Copper-catalyzed direct C-2 difluoromethylation of furans and benzofurans: Access to C-2 CF2H derivatives

Article abstract of DOI:10.1021/jo5010907

We report herein the first copper-catalyzed C-2 difluoromethylation of furans and benzofurans. The developed methodology allows the selective introduction of the CF₂CO₂Et moiety at C-2 using CuI as a catalyst. This process was applie

Full text of DOI:10.1021/jo5010907

Note
pubs.acs.org/joc
Copper-Catalyzed Direct C‑2 Difluoromethylation of Furans and
Benzofurans: Access to C‑2 CF2H Derivatives
Marie-Charlotte Belhomme, Thomas Poisson,* and Xavier Pannecoucke*
́ ́ ̀
Normandie Universite, COBRA, UMR 6014 et FR 3038; Universite de Rouen; INSA Rouen; CNRS, 1 rue Tesniere, 76821 Mont
Saint-Aignan Cedex, France
S
* Supporting Information
ABSTRACT: We report herein the first copper-catalyzed C-2
difluoromethylation of furans and benzofurans. The developed
methodology allows the selective introduction of the
CF2CO2Et moiety at C-2 using CuI as a catalyst. This process
was applied to a broad range of furans and benzofurans, giving
the functionalized products in moderate to good yields. The
resulting products were then decarboxylated to afford the
highly valuable C-2-CF2H-substituted furans and benzofurans
in good yields.
Scheme 1. Fluorofunctionalization of Furans and
BenzofuransState of the Art
luorine atom is very popular for modifying the properties of
Fbioactive compounds. Indeed, the electronegativity and size
of the F atom and the high energy of the C−F bond provide to
the fluorine atom a significant ability to modify the biological and
physical properties of a molecule.1 Hence, it is not surprising to
find this intriguing atom on more than 20% of pharmaceuticals
and 30% of agrochemicals.2 Thus, several methodologies have
been developed to introduce fluorinated building blocks and
particularly the CF3 group.3 Among all of these methodologies,
the introduction of fluorinated moieties by means of direct C−H
bond functionalization has become one of the most popular
approaches.3d−h Besides, furans and benzofurans are an
important class of heterocycles. Those two oxygenated rings
are encountered in several bioactive and natural compounds4 and
are versatile building blocks in organic chemistry and materials
science.5 Therefore, it is not surprising that a lot of effort has been
devoted to accessing highly functionalized derivatives in order to
improve the molecular diversity.6 The usual way to access these
backbones mainly focuses on the construction of the oxygenated
ring, and the most popular strategies remain (1) base-promoted
dehydrative cyclization of functionalized ethers7 and (2)
transition-metal-catalyzed cyclization of arylacetylene deriva-
tives.8 Recently, several interesting and elegant methodologies
involving C−H bond functionalization have been reported to
offer a new access to these valuable highly functionalized
products. This reaction manifold mainly focuses on the
introduction of aryl9 and alkyne10 derivatives at either the C-2
or C-3 position. Quite surprisingly, among these elegant
methodologies, only a few reports dealing with the direct
introduction of fluorinated building blocks onto furan and
benzofuran derivatives have been described to date (Scheme 1).
Most of these reports focus on the radical introduction of the CF3
moiety on furans and benzofurans.11 Moreover, only three
reports depict the radical introduction of the CF2CO2Et moiety
on the benzofuran ring (Scheme 1).12
As part of our research program devoted to the development
of new straightforward access to fluorinated molecules,13 we
report herein our contribution toward the copper-catalyzed
direct and selective C-2 introduction of the difluoromethyl motif,
a potential CF2H precursor for instance, on furans and
benzofurans.
Received: May 18, 2014
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
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At the outset of the study, benzofuran (1a) was chosen as a
model substrate to optimize the reaction conditions (Table 1).
smoothly to afford the difluorinated benzofuran 2b in 61% yield,
while 2-methylbenzofuran was unreactive under our reaction
conditions, thus highlighting the C-2 selectivity of our process.
Benzofuran 1c bearing a phenyl substituent at C-5 gave the
corresponding product 2c in modest yield (36%). 3-Phenyl-
benzofuran (1d) was tested and gave 2d in 67% isolated yield.
When the reaction was performed on a larger scale (2.5 g, 12.7
mmol), similar results were obtained, highlighting the efficiency
of the difluoromethylation process. The 4-bromophenyl
derivative 1e gave fluorinated benzofuran 2e in similar yield
(62%). It is noteworthy that no alteration of the bromine
substituent was observed, showing the compatibility of our
process with brominated substrates. Finally, the difluoromethy-
lation reaction was carried out with benzofuran 1f providing the
polysubstituted benzofuran 2f in a decent 62% yield and a 68%
yield on a gram scale. It is worthy of note that the crystal structure
of 2f was determined by X-ray crystallographic analysis and
confirmed the C-2 selectivity of the reaction.15
Next, we turned our attention to the furan backbone. First, the
reaction with furan (1g) was carried out under slightly modified
conditions (60 °C instead of 80 °C) and gave fluorinated furan
2g in 52% yield, despite the high volatility of the product. 2-
Methylfuran (1h) and 2,3-dimethylfuran (1i) reacted smoothly
to afford the difluoromethylated products 2h and 2i in 61% and
52% yield, respectively. Then, several O-protected 2-hydrox-
ymethylfurans were screened, and the reaction proceeded well
with all of the protecting groups. The O-benzyl derivative 2j was
isolated in 64% yield, while the O-MOM derivative 2k was
obtained in 65% yield. One should note that reaction performed
with 1j on a 2 g scale (10 mmol) gave the desired product in 70%
yield. The acetyl moiety was also compatible, and fluorinated
furan 2l was obtained in 63% yield. Then, C-3-substituted furan
2m was tested and gave a 66:34 mixture of the C-2 and C-5
regioisomers in 45% yield (66% based on the recovered starting
material). This result might be explained by the stability of the
putative carbocation resulting from the nucleophilic attack of the
aromatic ring on a highly electrophilic Cu(III) species (vide
infra). Finally, furans bearing aromatic substituents were tested.
2-Phenylfuran (1n) gave the C-5-difluoromethylated furan 2n in
58% yield. Similarly, furans 1o and 1p reacted nicely to give the
corresponding fluorinated furans 2o and 2p in 59% and 61%
yield, respectively.
a
Table 1. Optimization of the Reaction Conditions
b
entry
metal
base
solvent
yield (%)
1
2
Pd(PPh3)4
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
KH2PO4
2,6-lutidine
K2CO3
K2CO3
K2CO3
K2CO3
−
DMF
DMF
NMP
dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
−
c
CuI
51 (50 )
3
CuI
21
8
4
CuI
5
CuI
23
43
17
45
33
33
NR
NR
NR
6
CuI
7
CuI
8
CuCl
9
[Cu(OTf)]2.C6H6
10
11
12
Cu(OTf)2
−
CuI
d
13
CuI
K2CO3
a
Conditions: 1a (0.24 mmol), metal catalyst (0.024 mmol), 3 (mmol),
BrCF2CO2Et (1.92 mmol), base (0.48 mmol), solvent (1.2 mL), 80
b
°C, 20 h, air atmosphere. Yields were determined by 19F NMR using
α,α,α-trifluorotoluene as an internal standard. NR = no reaction.
c
d
Isolated yield. Reaction was performed without 1,10-phenanthroline.
First, the reaction was carried out in the presence of palladium
catalysts such as Pd(PPh3)4 (entry 1). Unfortunately, despite all
our attempts, no traces of the product were observed. To tackle
this lack of reactivity, we turned our attention to copper catalysts.
Indeed, we envisioned that the reaction might proceed through
an electrophilic metalation. Thus, copper catalysts might be more
efficient than palladium catalysts through the formation of highly
electrophilic Cu(III) species. After extensive investigations, we
were pleased to find that the CuI/1,10-phenanthroline (3)
system gave the C-2-CF2-substituted benzofuran 2a in 50%
isolated yield (entry 2). Next, a survey of solvents revealed that
DMF is the most adequate solvent for this transformation. For
instance, when the reaction was performed in NMP or dioxane,
the product was obtained in 21% or 8% yield, respectively
(entries 3 and 4). The nature of the base also played an important
role in this reaction. Among all of the inorganic bases tested,
K2CO3 was the most efficient for this reaction (entries 2, 5, and
6). In addition, lower yields were observed with organic bases
such as 2,6-lutidine (entry 7). Next, different copper catalysts
were examined. CuCl led to the formation of 2a in a yield
comparable to that with CuI (45%; entry 8), whereas both
[Cu(OTf)]2·C6H6 and Cu(OTf)2 gave lower yields (33%;
entries 9 and 10). The effectiveness of Cu(I) and Cu(II)
indicated that Cu(I) might be the active catalyst, probably
involving a Cu(I)/Cu(III) catalytic cycle.14 As expected, control
experiments revealed that no reaction occurred in the absence of
the copper catalyst or the base (entries 11 and 12). Finally, it was
noted that 1,10-phenanthroline (3) plays a crucial role in this
reaction, as no product was observed in the absence of this ligand
(entry 13).
To gain insight into the reaction pathway, the reaction was
carried out in the presence of radical inhibitors or scavengers
(Scheme 3). When the reaction was performed with 1 equiv of
TEMPO under the standard conditions, no deleterious effect was
observed, and benzofuran 2a was obtained in a slightly decreased
yield (40%); tert-butylhydroxytoluene (TBHT) led to similar
observations. It is noteworthy that no trace of the TEMPO−
CF2CO2Et adduct was detected in the crude reaction mixture.
Thus, taking into account these observations, we envisaged the
following reaction pathway: The Cu(I) catalyst reacts with ethyl
bromodifluoroacetate to form the Cu(III) species A.13a,16 The
furan or benzofuran 1 undergoes nucleophilic addition to the
metal center to give the most stabilized carbocation B. The base
reacts with B to form intermediate C, which undergoes reductive
elimination to deliver compound 2 and release the copper
catalyst.17
Finally, to highlight the versatility of these fluorinated
scaffolds, we turned our attention to transformation of the
ester into the valuable CF2H moiety.18 Indeed, the CF2H moiety
is well-appreciated in isostere-based drug design. The CF2H
group is recognized as a bioisostere of alcohol and thiol moieties
With these optimized conditions in hand, we moved on the
extension of the scope of the reaction to several benzofurans and
furans (Scheme 2). First, benzofuran derivatives were placed
under our reaction conditions. 3-Methylbenzofuran (1b) reacted
B
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Scheme 2. Scope of the Reaction
a
b
c
d
Isolated yield. Reaction was performed on a 2.5 g scale (12.7 mmol). Reaction was performed on a 1 g scale (4.1 mmol). Reaction was
e
f
performed at 60 °C. Reaction was performed on a 2 g scale (10 mmol). 2m was obtained as a 66:34 mixture of the C-2 and C-5 isomers; the major
isomer is shown.
and might behave as a lipohilic hydrogen-bond donor.19
Therefore, increasing attention has been recently paid to the
design of new access to these relevant CF2H compounds,20 and
several commercial pharmaceuticals21a,b and a drug candidate21c
bearing this motif have recently appeared. Thus, we decided to
convert the difluoroacetyl group into the CF2H moiety through a
saponification/decarboxylation sequence (Scheme 4). To
achieve the formation of the CF2H moiety from the CF2CO2Et
group, benzofuran 2a was first converted into the corresponding
acid 3a in quantitative yield, and 3a was directly engaged in a
CsF-mediated decarboxylation reaction.22 Pleasingly, the C-2-
CF2H-substituted benzofuran 4a was isolated in 65% yield. Then
the decarboxylation process was successfully applied to
benzofurans 3b and 3c, giving the decarboxylated products 4b
and 4c in 85% and 64% yield, respectively. Finally, this process
was applied to furan 3d, providing the C-2-CF2H-substituted
furan 4d in 47% isolated yield; the modest yield was due to the
high volatility of the product.
benzofuran skeletons. This reaction proved to be C-2-selective,
and the resulting products were obtained in moderate to good
yields. Moreover, the reaction proved to be efficient on larger
scales (up to 2.5 g). In addition, several functional groups were
tolerated under our conditions. Subsequently, the difluoracetyl
group was readily converted into the valuable CF2H group by
decarboxylation, affording a unique access to the CF2H-
substituted furan and benzofuran derivatives.
EXPERIMENTAL SECTION
■
Residual CHCl3 served as the internal standard for 1H NMR (δ 7.26),
and CFCl3 served as the internal standard for 19F NMR (δ 0.0); CDCl3
was used as the internal standard for 13C NMR (δ 77.0). Flash
chromatography was performed with silica gel (0.063−0.200 mm).
Analytical thin-layer chromatography (TLC) was performed on silica gel
aluminum plates with F-254 indicator and visualization by UV
fluorescence and/or staining with KMnO4 or PMA. HRMS analyses
were performed under ESI conditions with a micro-TOF detector. All
experiments were conducted in oven-dried glassware with magnetic
stirring. 5-Phenylbenzofuran,10b 3-phenylbenzofuran,10b,23 3-(4-
bromophenyl)benzofuran,24 2-(benzyloxymethyl)furan,25 2-
In summary, we have reported the first copper-catalyzed direct
introduction of the CF2CO2Et moiety onto furan and
C
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combined organic layers were washed with brine (30 mL) and dried over
MgSO4. The solvent was removed under vacuum, and the residue was
purified by flash chromatography (petroleum ether/ethyl acetate 19:1,
Rf = 0.44) to afford 1f as a colorless oil in 39% yield (109 mg). 1H NMR
(CDCl3, 300 MHz): δ 7.70 (s, 1H), 7.61−7.58 (m, 2H, Ph), 7.50−7.45
(m, 2H, Ph), 7.40−7.34 (m, 1H, Ph), 7.19 (s, 1H), 7.04 (s, 1H), 6.02 (s,
2H). 13C NMR (CDCl3, 75 MHz): δ 150.9, 146.3, 144.8, 140.7, 132.0,
128.9 (2C), 127.30, 127.25 (2C), 122.6, 119.6, 101.3, 98.7, 93.7. IR
(neat, cm−1): 2910, 1553, 1463, 1150. HRMS (EI): calcd for [M]
C15H10O3, 238.0630; found, 238.0637 (+2.9 ppm).
Scheme 3. Mechanistic Experiments and Proposed
Mechanism
2-(2-Fluoro-4-methoxyphenyl)furan (1p). A sealed tube was
charged with 2-fluoro-4-methoxyphenylboronic acid (277 mg, 1.63
mmol), P(PPh3)4 (157 mg, 0.14 mmol), K2CO3 (376 mg, 2.72 mmol),
DMF (5 mL), and H2O (2 mL). After the mixture was degassed with N2,
2-bromofuran (200 mg, 1.36 mmol) was added, and the tube was sealed.
The resulting mixture was heated at 80 °C for 12 h. The solution was
cooled, filtered through a plug of Celite, and extracted with Et2O (3 × 15
mL). The organic layer was washed with water (2 × 15 mL) and brine (2
× 15 mL) and dried over MgSO4. The solvent was removed under
vacuum, and the residue was purified by flash chromatography
(petroleum ether/ethyl acetate 19:1, Rf = 0.44) to afford 1p as a
1
colorless oil in 46% yield (119 mg). H NMR (CDCl3, 300 MHz): δ
7.73 (t, 1H, J = 8.7 Hz), 7.47 (d, 1H, J = 1.5 Hz), 6.78−6.67 (m, 3H),
6.50 (dd, 1H, J = 3.4, 1.5 Hz), 3.84 (s, 3H, OMe). 13C NMR (CDCl3, 75
MHz): δ 159.7 (d, JCF = 11.0 Hz), 159.2 (d, JCF = 249.8 Hz), 148.2 (d,
JCF = 3.3 Hz), 141.2, 126.6 (d, JCF = 4.9 Hz), 112.1 (d, JCF = 13.2 Hz),
Scheme 4. Decarboxylation ReactionEasy Access to the
111.7, 110.1 (d, JCF = 2.8 Hz), 108.0 (d, JCF = 10.6 Hz), 102.0 (d, JCF
=
25.9 Hz), 55.5 (d, JCF = 3.9 Hz). 19F NMR (CDCl3, CFCl3, 282 MHz): δ
−112.6 (s, 1F). IR (neat, cm−1): 2842, 1629, 1287, 1024. HRMS (EI):
calcd for [M] C11H9FO2, 192.0587; found, 192.0592 (+2.6 ppm).
General Procedure A: Copper-Catalyzed Difluoromethyla-
tion Reaction of Benzofurans and Furans. Under an air
atmosphere, CuI (5 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). Then the benzofuran or furan derivative (0.24 mmol) and
ethyl bromodifluoroacetate (0.25 mL, 1.92 mmol) were added, and the
tube was sealed. The resulting mixture was heated at 80 °C for 20 h. The
solution was cooled and extracted with Et2O (3 × 10 mL). The organic
layer was washed with water (2 × 10 mL) and brine (2 × 10 mL) and
dried over MgSO4. The solvent was removed under vacuum, and the
residue was purified by flash chromatography (SiO2, petroleum ether/
ethyl acetate or pentane/diethyl ether).
CF2H Derivatives
Ethyl 2-(Benzofuran-2-yl)-2,2-difluoroacetate (2a). Prepared fol-
lowing general procedure A from benzofuran 1a. Compound 2a was
obtained as a colorless oil in 50% yield (29 mg) after flash
chromatography (SiO2, petroleum ether/ethyl acetate 19:1, Rf =
a
Isolated yield.
1
((methoxymethoxy)methyl)furan,26 3-(benzyloxymethyl)furan,27 2-
phenylfuran,28 and 2-(4-methoxyphenyl)furan24 were prepared accord-
ing to the known procedures.
0.57). H NMR (CDCl3, 300 MHz): δ 7.66 (d, 1H, J = 7.7 Hz), 7.56
(d, 1H, J = 8.3 Hz), 7.42 (t, 1H, J = 7.7 Hz), 7.32 (t, 1H, J = 8.3 Hz), 7.16
(s, 1H), 4.42 (q, 2H, J = 7.2 Hz), 1.38 (t, 3H, J = 7.2 Hz). 13C NMR
(CDCl3, 75 MHz): δ 162.1 (t, JCF = 33.7 Hz), 155.4 (t, JCF = 1.1 Hz),
146.5 (dd, JCF = 33.4, 33.4 Hz), 126.5, 126.4, 123.7, 122.3, 112.0, 108.9
(t, JCF = 249.2 Hz), 108.1 (t, JCF = 3.9 Hz), 63.7, 13.9. 19F NMR (CDCl3,
CFCl3, 282 MHz): δ −104.6 (s, 2F). IR (neat, cm−1): 2986, 1770, 1292,
1105. HRMS (ESI+): calcd for [M + H]+ C12H11F2O3, 241.0676; found,
241.0686 (+4.1 ppm).
Ethyl 2,2-Difluoro-2-(3-methylbenzofuran-2-yl)acetate (2b). Pre-
pared following general procedure A from 3-methylbenzofuran (1b).
Compound 2b was obtained as a colorless oil in 61% yield (37 mg) after
flash chromatography (SiO2, petroleum ether/ethyl acetate 49:1, Rf =
0.38). 1H NMR (CDCl3, 300 MHz): δ 7.60 (d, 1H, J = 7.7 Hz), 7.50 (d,
1H, J = 8.1 Hz), 7.41 (t, 1H, J = 7.7 Hz), 7.32 (t, 1H, J = 8.1 Hz), 4.41 (q,
2H, J = 7.2 Hz), 2.43 (s, 3H), 1.37 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3,
75 MHz): δ 162.5 (t, JCF = 34.1 Hz), 154.2, 140.9 (t, JCF = 32.5 Hz),
α-O-(3,4-Dioxal)acetophenone. A solution of 2-bromoacetophe-
none (4.1 g, 21 mmol), sesamol (2.9 g, 21 mmol), and potassium
carbonate (4.3 g, 31 mmol) in acetone (30 mL) was refluxed for 6 h. The
reaction mixture was cooled to room temperature, poured into water,
and extracted with Et2O (3 × 100 mL). The combined organic layers
were washed with water (100 mL) and brine (100 mL) and dried over
MgSO4. The solvent was removed under vacuum, and the solid was
recrystallized from 2-propanol to afforδ α-O-(3,4-dioxal)acetophenone
as a yellow solid in 65% yield (3.5 g). 1H NMR (CDCl3, 300 MHz): δ
8.02−7.98 (m, 2H, Ph), 7.63 (tt, 1H, Ph, J = 7.2, 2.3 Hz), 7.53−7.48 (m,
2H, Ph), 6.69 (d, 1H, J = 8.3 Hz), 6.58 (d, 1H, J = 2.6 Hz), 6.36 (dd, 1H, J
= 8.3, 2.6 Hz), 5.92 (s, 2H), 5.21 (s, 2H). 13C NMR (CDCl3, 75 MHz): δ
194.5, 153.4, 148.3, 142.3, 134.4, 133.8, 128.7 (2C), 128.0 (2C), 107.8,
106.0, 101.2, 98.5, 71.7. IR (neat, cm−1): 2904, 1701, 1486, 1184.
HRMS (EI): calcd for [M] C15H12O4, 256.0736; found, 256.0732 (−1.6
ppm). Mp: 75−76 °C.
128.9, 126.3, 123.1, 120.3, 118.1 (t, JCF = 2.2 Hz), 111.8, 110.4 (t, JCF
=
249.8 Hz), 63.6, 13.9, 7.7. 19F NMR (CDCl3, CFCl3, 282 MHz): δ
−103.9 (s, 2F). IR (neat, cm−1): 2987, 1767, 1287, 1093. HRMS (AP+):
calcd for [M + H]+ C13H13F2O3, 255.0833; found, 255.0834 (+0.4
ppm).
7-Phenylfuro[2,3-f ]-1,3-benzodioxole (1f). BCl3 (1.4 mL, 1.40
mmol, 1 M in DCM) was added dropwise to a solution of α-O-(3,4-
dioxal)acetophenone (300 mg, 1.17 mmol) in DCM (10.5 mL) at −78
°C. After 30 min at room temperature, the reaction mixture was
quenched with cold water and extracted with DCM (3 × 20 mL). The
Ethyl 2,2-Difluoro-2-(5-phenylbenzofuran-2-yl)acetate (2c). Pre-
pared following general procedure A from 5-phenylbenzofuran (1c),
D
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except that the reaction mixture was heated at 80 °C for 15 h instead of
20 h. Compound 2c was obtained as a colorless oil in 36% yield (27 mg)
after flash chromatography (SiO2, petroleum ether/ethyl acetate 19:1, Rf
= 0.35). 1H NMR (CDCl3, 300 MHz): δ 7.84 (s, 1H), 7.66−7.60 (m,
4H), 7.48 (t, 2H, J = 7.6 Hz), 7.38 (tt, 1H, J = 7.6, 1.3 Hz), 7.21 (s, 1H),
4.43 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75
MHz): δ 162.1 (t, JCF = 33.0 Hz), 155.0, 147.0 (t, JCF = 33.6 Hz), 141.0,
137.6, 128.8 (2C), 127.4 (2C), 127.2, 127.1, 126.2, 120.6, 112.1, 108.8
(t, JCF = 249.2 Hz), 108.3 (t, JCF = 3.3 Hz), 63.8, 13.9. 19F NMR (CDCl3,
CFCl3, 282 MHz): δ −104.7 (s, 2F). IR (neat, cm−1): 2988, 1777, 1288,
1113. HRMS (AP+): calcd for [M + H]+ C18H15F2O3, 317.0989; found,
317.0994 (+1.6 ppm).
Ethyl 2,2-Difluoro-2-(3-phenylbenzofuran-2-yl)acetate (2d). Pre-
pared following general procedure A from 3-phenylbenzofuran (1d).
Compound 2d was obtained as a colorless oil in 67% yield (51 mg) after
flash chromatography (SiO2, petroleum ether/ethyl acetate 19:1, Rf =
0.46). When the reaction was performed on 12.7 mmol (2.5 g) of 1d,
compound 2d was obtained in 60% yield (2.4 g). 1H NMR (CDCl3, 300
MHz): δ 7.50−7.33 (m, 8H), 7.22 (t, 1H, J = 7.6 Hz), 4.09 (q, 2H, J = 7.2
Hz), 1.13 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 162.1 (t,
JCF = 33.0 Hz), 154.1, 140.8 (t, JCF = 30.8 Hz), 129.7 (2C), 129.5, 128.5
(3C), 128.0, 126.8, 123.7, 123.6 (t, JCF = 3.3 Hz), 121.3, 111.9, 109.7 (t,
JCF = 249.2 Hz), 65.6, 13.7. 19F NMR (CDCl3, CFCl3, 282 MHz): δ
−99.9 (s, 2F). IR (neat, cm−1): 2987, 1768, 1288, 1049. HRMS (AP+):
calcd for [M + H]+ C18H15F2O3, 317.0989; found, 317.0984 (−1.6
ppm).
obtained as a colorless oil in 61% yield (30 mg) after flash
chromatography (SiO2, pentane/diethyl ether 19:1, Rf = 0.55).
(Caution: the product is highly volatile). 1H NMR (CDCl3, 300 MHz):
δ 6.65−6.62 (m, 1H), 6.06−6.04 (m, 1H), 4.39 (q, 2H, J = 7.2 Hz), 2.34
(s, 3H), 1.37 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 162.6
(t, JCF = 34.1 Hz), 155.2 (t, JCF = 2.2 Hz), 142.6 (t, JCF = 33.6 Hz),
112.7−112.6 (m), 108.7 (t, JCF = 247.6 Hz), 106.8 (d, JCF = 3.9 Hz),
63.4, 13.9, 13.5. 19F NMR (CDCl3, CFCl3, 282 MHz): δ −102.5 (s, 2F).
IR (neat, cm−1): 2990, 1767, 1280, 1050. HRMS (EI): calcd for [M]
C9H10F2O3, 204.0598; found, 204.0608 (+4.9 ppm).
Ethyl 2,2-Difluoro-2-(4,5-dimethylfuran-2-yl)acetate (2i). Prepared
following general procedure A from 2,3-dimethylfuran (1i), except that
the reaction mixture was heated at 60 °C for 20 h. Compound 2i was
obtained as a colorless oil in 52% yield (27 mg) after flash
chromatography (SiO2, pentane/diethyl ether 49:1, Rf = 0.43).
(Caution: the product is highly volatile). 1H NMR (CDCl3, 300 MHz):
δ 6.52 (s, 1H), 4.38 (q, 2H, J = 7.2 Hz), 2.24 (s, 3H), 1.96 (s, 3H), 1.37
(t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 162.7 (t, JCF = 34.1
Hz), 150.6 (t, JCF = 2.2 Hz), 141.3 (t, JCF = 33.0 Hz), 115.4 (t, JCF = 1.1
Hz), 114.8−114.7 (m), 108.8 (t, JCF = 247.0 Hz), 63.3, 13.9, 11.4, 9.7.
19F NMR (CDCl3, CFCl3, 282 MHz): δ −102.6 (s, 2F). IR (neat,
cm−1): 2963, 1768, 1261, 1043. HRMS (EI): calcd for [M] C10H12F2O3,
218.0755; found, 218.0752 (−1.2 ppm).
Ethyl 2,2-Difluoro-2-(5-(benzyloxymethyl)furan-2-yl)acetate (2j).
Prepared following general procedure A from 2-(benzyloxymethyl)-
furan (1j), except that the reaction mixture was heated at 80 °C for 15 h
instead of 20 h. Compound 2j was obtained as a colorless oil in 64% yield
(47 mg) after flash chromatography (SiO2, pentane/diethyl ether 7:3, Rf
= 0.46). When the reaction was performed on 10.6 mmol (2.0 g) of 1j,
compound 2j was obtained in 70% yield (2.3 g). 1H NMR (CDCl3, 300
MHz): δ 7.38−7.29 (m, 5H), 6.73 (ddd, 1H, J = 3.4, 1.7, 1.7 Hz), 6.40
(d, 1H, J = 3.4 Hz), 4.57 (s, 2H), 4.52 (s, 2H), 4.39 (q, 2H, J = 7.2 Hz),
Ethyl 2,2-Difluoro-2-(3-(4-bromophenyl)benzofuran-2-yl)acetate
(2e). Prepared following general procedure A from 3-(4-bromophenyl)-
benzofuran (1e). Compound 2e was obtained as a colorless oil in 62%
yield (59 mg) after flash chromatography (SiO2, petroleum ether/ethyl
acetate 19:1, Rf = 0.52). 1H NMR (CDCl3, 300 MHz): δ 7.66−7.62 (m,
2H), 7.61−7.53 (m, 2H), 7.50−7.41 (m, 3H), 7.34 (t, 1H, J = 7.2 Hz),
4.27 (q, 2H, J = 7.2 Hz), 1.29 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75
1.36 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 162.3 (t, JCF
=
MHz): δ 162.0 (t, JCF = 33.0 Hz), 154.2 (t, JCF = 1.1 Hz), 141.0 (t, JCF
=
33.6 Hz), 154.7 (t, JCF = 1.7 Hz), 144.3 (t, JCF = 34.1 Hz), 137.5, 128.4
(2C), 127.9 (3C), 112.4 (t, JCF = 3.9 Hz), 110.0, 108.5 (t, JCF = 248.1
Hz), 72.3, 63.6, 63.5, 13.9. 19F NMR (CDCl3, CFCl3, 282 MHz): δ
−103.0 (s, 2F). IR (neat, cm−1): 2987, 1766, 1278, 1049. HRMS (EI):
calcd for [M] C16H16F2O4, 310.1017; found, 310.1021 (+1.4 ppm).
Ethyl 2,2-Difluoro-2-(5-((methoxymethoxy)methyl)furan-2-yl)-
acetate (2k). Prepared following general procedure A from 2-
((methoxymethoxy)methyl)furan (1k), except that the reaction mixture
was heated at 80 °C for 12 h instead of 20 h. Compound 2k was obtained
as a colorless oil in 65% yield (41 mg) after flash chromatography (SiO2,
pentane/diethyl ether 7:3, Rf = 0.43). 1H NMR (CDCl3, 300 MHz): δ
6.71 (ddd, 1H, J = 3.4, 1.7, 1.7 Hz), 6.40 (d, 1H, J = 3.4 Hz), 4.67 (s, 2H),
4.55 (s, 2H), 4.38 (q, 2H, J = 7.2 Hz), 3.39 (s, 3H), 1.36 (t, 3H, J = 7.2
Hz). 13C NMR (CDCl3, 75 MHz): δ 162.3 (t, JCF = 33.6 Hz), 154.3 (t,
JCF = 1.7 Hz), 144.5 (t, JCF = 33.6 Hz), 112.3 (t, JCF = 3.9 Hz), 110.0,
108.5 (t, JCF = 248.1 Hz), 95.5, 63.5, 60.6, 55.4, 13.8. 19F NMR (CDCl3,
CFCl3, 282 MHz): δ −103.0 (s, 2F). IR (neat, cm−1): 2945, 1767, 1278,
1038. HRMS (EI): calcd for [M] C11H14F2O5, 264.0809; found,
264.0823 (+5.0 ppm).
Ethyl 2,2-Difluoro-2-(5-(acetoxymethyl)furan-2-yl)acetate (2l).
Prepared following general procedure A from furfuryl acetate (1l),
except that the reaction mixture was heated at 80 °C for 15 h instead of
20 h. Compound 2l was obtained as a colorless oil in 63% yield (40 mg)
after flash chromatography (SiO2, pentane/diethyl ether 7:3, Rf = 0.47).
1H NMR (CDCl3, 300 MHz): δ 6.72 (ddd, 1H, J = 3.4, 1.7, 1.7 Hz), 6.47
(d, 1H, J = 3.4 Hz), 5.05 (s, 2H), 4.39 (q, 2H, J = 7.2 Hz), 2.08 (s, 3H),
1.36 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 170.4, 162.1 (t,
JCF = 33.6 Hz), 152.1 (t, JCF = 2.2 Hz), 144.8 (dd, JCF = 34.1, 34.1 Hz),
112.5 (t, JCF = 3.9 Hz), 111.3, 108.4 (t, JCF = 248.1 Hz), 65.5, 57.5, 20.7,
13.8. 19F NMR (CDCl3, CFCl3, 282 MHz): δ −103.1 (s, 2F). IR (neat,
cm−1): 2922, 1746, 1227, 1050. HRMS (E+): calcd for [M + Na]+
C11H12F2O5Na, 285.0550; found, 285.0545 (−1.8 ppm).
31.4 Hz), 131.8 (2C), 131.3 (2C), 128.5, 127.7 (t, JCF = 1.1 Hz), 126.9,
123.9, 122.8, 122.5 (t, JCF = 2.8 Hz), 121.1, 112.0, 109.7 (t, JCF = 250.3
Hz), 63.7, 13.8. 19F NMR (CDCl3, CFCl3, 282 MHz): δ −101.0 (s, 2F).
IR (neat, cm−1): 2983, 1769, 1288, 1049. HRMS (AP+): calcd for [M +
H]+ C18H14F2O3Br, 395.0094; found, 395.0094 (0.0 ppm).
Ethyl 2-(7-Phenylfuro[2,3-f ]-1,3-benzodioxol-8-yl)-2,2-difluoroa-
cetate (2f). Prepared following general procedure A from 7-phenylfuro-
[2,3-f ]-1,3-benzodioxole (1f), except that the reaction mixture was
heated at 80 °C for 8 h instead of 20 h. Compound 2f was obtained as a
yellow solid in 62% yield (53 mg) after flash chromatography (SiO2,
petroleum ether/ethyl acetate 9:1, Rf = 0.28). When the reaction was
performed on 4.19 mmol (1.0 g) of 1f, compound 2f was obtained in
68% yield (1.0 g). 1H NMR (CDCl3, 300 MHz): δ 7.49−7.43 (m, 5H),
7.04 (s, 1H), 6.87 (s, 1H), 6.02 (s, 2H), 4.15 (q, 2H, J = 7.2 Hz), 1.23 (t,
3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 162.2 (t, JCF = 33.0 Hz),
149.7 (t, JCF = 1.1 Hz), 148.2, 145.6, 140.2 (t, JCF = 31.4 Hz), 129.6,
129.5 (t, 2C, JCF = 1.7 Hz), 128.5 (2C), 128.4, 124.2 (t, JCF = 3.3 Hz),
121.4, 109.6 (t, JCF = 249.2 Hz), 101.7, 99.1, 93.6, 63.5, 13.7. 19F NMR
(CDCl3, CFCl3, 282 MHz): δ −99.8 (s, 2F). IR (neat, cm−1): 2983,
1767, 1461, 1304, 1030. HRMS (EI): calcd for [M] C19H14F2O5,
360.0809; found, 360.0815 (+1.7 ppm). Mp: 54−55 °C.
Ethyl 2,2-Difluoro-2-(furan-2-yl)acetate (2g). Prepared following
general procedure A from furan (1g), except that the reaction mixture
was heated at 60 °C for 25 h. Compound 2g was obtained as a colorless
oil in 52% yield (24 mg) after flash chromatography (SiO2, pentane/
diethyl ether 19:1, Rf = 0.55). (Caution: the product is highly volatile). 1H
NMR (CDCl3, 300 MHz): δ 7.53−7.52 (m, 1H), 6.78−6.77 (m, 1H),
6.48−6.46 (m, 1H), 4.39 (q, 2H, J = 7.2 Hz), 1.37 (t, 3H, J = 7.2 Hz). 13C
NMR (CDCl3, 75 MHz): δ 162.4 (t, JCF = 33.6 Hz), 144.9, 144.6 (t, JCF
= 34.1 Hz), 111.6 (t, JCF = 3.3 Hz), 110.8−110.7 (m), 108.7 (t, JCF
=
248.1 Hz), 63.5, 13.9. 19F NMR (CDCl3, CFCl3, 282 MHz): δ −103.1
(s, 2F). IR (neat, cm−1): 2990, 1767, 1260, 1010. HRMS (EI): calcd for
[M] C8H8F2O3, 190.0442; found, 190.0444 (+1.3 ppm).
Ethyl 2,2-Difluoro-2-(3-(benzyloxymethyl)furan-2-yl)acetate and
Ethyl 2,2-Difluoro-2-(4-(benzyloxymethyl)furan-2-yl)acetate (2m).
Prepared following general procedure A from 3-(benzyloxymethyl)-
furan (1m), except that the reaction mixture was heated at 60 °C for 24 h
instead of 20 h. Compound 2m was obtained as a 66:34 mixture of
Ethyl 2,2-Difluoro-2-(5-methylfuran-2-yl)acetate (2h). Prepared
following general procedure A from 2-methylfuran (1h), except that the
reaction mixture was heated at 60 °C for 20 h. Compound 2h was
E
dx.doi.org/10.1021/jo5010907 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
regioisomers as a colorless oil in 45% yield (66% based on recovered
starting material) (33 mg) after flash chromatography [SiO2, pentane/
diethyl ether 19:1, Rf = 0.22 (major regioisomer), 0.18 (minor
regioisomer)].
C-2-CF2CO2Et-substituted benzofuran or furan was dissolved in MeOH
(0.3 M), and an aqueous solution of K2CO3 (3 equiv, 1 M) was added.
After 30 min at room temperature, the reaction mixture was acidified to
pH 1 by addition of a solution of HCl (2 N), and the solution was
extracted with DCM (three times). The organic layer was washed with
brine and dried over MgSO4. The solvent was removed under vacuum to
afford the corresponding C-2-CF2CO2H-substituted product in
quantitative yield. This one was then added to a solution of CsF (5
equiv) in NMP (0.25 M) under a nitrogen atmosphere, and the tube was
sealed. The resulting mixture was heated at 200 °C for 16 h. The solution
was cooled and extracted with Et2O (three times). The organic layer was
washed with water (twice) and brine (twice) and dried over MgSO4.
The solvent was removed under vacuum, and the residue was purified by
flash chromatography (SiO2, pentane/diethyl ether).
2-(Difluoromethyl)benzofuran (4a). Prepared following general
procedure B from 2a (0.24 mmol). Compound 4a was obtained as a
colorless oil in 65% yield (26 mg) after flash chromatography (SiO2,
pentane, Rf = 0.51). 1H NMR (CDCl3, 300 MHz): δ 7.66 (d, 1H, J = 7.6
Hz), 7.56 (d, 1H, J = 8.1 Hz), 7.41 (t, 1H, J = 7.6 Hz), 7.31 (t, 1H, J = 8.1
Hz), 7.05 (s, 1H), 6.77 (t, 1H, J = 54.2 Hz). 13C NMR (CDCl3, 75
Ethyl 2,2-Difluoro-2-(3-(benzyloxymethyl)furan-2-yl)acetate
1
(Major Regioisomer). H NMR (CDCl3, 300 MHz): δ 7.47 (s, 1H),
7.37−7.29 (m, 5H), 6.60 (s, 1H), 4.60 (t, 2H, J = 1.9 Hz), 4.55 (s, 2H),
4.36 (q, 2H, J = 7.2 Hz), 1.34 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75
MHz): δ 162.3 (t, JCF = 34.1 Hz), 144.0, 140.1 (t, JCF = 34.7 Hz), 137.8,
128.4 (2C), 127.8 (2C), 127.7, 124.9 (t, JCF = 1.7 Hz), 112.4, 109.7 (t,
JCF = 249.2 Hz), 72.3, 63.5, 62.3, 13.9. 19F NMR (CDCl3, CFCl3, 282
MHz): δ −102.7 (s, 2F). IR (neat, cm−1): 2921, 1767, 1289, 1070.
HRMS (E+): calcd for [M + H]+ C16H17F2O4, 311.1095; found,
311.1097 (+0.6 ppm).
Ethyl 2,2-Difluoro-2-(4-(benzyloxymethyl)furan-2-yl)acetate
1
(Minor Regioisomer, Contaminated by the Major Regioisomer). H
NMR (CDCl3, 300 MHz): δ 7.50 (s, 1H), 7.37−7.32 (m, 5H), 6.81 (s,
1H), 4.56 (s, 2H), 4.42−4.35 (m, 4H), 1.37 (t, 3H, J = 7.2 Hz). 13C
NMR (CDCl3, 75 MHz): δ 162.3 (t, JCF = 33.6 Hz), 145.1 (t, JCF = 33.6
Hz), 142.7, 137.7, 128.5 (2C), 127.8 (3C), 123.6, 112.2 (t, JCF = 3.3 Hz),
108.5 (t, JCF = 248.1 Hz), 72.3, 63.5, 62.9, 13.9. 19F NMR (CDCl3,
CFCl3, 282 MHz): δ −103.3 (s, 2F). IR (neat, cm−1): 2922, 1768, 1290,
1091. HRMS (E+): calcd for [M + H]+ C16H17F2O4, 311.1095; found,
311.1104 (+2.9 ppm).
MHz): δ 155.2 (t, JCF = 1.1 Hz), 148.3 (t, JCF = 28.6 Hz), 126.6 (t, JCF
=
1.1 Hz), 126.1, 123.6, 122.1, 111.9, 108.8 (t, JCF = 236.6 Hz), 106.8 (t,
JCF = 5.0 Hz). 19F NMR (CDCl3, CFCl3, 282 MHz): δ −117.1 (dd, 2F, J
= 54.2, 2.0 Hz). IR (neat, cm−1): 1616, 1371, 1136. HRMS (EI): calcd
for [M] C9H6F2O, 168.0387; found, 168.0381 (−3.5 ppm).
Ethyl 2,2-Difluoro-2-(5-phenylfuran-2-yl)acetate (2n). Prepared
following general procedure A from 2-phenylfuran (1n), except that the
reaction mixture was heated at 80 °C for 15 h instead of 20 h.
Compound 2n was obtained as a colorless oil in 58% yield (37 mg) after
flash chromatography (SiO2, pentane/diethyl ether 19:1, Rf = 0.44). 1H
NMR (CDCl3, 300 MHz): δ 7.72−7.68 (m, 2H), 7.45−7.40 (m, 2H),
7.34 (tt, 1H, J = 7.4, 1.3 Hz), 6.84 (ddd, 1H, J = 3.4, 1.7, 1.7 Hz), 6.70 (d,
1H, J = 3.4 Hz), 4.42 (q, 2H, J = 7.2 Hz), 1.39 (t, 3H, J = 7.2 Hz). 13C
NMR (CDCl3, 75 MHz): δ 162.4 (t, JCF = 33.6 Hz), 156.3 (t, JCF = 2.2
Hz), 143.5 (dd, JCF = 33.6, 33.6 Hz), 129.5, 128.8 (2C), 128.5, 124.3
(2C), 113.6 (t, JCF = 3.9 Hz), 108.7 (t, JCF = 248.1 Hz), 105.6, 63.5, 13.9.
19F NMR (CDCl3, CFCl3, 282 MHz): δ −102.8 (s, 2F). IR (neat,
2-(Difluoromethyl)-3-phenylbenzofuran (4b). Prepared following
general procedure B from 2d (0.67 mmol). Compound 4b was obtained
as a colorless oil in 85% yield (140 mg) after flash chromatography
(SiO2, pentane, Rf = 0.30). 1H NMR (CDCl3, 300 MHz): δ 7.72 (d, 1H,
J = 7.6 Hz), 7.65 (d, 1H, J = 8.3 Hz), 7.57−7.47 (m, 6H), 7.37 (t, 1H, J =
7.6 Hz), 6.78 (t, 1H, J = 52.1 Hz). 13C NMR (CDCl3, 75 MHz): δ 154.5,
142.7 (t, JCF = 23.7 Hz), 129.6 (t, JCF = 1.7 Hz), 129.2 (2C), 129.1 (2C),
128.6, 127.0, 126.8, 123.9 (t, JCF = 6.6 Hz), 123.6, 121.1, 112.1, 108.3 (t,
JCF = 234.4 Hz). 19F NMR (CDCl3, CFCl3, 282 MHz): δ −114.3 (d, 2F,
J = 52.1 Hz). IR (neat, cm−1): 1613, 1395, 1085, 1026. HRMS (EI):
calcd for [M] C15H10F2O, 244.0700; found, 244.0703 (+1.2 ppm).
7-Phenyl-8-difluoromethylfuro[2,3-f ]-1,3-benzodioxole (4c). Pre-
pared following general procedure B from 2f (0.12 mmol), except that
the reaction mixture was heated at 200 °C for 4 h instead of 16 h.
Compound 4c was obtained as a colorless oil in 64% yield (22 mg) after
flash chromatography (SiO2, pentane/diethyl ether 49:1, Rf = 0.35). 1H
NMR (CDCl3, 300 MHz): δ 7.56−7.47 (m, 5H), 7.07 (s, 1H), 6.99 (s,
1H), 6.65 (t, 1H, J = 52.1 Hz), 6.04 (s, 2H). 13C NMR (CDCl3, 75
MHz): δ 150.1, 148.2, 145.5, 142.2 (t, JCF = 23.7 Hz), 129.7, 129.1 (4C),
128.6, 124.5 (t, JCF = 7.2 Hz), 120.3, 108.2 (t, JCF = 234.4 Hz), 101.7,
99.0, 93.8. 19F NMR (CDCl3, CFCl3, 282 MHz): δ −113.5 (d, 2F, J =
52.1 Hz). IR (neat, cm−1): 1608, 1460, 1238, 1153, 1021. HRMS (EI):
calcd for [M] C16H10F2O3, 288.0598; found, 288.0604 (+2.1 ppm).
2-(Benzyloxymethyl)-5-(difluoromethyl)furan (4d). Prepared fol-
lowing general procedure B from 2j (0.24 mmol), except that the
reaction mixture was heated at 200 °C for 4 h instead of 16 h.
Compound 4d was obtained as a colorless oil in 47% yield (27 mg) after
flash chromatography (SiO2, pentane/diethyl ether 19:1, Rf = 0.33). 1H
NMR (CDCl3, 300 MHz): δ 7.37−7.35 (m, 5H), 6.64 (s, 1H), 6.62 (t,
1H, J = 54.2 Hz), 6.39 (s, 1H), 4.59 (s, 2H), 4.52 (s, 2H). 13C NMR
(CDCl3, 75 MHz): δ 153.8 (t, JCF = 2.2 Hz), 146.7 (t, JCF = 29.7 Hz),
137.5, 128.5 (2C), 127.90 (2C), 127.85, 110.9 (t, JCF = 4.4 Hz), 109.9,
108.4 (t, JCF = 234.9 Hz), 72.3, 63.7. 19F NMR (CDCl3, CFCl3, 282
MHz): δ −115.3 (d, 2F, J = 54.2 Hz). IR (neat, cm−1): 1359, 1071, 1017.
HRMS (EI): calcd for [M] C13H12F2O2, 238.0805; found, 238.0815
(+4.2 ppm).
cm−1): 2988, 1765, 1273, 1042. HRMS (E+): calcd for [M + H]+
C14H13F2O3, 267.0833; found, 267.0841 (+3.0 ppm).
Ethyl 2,2-Difluoro-2-(5-(4-methoxyphenyl)furan-2-yl)acetate
(2o). Prepared following general procedure A from 2-(4-
methoxyphenyl)furan (1o), except that the reaction mixture was heated
at 80 °C for 15 h instead of 20 h. Compound 2o was obtained as a
colorless oil in 59% yield (42 mg) after flash chromatography (SiO2,
pentane/diethyl ether 19:1, Rf = 0.26). 1H NMR (CDCl3, 300 MHz): δ
7.65−7.62 (m, 2H), 6.96−6.93 (m, 2H), 6.81 (ddd, 1H, J = 3.4, 1.7, 1.7
Hz), 6.55 (d, 1H, J = 3.4 Hz), 4.41 (q, 2H, J = 7.2 Hz), 3.85 (s, 3H), 1.39
(t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 75 MHz): δ 162.5 (t, JCF = 33.6
Hz), 159.9, 156.5 (t, JCF = 2.2 Hz), 142.8 (dd, JCF = 34.1, 34.1 Hz), 125.9
(2C), 122.5, 114.2 (2C), 113.7 (t, JCF = 3.9 Hz), 108.8 (t, JCF = 247.6
Hz), 104.0, 63.4, 55.3, 13.9. 19F NMR (CDCl3, CFCl3, 282 MHz): δ
−102.5 (s, 2F). IR (neat, cm−1): 2977, 1765, 1274, 1021. HRMS (EI):
calcd for [M] C15H14F2O4, 296.0860; found, 296.0868 (+2.7 ppm).
Ethyl 2,2-Difluoro-2-(5-(2-fluoro-4-methoxyphenyl)furan-2-yl)-
acetate (2p). Prepared following general procedure A from 2-(2-
fluoro-4-methoxyphenyl)furan (1p), except that the reaction mixture
was heated at 80 °C for 15 h instead of 20 h. Compound 2p was obtained
as a colorless oil in 61% yield (46 mg) after flash chromatography (SiO2,
pentane/diethyl ether 19:1, Rf = 0.21). 1H NMR (CDCl3, 300 MHz): δ
7.74 (t, 1H, J = 8.9 Hz), 6.84 (ddd, 1H, J = 3.4, 1.7, 1.7 Hz), 6.79−6.67
(m, 3H), 4.42 (q, 2H, J = 7.2 Hz), 3.84 (s, 3H), 1.39 (t, 3H, J = 7.2 Hz).
13C NMR (CDCl3, 75 MHz): δ 162.4 (t, JCF = 34.1 Hz), 160.8 (d, JCF
11.0 Hz), 159.8 (d, JCF = 251.4 Hz), 150.8−150.7 (m), 142.6 (dt, JCF
=
=
33.6, 1.1 Hz), 127.1 (d, JCF = 5.0 Hz), 113.8 (dt, JCF = 3.9, 1.7 Hz), 110.8
(d, JCF = 12.7 Hz), 110.3 (d, JCF = 3.3 Hz), 108.8 (t, JCF = 248.1 Hz),
108.6 (d, JCF = 11.6 Hz), 102.0 (d, JCF = 25.3 Hz), 63.5, 55.6 (d, JCF = 4.4
Hz), 13.9. 19F NMR (CDCl3, CFCl3, 282 MHz): δ −102.7 (s, 2F),
−111.9 (s, 1F). IR (neat, cm−1): 2999, 1760, 1273, 1032. HRMS (EI):
calcd for [M] C15H13F3O4, 314.0766; found, 314.0779 (+4.2 ppm).
General Procedure B: Saponification/Decarboxylation Se-
quence for the CF2CO2Et Moiety. Under a nitrogen atmosphere, the
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra and crystallographic data (CIF). This
material is available free of charge via the Internet at http://pubs.
acs.org.
F
dx.doi.org/10.1021/jo5010907 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Bonnaire, S.; Pannecoucke, X. J. Org. Chem. 2014, 79, 2916. (c) Poisson,
T.; Belhomme, M.-C.; Pannecoucke, X. J. Org. Chem. 2012, 77, 9277.
(d) Ivashkin, P.; Couve-Bonnaire, S.; Jubault, P.; Pannecoucke, X. Org.
Lett. 2012, 14, 2270. (e) Milanole, G.; Couve-Bonnaire, S.; Bonfanti, J.-
F.; Jubault, P.; Pannecoucke, X. J. Org. Chem. 2013, 78, 212.
(f) Lemonnier, G.; Zoute, L.; Quirion, J.-C.; Jubault, P. Org. Lett.
2010, 12, 844.
(14) The active Cu(I) species can be generated through either
reduction or disproportionation of Cu(II). For reduction, see:
(a) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc.
2008, 130, 8172. For disproportion, see: (b) Ribas, X.; Calle, C.; Poater,
AUTHOR INFORMATION
Corresponding Authors
*E-mail: thomas.poisson@insa-rouen.fr.
*E-mail: xavier.pannecoucke@insa-rouen.fr.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was partially supported by INSA Rouen, Rouen
University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-
0029), and Region Haute-Normandie (Crunch Network). M.-
́
C.B. thanks the MESR for a doctoral fellowship.
■
A.; Casitas, A.; Gom
Schweiger, A.; Mitrikas, G.; Sola,
Chem. Soc. 2010, 132, 12299 and references therein.
́
ez, L.; Xifra, R.; Parella, T.; Benet-Buchholz, J.;
M.; Llobet, A.; Stack, T. D. P. J. Am.
̀
(15) See the Supporting Information for details.
(16) An alternative mechanism involving cupration of the benzofuran
ring followed by an oxidative addition step with BrCF2CO2Et cannot be
precluded.
(17) We cannot rule out the possibility that the reductive elimination
proceeds before the abstraction of the proton. On the other hand,
cupration of the benzofuran ring followed by oxidative insertion into the
C−Br bond of the BrCF2CO2Et moiety might be considered as a
plausible alternative pathway.
(18) For related process, see: (a) Fujikawa, K.; Fujioka, Y.; Kobayashi,
A.; Amii, H. Org. Lett. 2011, 13, 5560. (b) Fujikawa, K.; Kobayashi, A.;
Amii, H. Synthesis 2012, 44, 3015.
(19) (a) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529. (b) Kirk, K. L.
Org. Process Res. Dev. 2008, 12, 305. (c) Prakash, G. K. S.; Chacko, S.
Curr. Opin. Drug Discovery Dev. 2008, 11, 793. (d) Graton, J.; Wang, Z.;
REFERENCES
■
(1) (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (b) Purser, S.;
Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320.
(c) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller,
̈
̈
K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637.
(2) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881.
̈
(3) (a) Landelle, G.; Panossian, A.; Pazenok, S.; Vors, J.-P.; Leroux, F.
R. Beilstein J. Org. Chem. 2013, 9, 2476. (b) Liu, H.; Gu, Z.; Jiang, X. Adv.
Synth. Catal. 2013, 355, 617. (c) Liang, T.; Neumann, C. N.; Ritter, T.
Angew. Chem., Int. Ed. 2013, 52, 8214. (d) Chen, P.; Liu, G. Synthesis
2013, 45, 2919. (e) Wang, X.; Truesdale, L.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 3648. (f) Zhang, X.-G.; Dai, H.-X.; Wasa, M.; Yu, J.-Q. J. Am.
Chem. Soc. 2012, 134, 11948. (g) Parsons, A. T.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2011, 50, 9120. (h) Ye, Y.; Lee, S. H.; Sanford, M. S. Org.
Lett. 2011, 13, 5464. (i) Zeng, Y.; Zhang, L.; Zhao, Y.; Ni, C.; Zhao, J.;
Hu, J. J. Am. Chem. Soc. 2013, 135, 2955.
Brossard, A.-M.; Gonca̧ lves Monteiro, D.; Le Questel, J.-Y.; Linclau, B.
Angew. Chem., Int. Ed. 2012, 51, 6176. (e) Giuffredi, G. T.; Gouverneur,
V.; Bernet, B. Angew. Chem., Int. Ed. 2013, 52, 10524.
(4) (a) Comprehensive Heterocyclic Chemistry III, 1st ed.; Katritzky, A.
R., Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier:
Amsterdam, 2008. (b) De Luca, L.; Nieddu, G.; Porcheddu, A.;
Giacomelli, G. Curr. Med. Chem. 2009, 16, 1−20.
(5) (a) Lee, C. F.; Yang, L. M.; Hwu, T. Y.; Feng, A. S.; Tseng, J. C.;
Luh, T. Y. J. Am. Chem. Soc. 2000, 122, 4992. (b) Liu, C. Y.; Luh, T. Y.
Org. Lett. 2002, 4, 4305.
(6) Hou, X. L.; Yang, S.; Yeung, K.-S.; Wong, H. N. C. Prog. Heterocycl.
Chem. 2007, 18, 187.
(7) (a) Katrizky, A. R.; Ji, Y.; Fang, Y.; Prakash, I. J. Org. Chem. 2001,
66, 5613. (b) Ando, K.; Kawamura, Y.; Akai, Y.; Kunitomo, J.;
Yokomizo, T.; Yamashita, M.; Ohta, S.; Ohishi, T.; Ohishi, Y. Org.
Biomol. Chem. 2008, 6, 296.
(20) (a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465. For
recent examples, see: (b) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder,
̀
E.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, A. B.; Sach, N.;
Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95. (c) Fier, P.
S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524. (d) Prakash, G. K. S.;
Krishnamoorthy, S.; Ganesh, S. K.; Kulkarni, A.; Haiges, R.; Olah, G. A.
Org. Lett. 2014, 16, 54. (e) Wang, X.; Liu, G.; Xu, X.-H.; Shibata, N.;
Tokunaga, E.; Shibata, N. Angew. Chem., Int. Ed. 2014, 53, 1827.
(21) (a) Casero, R. A., Jr.; Woster, P. M. J. Med. Chem. 2009, 52, 4551.
(b) Takagi, H.; Tanaka, K.; Tsuda, H.; Kobayashi, H. Int. J. Antimicrob.
Agents 2008, 32, 468. (c) Rewcastle, G. W.; Gamage, S. A.; Flanagan, J.
U.; Frederick, R.; Denny, W. A.; Baguley, B. C.; Kestell, P.; Singh, R.;
Kendall, J. D.; Marshall, E. S.; Lill, C. L.; Lee, W.-J.; Kolekar, S.;
Buchanan, C. M.; Jamieson, S. M. F.; Shepherd, P. R. J. Med. Chem. 2011,
54, 7105.
(22) (a) Kim, Y. S. J. Korean Chem. Soc. 1963, 7, 189. (b) Battais, A.;
Boutevin, B.; Pietrasanta, Y. J. Fluorine Chem. 1979, 14, 467.
(23) (a) Enthaler, S.; Spilker, B.; Erre, G.; Junge, K.; Tse, M.; Beller, M.
Tetrahedron 2008, 64, 3867. (b) Kim, I.; Lee, S.-H.; Lee, S. Tetrahedron
Lett. 2008, 49, 6579.
(8) (a) Furstner, A.; Davies, P. J. Am. Chem. Soc. 2005, 127, 15024.
̈
(b) Oppenheimer, J.; Johnson, W.; Tracey, M.; Hsung, R.; Yao, P. Y.;
Liu, R.; Zhao, K. Org. Lett. 2007, 9, 2361.
(9) (a) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (b) Do, H.-
Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185.
(c) Yanagisawa, S.; Itami, K. Tetrahedron 2011, 67, 4425. (d) Carrer, A.;
̈
Rousselle, P.; Florent, J.-C.; Bertounesque, E. Adv. Synth. Catal. 2012,
354, 2751. (e) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.;
DeBoef, B. Org. Lett. 2007, 9, 3137.
(10) (a) Li, Y.; Brand, J. P.; Waser, J. Angew. Chem., Int. Ed. 2013, 52,
6743. (b) Li, Y.; Waser, J. Beilstein J. Org. Chem. 2013, 9, 1763.
(11) (a) Mejía, E.; Togni, A. ACS Catal. 2012, 2, 521. (b) Iqbal, N.;
Choi, S.; Ko, E.; Cho, E. J. Tetrahedron Lett. 2012, 53, 2005. (c) Kino, T.;
Nagase, Y.; Ohtsuka, Y.; Yamamoto, K.; Uraguchi, D.; Tokuhisa, K.;
Yamakawa, T. J. Fluorine Chem. 2010, 131, 98. (d) Seo, S.; Taylor, J. B.;
Greaney, M. F. Chem. Commun. 2013, 49, 6385.
(24) Malamas, M. S.; Adebayo, F. O.; Dollings, P. J. U.S. Patent
6,221,902 B1, 2001.
(25) Kuhl, N.; Hopkinson, M.; Glorius, F. Angew. Chem., Int. Ed. 2012,
51, 8230.
(26) Ikoma, M.; Oikawa, M.; Sasaki, M. Tetrahedron 2008, 64, 2740.
(27) Larsen, M. M.; Boydson, A. J. J. Am. Chem. Soc. 2013, 135, 8189.
(28) Haner, J.; Jack, K.; Nagireddy, J.; Racheem, M.; Durham, R.; Tam,
W. Synthesis 2011, 731.
(12) (a) Ohtsuka, Y.; Yamakawa, T. Tetrahedron 2011, 67, 2323.
(b) Lin, Q.; Chu, L.; Qing, F.-L. Chin. J. Chem. 2013, 31, 885.
(c) Murakami, S.; Ishii, H.; Tajima, T.; Fuchigami, T. Tetrahedron 2006,
62, 3761. For an alternative strategy based on an oxidative coupling
reaction with difluoroenol silyl ethers, see: (d) Uneyama, K.; Tanaka,
H.; Kobayashi, S.; Shioyama, M.; Amii, H. Org. Lett. 2004, 6, 2733−
2736.
(13) (a) Belhomme, M.-C.; Poisson, T.; Pannecoucke, X. Org. Lett.
2013, 15, 3428. (b) Lemonnier, G.; Hijfte, N. V.; Poisson, T.; Couve-
G
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