H11BrF2NO2: 305.9941;
found: 305.9928 (–1.3 ppm).
IR (neat): 2988, 1769, 1658, 1502, 1296, 1144, 1073, 852 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.51–6.66 (m, 4.39 H, E and Z),
6.53 (t, JH,F = 11.7 Hz, 1 H, E), 4.39–4.21 (m, 0.67 H, Z), 4.11 (q,
JH,H = 7.2 Hz, 2 H, E), 1.36–1.27 (m, 1.01 H, Z), 1.23 (t, JH,H = 7.2
Hz, 3 H, E).
13C NMR (75 MHz, CDCl3): δ = 163.8 (dd, JC,F = 251.7, 11.6 Hz,
E), 162.2 (t, JC,F = 33.6 Hz, E), 159.2 (dd, JC,F = 254.7, 12.4 Hz, Z),
158.8 (dd, JC,F = 252.5, 12.2 Hz, E), 132.2 (d, JC,F = 9.9 Hz, Z),
131.3 (d, JC,F = 10.0 Hz, E), 129.7 (dd, JC,F = 9.8, 4.5 Hz, Z), 128.2
(t, JC,F = 27.2 Hz, E), 124.7 (t, JC,F = 8.6 Hz, E), 121.5 (dd,
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-5-phenylpent-3-
enoate (4l)
Prepared by following the general procedure from prop-2-yn-1-yl-
benzene(3l) as a mixture of stereoisomers in an E/Z ratio of 53:47.
The crude mixture was purified by column chromatography (silica
gel) to give a colorless oil; yield: 0.030 g (23%); Rf = 0.44 (pentane–
Et2O, 9:1).
JC,F = 15.3, 4.1 Hz, E), 111.6 (t, JC,F = 247.6 Hz, Z), 111.4 (dd,
JC,F = 21.7, 3.6 Hz, E), 110.8 (t, JC,F = 249.5 Hz, E), 104.5 (t,
JC,F = 25.5 Hz, Z), 104.3 (t, JC,F = 25.2 Hz, E), 63.4 (E), 63.2 (Z),
13.8 (Z), 13.7 (E). Some signals from the minor isomer overlapped.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –98.9 (d, JFH = 11.7 Hz,
CF2, E), –99.0 (d, JFH = 11.0 Hz, CF2, Z), –106.4 (m, F, E), –106.5
(m, F, Z), –107.6 (m, F, Z), –107.9 (m, F, E).
IR (neat): 2965, 1769, 1663, 1261, 1091, 799 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.37–7.06 (m, 5 H, E and Z), 6.23
(t, JH,F = 13.2 Hz, 1 H, E), 6.14 (t, JH,F = 10.8 Hz, 0.27 H, Z), 4.27
(m, 2.77 H, E and Z), 3.97 (s, 2 H, E), 3.77 (s, 0.5 H, Z), 1.28 (m,
4.17 H, E and Z).
MS (EI): m/z = 341 [M]+.
13C NMR (75 MHz, CDCl3): δ = 163.2 (t, JC,F = 34.3 Hz, E), 162.7
(t, JC,F = 33.9 Hz, Z), 138.2 (t, JC,F = 7.1 Hz, E), 136.0 (E), 135.7
(Z), 134.9 (t, JC,F = 10.3 Hz, Z), 129.1 (Z), 128.9 (E), 128.8 (Z),
128.6 (E), 127.5 (Z), 127.2 (E), 124.5 (t, JC,F = 26.8 Hz, E), 123.9 (t,
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-(3-thienyl)-but-3-
enoate (4j)
Prepared by following the general procedure from 3-ethynylthio-
phene (3j) as a mixture of stereoisomers in an E/Z ratio of 68:32.
The crude mixture was purified by flash chromatography (silica gel)
to give a colorless oil; yield: 0.066 g (53%); Rf = 0.56 (pentane–
Et2O, 19:1).
J
C,F = 30.2 Hz, Z), 111.7 (t, JC,F = 245.7 Hz, Z), 111.5 (t,
J
C,F = 250.2 Hz, E), 63.6 (E), 63.2 (Z), 48.4 (Z), 43.1 (E), 13.9 (E),
13.8 (Z).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –97.5 (d, JFH = 13.2 Hz,
CF2, E), –97.9 (d, JFH = 10.8 Hz, CF2, Z).
MS (EI): m/z = 320 [M]+.
HRMS (EI): m/z [M – Br]+ calcd for C13H13F2O2: 239.0884; found:
239.0886 (+1.1 ppm).
IR (neat): 2988, 1766, 1635, 1291, 1190, 1098, 684 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.67–7.66 (m, 0.46 H, Z), 7.51
(dd, JH,F = 3.0, 1.3 Hz, 1 H, E), 7.40–7.28 (m, 2.13 H, E and Z), 7.17
(dd, JH,F = 5.1, 1.3 Hz, 1 H, E), 6.70 (t, JH,F = 11.3 Hz, 0.49 H, Z),
6.46 (t, JH,F = 11.0 Hz, 1 H, E), 4.39 (q, JH,H = 7.2 Hz, 1.05 H, Z),
4.06 (q, JH,H = 7.2 Hz, 2 H, E), 1.38 (t, JH,H = 7.2 Hz, 1.59 H, Z),
1.21 (t, JH,H = 7.2 Hz, 3 H, E).
13C NMR (75 MHz, CDCl3): δ = 162.8 (t, JC,F = 33.6 Hz, Z), 162.4
(t, JC,F = 34.7 Hz, E), 139.1 (Z), 136.8 (E), 128.1 (t, JC,F = 1.7 Hz,
Z), 127.8 (t, JC,F = 10.5 Hz, E), 127.7 (t, JC,F = 2.8 Hz, E), 127.0 (E),
126.9 (Z), 126.1 (t, JC,F = 10.5 Hz, Z), 125.9 (E), 125.2 (Z), 125.0 (t,
Ethyl (3E)- and (3Z)-4-Bromo-3-ethyl-2,2-difluoro-4-phenyl-
but-3-enoate (4m)
Prepared by following the general procedure from 1-phenylbutyne
(3m) as a mixture of stereoisomers in an E/Z ratio of 83:17. The
crude mixture was purified by column chromatography (silica gel)
to give a colorless oil; yield: 0.066 g (49%); Rf = 0.71 (pentane–
Et2O, 9:1).
JC,F = 29.2 Hz, E), 121.2 (t, JC,F = 30.3 Hz, Z), 112.2 (t, JC,F = 247.0
Hz, Z), 111.2 (t, JC,F = 248.1 Hz, E), 63.3 (Z), 63.2 (E), 13.9 (Z),
13.7 (E).
IR (neat): 2983, 1773, 1638, 1445, 1227, 1122, 1073, 763 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.52–7.14 (m, 6.90 H, E and Z),
4.41 (q, JH,H = 7.2 Hz, 0.50 H, Z), 3.87 (q, JH,H = 7.2 Hz, 2 H, E),
2.65 (q, JH,H = 7.5 Hz, 0.50 H, E), 2.23 (q, JH,H = 7.5 Hz, 2 H, Z),
1.41 (t, JH,H = 7.2 Hz, 1.76 H, Z), 1.24 (t, JH,H = 7.5 Hz, 3 H, E),
1.18 (t, JH,H = 7.2 Hz, 1.76 H, E), 1.06 (t, JH,H = 7.5 Hz, 3 H, Z).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –93.3 (d, JFH = 11.0 Hz,
CF2, E), –97.6 (d, JFH = 11.3 Hz, CF2, Z).
HRMS (EI): m/z [M+] calcd for C10H9BrF2O2S: 309.9475; found:
309.9479 (+1.3 ppm).
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-4-pyridin-2-yl-but-
3-enoate (4k)
Prepared by following the general procedure from 2-
ethynylpyridine (3k) as a mixture of diastereoisomers in a Z/E ratio
of 59:41. The crude mixture was purified by flash chromatography
13C NMR (75 MHz, CDCl3): δ = 163.2 (t, JC,F = 33.8 Hz, Z), 162.8
(t, JC,F = 33.5 Hz, E), 139.8 (Z), 138.8 (E), 137.6 (t, JC,F = 23.9 Hz,
Z), 136.0 (t, JC,F = 23.6 Hz, E), 131.7, 129.9 (t, JC,F = 8.5 Hz), 129.2
(t, JC,F = 1.7 Hz, E), 128.9 (Z), 128.6 (Z), 127.94 (E), 127.88 (t,
J
C,F = 1.2 Hz, Z), 113.6 (t, JC,F = 250.6 Hz, Z), 112.6 (t, JC,F = 251.0
Synthesis 2014, 46, 1859–1870
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Copper-Mediated Difluoromethylation
1869
Hz, E), 63.1 (Z), 62.8 (E), 26.8 (t, JC,F = 3.4 Hz, E), 24.7 (t,
JC,F = 4.1 Hz, Z), 13.9 (Z), 13.8 (Z), 13.6 (E), 12.2 (E). Note that one
carbon is overlapped.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –93.9 (s, CF2, E), –99.9 (s,
CF2, Z).
MS (EI): m/z = 253 [M-Br]+.
HRMS (EI): m/z [M – Br]+ calcd for C14H15F2O2: 253.1040; found:
HRMS (EI): m/z [M+] calcd for C12H10F2O2: 224.0649; found:
224.0647 (–0.7 ppm).
Ethyl 2,2-Difluoro-4-(4-(trifluoromethyl)phenyl)but-3-ynoate
(5b)
Yellow oil; yield: 22% (19F NMR); Rf = 0.65 (pentane–Et2O, 95:5).
IR (neat): 2932, 1658, 1410, 1387, 1256, 1166, 1094 cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.77–7.57 (m, 4 H), 4.42 (q,
253.1042 (+0.6 ppm).
J
H,H = 7.2 Hz, 2 H), 1.41 (t, JH,H = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 162.2 (t, JC,F = 33.2 Hz), 132.70 (t,
C,F = 1.9 Hz), 132.67 (q, JC,F = 33.2 Hz), 125.5 (q, JC,F = 3.7 Hz),
Ethyl (3E)- and (3Z)-4-Bromo-2,2-difluoro-3,4-diphenylbut-3-
enoate (4n)
J
Prepared by following the general procedure from diphenylacetyl-
ene (3n) as a mixture of stereoisomers in an E/Z ratio of 75:25. The
crude mixture was purified by column chromatography (silica gel)
to give a colorless oil; yield: 0.056 g (36%); Rf = 0.53 (pentane–
Et2O, 9:1).
121.7, 104.7 (t, JC,F = 241.8 Hz), 87.6, 80.3 (t, JC,F = 37.5 Hz), 64.0,
13.9. One carbon is overlapped.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –63.2 (s, CF3), –90.6 (s).
MS (EI): m/z = 292 [M]+.
HRMS (EI): m/z [M+] calcd for C13H9F5O2: 292.0523; found:
IR (neat): 2988, 1772, 1635, 1445, 1265, 1148, 1084, 715 cm−1.
292.0518 (–1.6 ppm).
1H NMR (300 MHz, CDCl3): δ = 7.60–7.32 (m, 10.72 H, E and Z),
7.23–7.05 (m, 3.52 H, E and Z), 4.45 (q, JH,H = 7.2 Hz, 0.67 H, Z),
3.90 (q, JH,H = 7.2 Hz, 2 H, E), 1.44 (t, JH,H = 7.2 Hz, 1.17 H, Z),
1.16 (t, JH,H = 7.2 Hz, 3 H, E).
Ethyl 4-(4-Cyanophenyl)-2,2-difluorobut-3-ynoate (5c)
Yellow oil; yield: 18% (19F NMR); Rf = 0.32 (pentane–Et2O,
90:10).
13C NMR (75 MHz, CDCl3): δ = 163.2 (t, JC,F = 33.8 Hz, Z), 162.7
(t, JC,F = 33.3 Hz, E), 139.4 (Z), 138.5 (E), 137.1 (Z), 136.6 (E),
135.8 (t, JC,F = 24.8 Hz, E), 134.5 (t, JC,F = 2.3 Hz, Z), 132.7 (t,
IR (neat): 2993, 2234, 1718, 1658, 1596, 1276, 1178, 1142, 938
cm−1.
1H NMR (300 MHz, CDCl3): δ = 7.77–7.59 (m, 4 H), 4.42 (q,
JH,H = 7.2 Hz, 2 H), 1.41 (t, JH,H = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 132.9, 132.2, 64.1, 13.9. Only a
few signals were observed.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –90.8 (s).
MS (EI): m/z = 249 [M]+.
HRMS (EI): m/z [M+] calcd for C13H9F2NO2: 249.0601; found:
JC,F = 6.5 Hz, E), 131.6 (Z), 130.4 (Z), 129.52 (E), 129.48 (E), 129.2
(Z), 128.9 (t, JC,F = 2.0 Hz, E), 128.62 (E), 128.57 (Z), 128.4 (E),
128.1 (E), 128.0 (Z), 127.9 (Z), 127.8 (Z), 112.4 (t, JC,F = 256.5 Hz,
Z), 111.6 (t, JC,F = 253.9 Hz, E), 63.3 (Z), 63.0 (E), 13.9 (Z), 13.6
(E).
19F NMR (282 MHz, CDCl3, CFCl3): δ = –91.7 (s, CF2, E), –96.5 (s,
CF2, Z).
MS (EI): m/z = 380 [M]+.
HRMS (EI): m/z [M – Br]+ calcd for C18H15F2O2: 301.1040; found:
249.0597 (–1.9 ppm).
301.1028 (–4.0 ppm).
Acknowledgment
Ethyl 4-Aryl-2,2-difluorobut-3-ynoates 5a–c; General Proce-
dure
This work has been partially supported by INSA de Rouen, Univer-
sité de Rouen, CNRS, LABEX SynOrg (ANR-11-LABX-0029) and
Région Haute-Normandie (CRUNCh network). M.-C.B. thanks the
MESR for a doctoral fellowship. D.D. thanks the LABEX SynOrg
for an undergraduate fellowship. H.-Y.X thanks the China Scholar-
ship Council for a doctoral fellowship. The contribution of Monya
Harouel (INSA Rouen) in performing preliminary experiments is
gratefully acknowledged.
A 10 mL Schlenk flask was charged with Cu(acac)2 (0.005 g, 0.02
mmol, 10 mol%), 1,10-phenanthroline (0.004 g, 0.022 mmol, 11
mol%), Cu(OAc)2 (0.054 g, 1.5 equiv), NaOAc (0.034 g, 2.1 equiv),
and DMF (2 mL) under air. Alkyne 3 (0.2 mmol) and BrCF2CO2Et
(5 equiv) were added, and the reactor was closed and held at 100 °C
for 16 h. (Note: Solid alkynes were added in the Schlenk flask be-
fore the solvent.) The reactor was then cooled to r.t. and the mixture
was diluted with Et2O (15 mL) and H2O (15 mL). The organic layer
was washed successively with H2O (2 × 20 mL) and brine (2 × 20
mL), and then the aqueous layers were combined and extracted with
Et2O (2 × 20 mL). The organic layer was dried (MgSO4) and the sol-
vent was carefully removed under vacuum (Caution: the products
are highly volatile). Analyses for characterization of the products
were performed on a pure fraction obtained by purification by col-
umn chromatography [pentane to pentane–Et2O (9:1)].
Supporting Information for this article is available online
at
http://www.thieme-connect.com/products/ejournals/journal/
10.1055/s-00000084.SunogIpimrfiantoSuIpg
n
fonirtat
ori
References
(1) These authors contributed equally.
Ethyl 2,2-Difluoro-4-phenylbut-3-ynoate (5a)
Colorless oil; yield: 29% (19F NMR); Rf = 0.19 (pentane–Et2O,
95:5).
IR (neat): 2987, 2242, 1772, 1491, 1446, 1273, 1141, 1076 cm−1.
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1859–1870

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SPECIAL TOPIC
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Synthesis 2014, 46, 1859–1870
© Georg Thieme Verlag Stuttgart · New York