Copper-catalyzed innate ethoxycarbonyldifluoromethylation of electron-rich arenes

Article abstract of DOI:10.1002/ejoc.201403656

We report the direct introduction of the CF₂CO₂Et moiety into electron-rich arenes. The copper-catalyzed process uses commercially available and inexpensive BrCF₂CO₂Et as a fluorinated building block. This radic

Full text of DOI:10.1002/ejoc.201403656

Job/Unit: O43656
/KAP1
Date: 30-01-15 13:12:49
Pages: 9
FULL PAPER
DOI: 10.1002/ejoc.201403656
Copper-Catalyzed Innate Ethoxycarbonyldifluoromethylation of Electron-Rich
Arenes
Marie-Charlotte Belhomme,[a] Alexandre Bayle,[a] Thomas Poisson,*[a] and
Xavier Pannecoucke*[a]
Keywords: Synthetic methods / Homogeneous catalysis / Aromatic substitution / Arenes / Fluorine / Copper
We report the direct introduction of the CF2CO2Et moiety
into electron-rich arenes. The copper-catalyzed process uses
commercially available and inexpensive BrCF2CO2Et as a
fluorinated building block. This radical-free reaction pro-
ceeds smoothly to give the desired difluoromethylated ar-
gioselectivity. The direct introduction of α,α-difluorometh-
ylated amides was also investigated, and this gave the corre-
sponding difluoromethylated arenes, albeit in moderate
yields. This method represents the first transition-metal-cata-
lyzed direct introduction of a functionalized fluorinated moi-
enes in modest to good yields with a Friedel–Crafts-type re- ety into electron-rich arenes.
1) radical processes,[7] or 2) transition-metal-catalyzed
Introduction
cross-coupling reactions with fluorinated organometallic
derivatives or halogenated fluorinated species (Scheme 1).[8]
As the second-smallest element of the periodic table, the
fluorine atom has impressive features: its electronegativity,
its small size, and the strength of the C–F bond provide it
with an impressive ability to modify the physical and bio-
logical properties of molecules. Therefore, fluorine atoms or
fluorinated groups are found in numerous pharmaceuticals
and agrochemicals.[1] For instance, fluorine is considered as
a good bioisostere of hydrogen and oxygen atoms, and its
presence in a biologically active molecule might improve the
metabolic stability of the molecule. As a result, organofluo-
rine chemistry is a rapidly expanding field, and recent ef-
forts have culminated in the development of new reactions
and elegant routes to key fluorinated backbones.[2] Among
all these new strategies, the direct functionalization of a C–
H bond has appeared as one of the most promising ap-
proaches. This is a powerful synthetic method, since it al-
lows the functionalization of molecules without prior func-
tional group manipulation.[3] The strategy is atom-efficient,
and thus it addresses current concerns about the develop-
ment of sustainable processes.[4] However, while much at-
tention has been paid to the direct introduction of the
fluorine atom and the CF3 group,[5] the direct introduction
of functionalized fluorinated moieties that might easily al-
low further postfunctionalization still remains underex-
plored.[6] Indeed, the main ways to access to such key func-
tionalized fluorinated building blocks have focused on
Scheme 1. State of the art and proposed strategy; Fg = functional
group, EDG = electron-donating group.
[a] Normandie Université, COBRA, UMR 6014 et FR 3038,
Université de Rouen, INSA Rouen, CNRS,
1 rue Tesnière, 76821 Mont Saint-Aignan Cedex, France
E-mail: thomas.poisson@insa-rouen.fr
Bearing in mind the lack of attention paid to the transi-
tion-metal-catalyzed direct introduction of functionalized
fluorinated moieties into molecules by means of direct C–
H bond functionalization, and since the direct introduction
xavier.pannecoucke@insa-rouen.fr
http://www.lab-cobra.fr/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403656.
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M.-C. Belhomme, A. Bayle, T. Poisson, X. Pannecoucke
FULL PAPER
of the CF2CO2Et moiety into arenes has, to date, only been Table 1. Optimization of the reaction conditions.[a]
achieved by radical processes, the development of a transi-
tion-metal-catalyzed transformation would be highly desir-
able. As part of our ongoing research program devoted to
the development of new routes for the synthesis of function-
alized fluorinated building blocks,[9] herein is described the
copper-catalyzed innate introduction of the CF2CO2Et
moiety into electron-rich arenes.
Entry [Cu]
Ligand Base
Yield[b] o/m/p[c]
1
2
3
4
5
6
7
8
Cu2O
CuOAc
CuCl
CuTC
CuPF6·[MeCN]4 Phen
Cu(OTf)2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Phen
Phen
Phen
Phen
K2CO3
49 (47) 0.62:0.1:0.28
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
K2HPO4
Na2CO3
Lutidine
Et3N
42
45
45
47
n.r.
37
0.56:0.08:0.36
0.56:0.09:0.35
0.56:0.09:0.35
0.59:0.08:0.33
–
0.66:0.08:0.26
0.63:0.1:0.27
–
Results and Discussion
We began our investigation with anisole (1a) as a model
substrate, and BrCF2CO2Et as a readily available fluori-
nated reagent (Table 1). First, we examined the copper
source, and we were pleased to find that the use of Cu2O
as a catalyst with 1,10-phenanthroline (Phen) as a ligand
and K2CO3 in DMF at 80 °C provided the desired fluori-
nated arenes (i.e., 2a) in 47% yield with a 0.62:0.10:0.28
Phen
Phen
Phen
Phen
Phen
Phen
L1
46
9
n.r.
n.r.
11
10
11
12
–
n.d.
K2CO3
51 (50) 0.59:0.1:0.31
ortho/meta/para regioselectivity (Table 1, entry 1).[10]
A
screening of copper salts was undertaken. Several CuI
sources were effective in this transformation, but neither the
yield nor the regioselectivity were improved (Table 1, en-
tries 2–5). It is noteworthy that in contrast to our previous
observations,[11] CuII salts did not promote the reaction
(Table 1, entry 6). Next, the effect of the base was explored.
The use of K3PO4 gave the desired product (i.e., 2a) in
lower yield, 37%, while K2HPO4 gave similar results to
K2CO3 (Table 1, entries 7–8). Surprisingly, replacement of
K2CO3 by Na2CO3 did not give the difluoromethylated
product, and no reaction occurred (Table 1, entry 9). It
worth mentioning that organic bases were less efficient in
this process; no trace of product was observed with 2,6-
[a] 1a (0.48 mmol), [Cu] (10 mol-%), ligand (12 mol-%),
BrCF2CO2Et (3.8 mmol), base (0.96 mmol), DMF (0.8 mL), 80 °C,
16 h, air. [b] Yield determined by 19F NMR spectroscopy using
α,α,α-trifluorotoluene as an internal standard. Isolated yields are
given in parentheses. [c] Determined by 19F NMR spectroscopic
analysis of the crude reaction mixture; TC = 2-thiophene carboxyl-
ate, n.r.: no reaction, n.d.: not determined, L1 = 3,4,7,8-tet-
ramethyl-1,10-phenanthroline.
On the basis of these results, we decided to explore fur-
lutidine, while Et3N gave 2a in a very poor yield (Table 1, ther electron-rich substrates, and particularly aniline deriva-
entries 10 and 11). Finally, a ligand screening[12] shown that tives. Initially, we attempted to perform the reaction on un-
L1 (3,4,7,8-tetramethyl-1,10-phenanthroline) was the most protected aniline; however, only degradation products were
effective ligand, giving the desired difluoromethylated anis- observed, so a panel of protecting groups was screened. A
ole (i.e., 2a) in 50% isolated yield, with a 0.59:0.1:0.31 o/m/ tosyl protecting group gave no reaction, and the starting
p regioisomeric ratio (Table 1, entry 12). Notably, the ob- material was recovered. Boc (tert-butoxycarbonyl) protec-
served regioselectivity is similar to that observed for a Frie- tion of the amino group gave the desired fluorinated prod-
del–Crafts-type reaction; this observation led us to assume uct (i.e., 2i) in 44% isolated yield as a 0.16:0.84 regioisom-
a plausible nucleophilic attack of the aromatic ring onto a eric mixture (meta/para). Pleasingly, the pivaloyl protecting
transient electrophilic metallic species (vide infra).
group was more efficient, and a 0.16:0.84 meta/para re-
Having established these optimized conditions, we went gioisomeric mixture of the desired fluorinated arene (i.e.,
on to investigate the scope of the reaction (Scheme 2). First, 2j) was obtained in 57% isolated yield. Next, we extended
1,4-dimethoxybenzene (1b) was tested, and it reacted the scope of the reaction to other aniline derivatives. 3-
smoothly to give the difluoromethylated arenes (i.e., 2b) in Bromo-N-pivaloylaniline (1k) reacted nicely under our re-
70% yield. In the same vein, 1,2-dimethoxybenzene (1c) action conditions to give the expected difluoromethylated
gave the corresponding fluorinated arene (i.e., 2c) in 68% product (i.e., 2k) in 52% yield as a mixture of regioisomers
yield, while electron-rich 1,3,5-trimethoxybenzene (1d) pro- without affecting the bromine atom. The reaction was also
vided difluoromethylated arenes 2d in 79% isolated yield. performed with 4-methyl-N-pivaloylaniline (1l) and 4-meth-
It is worth noting that an increase of the electron density oxy-N-pivaloylanilines (1m) to give compounds 2l and 2m
of the arene ring is correlated to an increase of the reaction in somewhat lower yields (28 and 24%, respectively) and
yield. 1,3-Benzodioxole (1e) gave difluorinated product 2e similar regioisomeric ratios. Finally, aniline derivative 1n re-
in 69% yield as a mixture of two isomers, along with a trace acted smoothly to give difluorinated product 2n in a fairly
of the product resulting from a double functionalization of decent yield of 72%.
the aromatic backbone. Next, thioanisole (1f) was tested,
and the reaction proceeded, albeit in moderate yield com- fluorinated amides into trimethoxybenzene 1d, and we ex-
pared to the oxygenated analog. amined morpholine-derived and N,N-diethylbromodifluo-
Next, we turned our attention to the introduction of di-
2
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Ethoxycarbonyldifluoromethylation of Electron-Rich Arenes
ence of TEMPO [(2,2,6,6-tetramethylpiperidin-1-yl)oxyl;
20 mol-% or 1 equiv.], a slight decrease in the reaction yield
was observed, and the corresponding difluorinated arene
(i.e., 2b) was obtained in 71 and 63% yields, respectively
(Scheme 3, entries 2 and 3). No trace of a TEMPO–
CF2CO2Et adduct was detected by NMR spectroscopy or
MS analysis. The same trend was observed with BHT (2,6-
di-tert-butyl-4-methylphenol), where 2b was obtained in
66% yields (Scheme 3, entry 5). Finally, a reaction carried
out in the presence of 1,4-benzoquinone (20 mol-%) gave
fluorinated product 2b in a similar yield (Scheme 3, en-
try 6). These observations prompted us to rule out a radical
mechanism and to propose a plausible CuI/CuIII catalytic
cycle (Scheme 4).
Scheme 3. Mechanistic investigations. [a] Determined by 19F NMR
spectroscopy using α,α,α-trifluorotoluene as an internal standard.
Scheme 2. Scope of the reaction (the major isomer is represented,
and the regioisomeric ratio is given in parantheses; n.r.: no reac-
tion). [a] The product was contaminated with traces of difunction-
alized product. [b] Isolated after reduction of the ester group into
the alcohol; see Supporting Information for details. [c] 48 h reac-
tion time instead of 16 h.
roacetamides.
Bromodifluoroacetmorpholide
reacted
smoothly with 1d to give the desired product (i.e., 2o) in
63%, whereas N,N-diethylbromodifluoroacetamide gave the
desired product (i.e., 2p) in a poorer yield of 21%. Finally,
the difluoromethylated morpholine-derived amide motif
Scheme 4. Proposed mechanism.
Based on this hypothesis, we propose the following
was introduced into 1,2-dimethoxybenzene (1c) and aniline mechanism: the copper catalyst undergoes an oxidative ad-
1m in low yields of 18 and 22%, respectively. These results dition into the C–Br bond of the BrCF2CO2Et to give an
highlight the lower reactivity of amide derivatives compared electrophilic CuIII intermediate A. Subsequent nucleophilic
to esters.[13]
attack of electron-rich arene 1 onto A gives CuIII species B,
To gain insight into the reaction mechanism, the reaction which is then deprotonated to restore the aromaticity (to
was carried out in the presence of radical inhibitors give intermediate C). This hypothesis might explain the
(Scheme 3). When the reaction was carried out in the pres- Friedel–Crafts-type regioselectivity of the difluorometh-
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M.-C. Belhomme, A. Bayle, T. Poisson, X. Pannecoucke
FULL PAPER
30 min at 0 °C, ethyl bromodifluoroacetate (2.1 mL, 16.4 mmol)
was added dropwise. The suspension was warmed up to room tem-
perature. After 12 h, the reaction mixture was quenched with 1 n
HCl (100 mL). The aqueous phase was extracted with CH2Cl2 (2ϫ
100 mL). The combined organic phases were washed with brine
(100 mL), and dried with MgSO4. The solvent was removed under
vacuum, and the residue was filtered through silica gel to give N,N-
diethyl-2-bromo-2,2-difluoroacetamide (2.4 g, 63%) as a colorless
ylation process. A final reductive elimination step delivers
2 and regenerates the catalyst.
Conclusions
In conclusion, we have carried out the first direct intro-
duction of a CF2CO2Et moiety into electron-rich arenes
catalyzed by copper. This process was applied to several
electron-rich scaffolds, including anisoles and anilines deriv-
atives, to give the corresponding difluoromethylated prod-
ucts in good to moderate yields. The observed regioselectiv-
ity of the reaction followed the pattern expected for a Frie-
del–Crafts-type reaction. Finally, rudimentary mechanistic
1
oil. H NMR (300 MHz, CDCl3): δ = 3.53 (q, JH,H = 7.2 Hz, 2 H,
Ha), 3.43 (q, JH,H = 7.2 Hz, 2 H, HaЈ), 1.26 (t, JH,H = 7.2 Hz, 3 H,
Hb), 1.20 (t, JH,H = 7.2 Hz, 3 H, Hb) ppm. 13C NMR (75 MHz,
CDCl3): δ = 158.4 (t, JC,F = 24.8 Hz), 111.0 (t, JC,F = 314.2 Hz),
42.7, 41.9, 13.6, 11.6 ppm. 19F NMR (282 MHz, CDCl3, CFCl3):
δ = –54.9 (s, 2 F) ppm. IR (neat): ν = 2981, 1675, 1136, 1100 cm–1.
˜
HRMS (EI): calcd. for C6H10BrF2NO [M]+ 228.9914; found
studies suggested a plausible CuI/CuIII catalytic cycle, since 228.9911 (–1.3 ppm).
radical inhibitors had no deleterious effects on the reaction.
General Procedure for the Copper-Catalyzed Ethoxycarbonyldifluor-
omethylation and Difluoroamidation of Anisole and Aniline Deriva-
tives: Under an air atmosphere, Cu2O (3 mg, 0.024 mmol), L1
(3,4,7,8-tetramethyl-1,10-phenanthroline; 14 mg, 0.06 mmol), and
K2CO3 (133 mg, 0.96 mmol) were dissolved in DMF (0.8 mL).
Then, the anisole or aniline derivative (0.48 mmol) and
BrCF2CO2Et or BrCF2CONR2 (3.8 mmol) were added, and the
tube was sealed. The resulting mixture was heated at 80 °C for 16 h.
The solution was cooled and diluted with Et2O (10 mL) and water
(10 mL). The aqueous phase was extracted with Et2O (2ϫ 10 mL).
The combined organic layers were washed with water (2ϫ 10 mL),
and brine (2ϫ 10 mL), and dried with MgSO4. The solvent was
removed under vacuum, and the residue was purified by flash
chromatography (SiO2).
Experimental Section
General Methods: All reactions were carried out using oven-dried
glassware and magnetic stirring under an atmosphere of argon un-
less otherwise stated. Flash chromatography was carried out with
silica gel (0.040–0.060 nm). Analytical thin-layer chromatography
was carried out on silica gel aluminium plates with F-254 indicator,
which were visualized using UV light (254 nm) and/or chemical
staining with a KMnO4 solution. NMR spectra were recorded with
a Bruker DXP 300 spectrometer: H at 300 MHz, 13C at 75 MHz,
1
and 19F at 282 MHz. Chemical shifts (δ) are quoted in parts per
million (ppm), and spectra were calibrated using residual solvent
signals (CHCl3: δ = 7.27 ppm for 1H, δ = 77.0 ppm for 13C), or
using external CFCl3: δ = 0 ppm. The following abbreviations have
been used: δ (chemical shift), J (coupling constant), s (singlet), br.
s (broad singlet), d (doublet), dd (doublet of doublets), ddd (doub-
let of doublet of doublets), t (triplet), q (quartet), m (multiplet).
High-resolution mass spectra (HRMS) were recorded with a
Waters LCT Premier instrument, and IR spectra were recorded
with a Perkin–Elmer Spectrum 100 instrument. Dry DMF (sureseal
bottle) was purchased from Acros, K2CO3 from Carlo Erba, Cu2O
from Aldrich, and 3,4,7,8-tetramethyl-1,10-phenanthroline from
TCI. All starting materials were distilled or recrystallized before
use.
Ethyl 2,2-Difluoro-2-(2-methoxyphenyl)acetate, Ethyl 2,2-Difluoro-
2-(3-methoxyphenyl)acetate, and Ethyl 2,2-Difluoro-2-(4-meth-
oxyphenyl)acetate (2a): Prepared following the general procedure
from anisole (1a) and ethyl bromodifluoroacetate. Colorless oil
(55%, 0.48 mmol scale). A 0.59:0.10:0.31 mixture of ortho/meta/
para regioisomers (based on the 19F NMR spectrum of the crude
1
reaction mixture). H NMR (300 MHz, CDCl3): δ = 7.65 (d, J =
7.7 Hz, 0.60 H, para), 7.54 (d, J = 8.3 Hz, 0.59 H, ortho), 7.47 (t,
J = 8.3 Hz, 0.59 H, ortho), 7.37 (t, J = 8.7 Hz, 0.08 H, meta), 7.19
(d, J = 8.7 Hz, 0.08 H, meta), 7.14 (s, 0.08 H, meta), 7.09–7.02 (m,
0.68 H, ortho and meta), 6.97–6.94 (m, 1.18 H, ortho and para),
4.41–4.29 (m, 2 H, ortho and meta and para), 3.84–3.82 (m, 3 H,
ortho and meta and para), 1.41–1.28 (m, 3 H, ortho and meta and
2-Bromo-2,2-difluoroacetmorpholide:
Morpholine
(5.7 mL,
para) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.4 (t, JC,F
36.3 Hz, para), 164.1 (t, JC,F = 33.6 Hz, ortho), 161.5 (t, JC,F
=
=
65.6 mmol) was added dropwise to a solution of Me2AlCl (1 m in
hexanes; 66 mL, 65.6 mmol) in CH2Cl2 (70 mL) at 0 °C. After
30 min at 0 °C, ethyl bromodifluoroacetate (2.1 mL, 16.4 mmol)
was added dropwise. The suspension was warmed up to room tem-
perature. After 12 h, the reaction mixture was quenched with 1 n
HCl (100 mL). The aqueous phase was extracted with CH2Cl2 (2ϫ
100 mL). The combined organic phases were washed with brine
(100 mL), and dried with MgSO4. The solvent was removed under
vacuum, and the residue was filtered through silica gel to give 2-
bromo-2,2-difluoroacetmorpholide (3.0 g, 75%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 3.77–3.71 (m, 8 H, Ha,b) ppm.
13C NMR (75 MHz, CDCl3): δ = 157.5 (t, JC,F = 26.4 Hz), 110.2 (t,
JC,F = 314.2 Hz), 66.2, 65.8, 47.0, 43.6 ppm. 19F NMR (282 MHz,
1.7 Hz, meta), 160.7 (t, JC,F = 30.8 Hz, meta), 159.7 (para), 156.7
(t, JC,F = 5.0 Hz, ortho), 132.3 (t, JC,F = 1.7 Hz, 2 C, para), 129.8
(meta), 127.0 (t, JC,F = 6.1 Hz, ortho), 126.3 (t, JC,F = 7.7 Hz, or-
tho), 124.9 (t, JC,F = 26.4 Hz, para), 121.9 (t, JC,F = 23.7 Hz, ortho),
120.6 (ortho), 117.6 (t, JC,F = 6.1 Hz, meta), 116.8 (meta), 113.9 (2
C, para), 113.5 (t, JC,F = 25.8 Hz, meta), 113.2 (t, JC,F = 251.4 Hz,
para), 112.2 (t, JC,F = 248.1 Hz, ortho), 111.3 (ortho), 110.7 (t, JC,F
= 6.6 Hz, meta), 63.1 (meta), 63.0 (para), 62.6 (ortho), 55.6 (ortho),
55.4 (meta), 55.3 (para), 13.9 (ortho), 13.83 (para), 13.76 (meta)
ppm. Due to the low concentration and despite a very long acqui-
sition time, the CF2 of the meta regioisomer was not observed. 19
NMR (282 MHz, CDCl3, CFCl3): δ = –103.0 (s, 0.62 F, para),
–103.2 (s, 1.18 F, ortho), –104.3 (s, 0.20 F, meta) ppm. IR (neat): ν
F
CDCl , CFCl ): δ = –55.0 (s, 2 F) ppm. IR (neat): ν = 2860, 1685,
˜
3
3
1162, 1114 cm–1. HRMS (EI): calcd. for C6H8BrF2NO2 [M]+
˜
=
2920, 1759, 1530, 1096 cm–1. HRMS (ESI): calcd. for
242.9706; found 242.9710 (+1.6 ppm).
C11H12F2O3 [M]+ 230.0755; found 230.0750.
N,N-Diethyl-2-bromo-2,2-difluoroacetamide: Diethylamine (6.8 mL,
65.6 mmol) was added dropwise to a solution of Me2AlCl (1 m in
hexanes; 66 mL, 65.6 mmol) in CH2Cl2 (70 mL) at 0 °C. After
Ethyl 2,2-Difluoro-2-(2,5-dimethoxyphenyl)acetate (2b): Prepared
following the general procedure from 1,4-dimethoxybenzene (1b)
4
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Ethoxycarbonyldifluoromethylation of Electron-Rich Arenes
and ethyl bromodifluoroacetate. Colorless oil (70%, 0.48 mmol JC,F = 33.1 Hz) ppm. 19F NMR (282 MHz, CDCl3, CFCl3): δ =
scale). Single isomer (contaminated with 8% of a product contain-
ing two CF2CO2Et moieties, based on the 19F NMR spectrum of
the crude reaction mixture). 1H NMR (300 MHz, CDCl3): δ = 7.22
(s, 1 H), 7.01 (d, J = 8.9 Hz, 1 H), 6.89 (d, J = 8.9 Hz, 1 H), 4.35
(q, J = 7.0 Hz, 2 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 1.32 (t, J =
7.0 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.9 (t, JC,F
= 33.6 Hz), 153.5, 150.7 (t, JC,F = 5.0 Hz), 122.7 (t, JC,F = 23.7 Hz),
117.3 (t, JC,F = 1.7 Hz), 112.9, 112.0 (t, JC,F = 248.7 Hz), 111.8 (t,
JC,F = 7.7 Hz), 62.6, 56.3, 55.7, 13.9 ppm. 19F NMR (282 MHz,
–105.7 (s, 2 F) ppm. IR (neat): ν = 3347, 2960, 2920, 1600, 1433,
˜
1268, 1176, 1069 cm–1. HRMS (ESI): calcd. for C9H9F2O3 [M +
H]+ 203.0520; found 203.0521.
Ethyl 2-(1,3-Benzodioxol-4-yl)-2,2-difluoroacetate (2eЈ): Minor iso-
1
mer, which has been isolated after reduction. Yellow oil. H NMR
(300 MHz, CDCl3): δ = 7.03 (dd, J = 7.1, 2.2 Hz, 1 H), 6.96–6.86
(m, 2 H), 6.03 (s, 2 H), 4.35 (q, J = 7.1 Hz, 2 H), 1.33 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.6 (t, JC,F
= 34.4 Hz), 148.5, 145.1 (t, JC,F = 4.2 Hz), 122.0, 118.6 (t, JC,F
=
CDCl , CFCl ): δ = –102.4 (s, 2 F) ppm. IR (neat): ν = 2988,
˜
3
3
6.3 Hz), 114.9 (t, JC,F = 27.2 Hz), 112.1 (t, JC,F = 251.4 Hz), 111.1
1759, 1743, 1183 cm–1. HRMS (ESI): calcd. for C12H14F2O4 [M]+
(t, JC,F = 1.1 Hz), 102.0, 63.4, 14.0 ppm. 19F NMR (282 MHz,
260.0860; found 260.0858.
CDCl , CFCl ): δ = –102.7 (s, 2 F) ppm. IR (neat): ν = 2960, 1763,
˜
3
3
Ethyl 2-(3,4-Dimethoxyphenyl)-2,2-difluoroacetate (2c): Prepared 1460, 1277, 1246, 1050 cm–1. HRMS (ESI): calcd. for C11H11F2O4
following the general procedure from 1,3,5-trimethoxybenzene (1c)
and ethyl bromodifluoroacetate. Yellow oil (68%, 0.48 mmol scale).
Single isomer (based on the 19F NMR spectrum of the crude reac-
[M + H]+ 245.0625; found 245.0620.
Diethyl
2,2Ј-(1,3-Benzodioxole-4,6-diyl)bis(2,2-difluoroacetate)
(2eЈЈ): See Scheme 2, comment [a]; isolated before reduction. Yel-
low oil. 1H NMR (300 MHz, CDCl3): δ = 7.33 (br. s, 1 H), 7.16
(br. s, 1 H), 6.12 (s, 2 H), 4.36 (q, J = 7.1 Hz, 2 H), 4.31 (q, J =
7.1 Hz, 2 H), 1.33 (t, J = 7.2 Hz, 3 H), 1.32 (t, J = 7.1 Hz, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 163.9 (t, JC,F = 35.5 Hz),
163.0 (t, JC,F = 34.1 Hz), 149.2, 147.6 (t, JC,F = 4.1 Hz), 127.1 (t,
JC,F = 26.7 Hz), 117.1 (t, JC,F = 6.8 Hz), 114.8 (t, JC,F = 27.8 Hz),
112.8 (t, JC,F = 253.3 Hz), 111.6 (t, JC,F = 252.6 Hz), 108.5 (t, JC,F
= 5.8 Hz), 103.2, 63.7, 63.5, 14.0 ppm. 19F NMR (282 MHz,
CDCl3, CFCl3): δ = –103.0 (s, 2 F), –103.1 (s, 2 F) ppm. IR (neat):
1
tion mixture). H NMR (300 MHz, CDCl3): δ = 7.16 (dd, J = 8.4,
1.9 Hz, 1 H), 7.07 (d, J = 2.0 Hz, 1 H), 6.88 (d, J = 8.4 Hz, 1 H),
4.28 (q, J = 7.1 Hz, 2 H), 3.89 (s, 3 H), 3.88 (s, 3 H), 1.28 (t, J =
7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.4 (t, JC,F
= 36.0 Hz), 151.2 (t, JC,F = 1.7 Hz), 149.1, 125.1 (t, JC,F = 26.2 Hz),
118.6 (t, JC,F = 6.6 Hz), 113.5 (t, JC,F = 252.0 Hz), 110.9, 108.4 (t,
JC,F = 6.0 Hz), 63.1, 56.1, 56.0, 13.9 ppm. 19F NMR (282 MHz,
CDCl , CFCl ): δ = –103.3 (s, 2 F) ppm. IR (neat): ν = 2942, 1760,
˜
3
3
1518, 1266, 1096, 1022 cm–1. HRMS (ESI): calcd. for C12H15F2O4
[M + H]+ 261.0938; found 261.0936.
ν = 2917, 1764, 1448, 1288, 1256, 1093, 1075, 1050 cm–1. HRMS
˜
Ethyl 2,2-Difluoro-2-(2,4,6-trimethoxyphenyl)acetate (2d): Prepared (ESI): calcd. for C15H18F4NO6 [M + NH4]+ 384.1070; found
following the general procedure from 1,3,5-trimethoxybenzene (1d)
and ethyl bromodifluoroacetate. Brown gummy solid (79%,
0.48 mmol scale). Single isomer (based on the 19F NMR spectrum
384.1063.
Ethyl 2,2-Difluoro-2-[2-(methylthio)phenyl]acetate (2f): Prepared
following the general procedure from thioanisole (1f) and ethyl bro-
modifluoroacetate. Colorless foam (30%, 0.48 mmol scale). A
0.03:0.15:0.82 mixture of ortho/meta/para regioisomers (based on
the 19F NMR spectrum of the crude reaction mixture). The mixture
of isomers was isolated after reduction of the ester moiety.
1
of the crude reaction mixture). H NMR (300 MHz, CDCl3): δ =
6.10 (s, 2 H), 4.29 (q, J = 7.1 Hz, 2 H), 3.78 (s, 3 H), 3.76 (s, 6 H),
1.29 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
164.8 (t, JC,F = 33.3 Hz), 163.4, 160.2 (t, JC,F = 2.6 Hz), 113.5 (t,
JC,F = 247.5 Hz), 102.7 (t, JC,F = 24.1 Hz), 91.5, 62.4, 56.1, 55.4,
14.0 ppm. 19F NMR (282 MHz, CDCl3, CFCl3): δ = –96.9 (s, 2 F)
2,2-Difluoro-2-[4-(methylthio)phenyl]ethanol and 2,2-Difluoro-2-[3-
(methylthio)phenyl]ethanol (2f-red): The esters were reduced in
quantitative yield. Colorless foam. A 0.03:0.15:0.82 mixture of
ortho/meta/para regioisomers (based on the 19F NMR spectrum of
the crude reaction mixture). 1H NMR (300 MHz, CDCl3): δ = 7.54
(d, J = 7.6 Hz, 0.2 H, meta), 7.42 (d, J = 8.5 Hz, 1.9 H, para), 7.34
(m, 0.42 H, meta), 7.29 (d, J = 8.4 Hz, 1.8 H, para), 7.21 (d, J =
7.3 Hz, 0.2 H, meta), 4.20 (dt, J = 13.9, 6.9 Hz, 0.3 H, meta), 3.94
(dt, J = 13.9, 6.9 Hz, 1.8 H, para), 2.50 (s, 2.5 H, para), 2.49 (s, 0.5
H, meta), 2.10 (app t, J = 6.9 Hz, 1.2 H, meta and para) ppm. 13C
NMR (75 MHz, CDCl3): δ = 141.9 (t, JC,F = 1.9 Hz, para), 137.3
(t, JC,F = 2.5 Hz, meta), 132.0 (t, JC,F = 24.2 Hz, meta), 130.9 (t,
JC,F = 26.0 Hz, para), 129.1 (meta), 128.7 (t, JC,F = 1.6 Hz, meta),
126.0 (t, JC,F = 6.1 Hz, para), 126.0 (para), 123.4 (t, JC,F = 6.4 Hz,
ppm. IR (neat): ν = 2987, 1770, 1587, 1231, 1088, 1054 cm–1.
˜
HRMS (ESI): calcd. for C13H17F2O5 [M + H]+ 291.1044; found
291.1037.
Ethyl 2-(1,3-Benzodioxol-5-yl)-2,2-difluoroacetate (2e): Prepared
following the general procedure from 1,3-benzodioxole (1e) and
ethyl bromodifluoroacetate (69%, 0.48 mmol). A 0.84:0.16 mixture
of ortho/meta regioisomers (based on the 19F NMR spectrum of
the crude reaction mixture).
Compound 2e was separated after reduction of the ester group.
Compound 2e was dissolved in MeOH (c = 0.1 molL–1), and
NaBH4 (5 equiv.) was added portionwise at room temperature. The
mixture was stirred for 30 min, then it was quenched with saturated
aqueous NH4Cl, and diluted with H2O. The aqueous layer was meta), 122.2 (t, JC,F = 6.2 Hz, meta), 121.4 (t, JC,F = 245.5 Hz,
extracted with Et2O (3ϫ). The combined organic layers were
washed with brine, and dried with MgSO4, and the solvents were
removed in vacuo. Purification by flash column chromatography
gave the desired alcohol 2e-red.
meta), 120.7 (t, JC,F = 243.6 Hz, para), 66.1 (t, JC,F = 32.9 Hz,
para), 64.2 (t, JC,F = 30.3 Hz, meta), 15.7 (meta), 15.4 (para) ppm.
19F NMR (282 MHz, CDCl3, CFCl3): δ = –107.1 (s, 1.8 F), –107.8
(s, 0.2 F) ppm. IR (neat): ν = 3347, 2960, 2920, 1600, 1433, 1268,
˜
1176, 1069 cm–1. HRMS (ESI): calcd. for C9H11F2OS [M + H]+
205.0499; found 205.0503.
2-(1,3-Benzodioxol-5-yl)-2,2-difluoroethanol (2e-red): Colorless oil.
Single isomer (based on the 19F NMR spectrum of the crude reac-
1
tion mixture). H NMR (300 MHz, CDCl3): δ = 7.00 (app. dd, J
Ethyl 2-{4-[(tert-Butoxycarbonyl)amino]phenyl}-2,2-difluoroacetate
and Ethyl 2-{3-[(tert-Butoxycarbonyl)amino]phenyl}-2,2-difluoro-
= 8.1, 0.7 Hz, 1 H), 6.96 (d, J = 1.5 Hz, 1 H), 6.84 (d, J = 8.1 Hz,
1 H), 6.00 (s, 2 H), 3.91 (t, J = 13.3 Hz, 2 H), 2.34 (br. s, 1 H) acetate (2i): Prepared following the general procedure from tert-
ppm. 13C NMR (75 MHz, CDCl3): δ = 149.3 (t, JC,F = 1.8 Hz),
butyl phenylcarbamate (1i) and ethyl bromodifluoroacetate. Yellow
148.0, 128.3 (t, JC,F = 26.2 Hz), 120.6 (t, JC,F = 244.0 Hz), 119.8 oil (44%, 0.48 mmol scale). A 0:0.16:0.84 mixture of ortho/meta/
(t, JC,F = 6.8 Hz), 108.4, 106.3 (t, JC,F = 6.4 Hz), 101.7, 66.1 (t,
para regioisomers (based on the 19F NMR spectrum of the crude
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O43656
/KAP1
Date: 30-01-15 13:12:49
Pages: 9
M.-C. Belhomme, A. Bayle, T. Poisson, X. Pannecoucke
19F NMR (282 MHz, CDCl3, CFCl3): δ = –103.8 (s, 2 F, ortho),
FULL PAPER
reaction mixture). 1H NMR (300 MHz, CDCl3): δ = 7.58–7.49 (m,
0.4 H, meta), 7.53 (d, J = 8.8 Hz, 1.6 H, para), 7.44 (d, J = 8.8 Hz,
1.6 H, para), 7.37 (app. t, J = 8.1 Hz, 0.2 H, meta), 7.26 (d, J =
–104.3 (s, 2 F, meta) ppm. IR (neat): ν = 2980, 1758, 1660, 1597,
˜
1518, 1266, 1092 cm–1. HRMS (ESI): calcd. for C15H20F2NO3 [M
7.6 Hz, 0.2 H, meta), 6.61 and 6.51 [br. s, (para), and br. s, (meta), + H – Br]+ 300.1411; found 300.1405.
1 H], 4.31 and 4.30 [q, J = 7.1 Hz (meta), and q, J = 7.1 Hz (para),
Ethyl 2,2-Difluoro-2-(5-methyl-2-pivalamidophenyl)acetate (2l) and
2 H], 1.54 (app. s, 9 H, meta and para), 1.33 and 1.31 [t, J = 7.1 Hz
(meta), and t, J = 7.1 Hz (para), 3 H] ppm. 13C NMR (75 MHz,
CDCl3): δ = 164.4 (t, JC,F = 35.9 Hz, para), 164.2 (t, JC,F = 35.1 Hz,
meta), 152.7 (meta), 152.6 (para), 141.1 (t, JC,F = 1.4 Hz, para),
139.0 (para), 133.7 (t, JC,F = 25.6 Hz, meta), 129.5 (para), 129.2
(meta), 128.3 (meta), 127.0 (t, JC,F = 26.1 Hz, para), 126.5 (t, JC,F
= 6.1 Hz, para), 121.0 (meta), 119.9 (t, JC,F = 6.1 Hz, meta), 118.2
(para), 115.5 (t, JC,F = 6.0 Hz, meta), 113.5 (t, JC,F = 251.8 Hz,
para), 113.3 (t, JC,F = 252.3 Hz, meta), 81.2 (para), 81.1 (meta), 63.3
(meta), 63.2 (para), 28.3, 14.0 ppm. 19F NMR (282 MHz, CDCl3,
CFCl3): δ = –103.8 (s, 2 F, para), –104.4 (s, 2 F, meta) ppm. IR
Ethyl 2,2-Difluoro-2-(2-methyl-5-pivalamidophenyl)acetate (2lЈ):
Prepared following the general procedure from N-(p-tolyl)pival-
amide (1l) and ethyl bromodifluoroacetate. Colorless oil (28%,
0.48 mmol scale). A 0.77:0.23 mixture of ortho/meta regioisomers
(based on the 19F NMR spectrum of the crude reaction mixture).
Data for 2l: 1H NMR (300 MHz, CDCl3): δ = 8.36 (br. s, 1 H),
8.06 (d, J = 8.4 Hz, 1 H), 7.35 (d, J = 2.0 Hz, 1 H), 7.28 (dd, J =
8.4, 1.9 Hz, 1 H), 4.30 (q, J = 7.1 Hz, 2 H), 2.35 (s, 3 H), 1.32 (s,
9 H), 1.28 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 177.1, 164.8 (t, JC,F = 35.1 Hz), 134.2, 133.7 (t, JC,F = 3.1 Hz),
132.6, 126.5 (t, JC,F = 8.5 Hz), 124.5, 122.0 (t, JC,F = 23.6 Hz),
113.6 (t, JC,F = 252.8 Hz), 63.9, 39.9, 27.4, 21.0, 14.0 ppm. 19F
NMR (282 MHz, CDCl3, CFCl3): δ = –104.0 (s, 2 F) ppm. IR
(neat): ν = 2980, 1763, 1730, 1704, 1526, 1232, 1154 cm–1. HRMS
˜
(ESI): calcd. for C15H23F2N2O4 [M + NH4]+ 333.11626; found
333.11626.
(neat): ν = 2967, 1767, 1746, 1691, 1513, 1298, 1090 cm–1. HRMS
˜
Ethyl 2,2-Difluoro-2-(3-pivalamidophenyl)acetate and Ethyl 2,2-Di-
fluoro-2-(4-pivalamidophenyl)acetate (2j): Prepared following the
general procedure from N-pivaloylaniline (1j) and ethyl bromodi-
fluoroacetate. Colorless oil (57%, 0.48 mmol scale). A 0:0.16:0.84
mixture of ortho/meta/para regioisomers (based on the 19F NMR
spectrum of the crude reaction mixture). 1H NMR (300 MHz,
CDCl3): δ = 7.80 (d, J = 8.1 Hz, 0.16 H, meta), 7.69 (s, 0.16 H,
meta), 7.63 (d, J = 8.2 Hz, 1.68 H, para), 7.55–7.52 (m, 2.53 H,
para and meta), 7.39 (t, J = 8.1 Hz, 0.17 H, meta), 7.32 (d, J =
8.1 Hz, 0.16 H, meta), 4.31–4.24 (m, 2 H, para and meta), 1.31–
1.26 (m, 12 H, para and meta) ppm. 13C NMR (75 MHz, CDCl3):
δ = 176.9 (para), 176.8 (meta), 164.2 (t, JC,F = 35.8 Hz, para), 164.0
(t, JC,F = 35.2 Hz, meta), 140.5 (para), 138.5 (meta), 133.4 (t, JC,F
= 25.3 Hz, meta), 129.3 (meta), 128.0 (t, JC,F = 25.9 Hz, para),
(ESI): calcd. for C16H22F2NO3 [M + H]+ 314.1568; found 314.1565.
1
Data for 2lЈ: Colorless oil. H NMR (300 MHz, CDCl3): δ = 7.76
(dd, J = 8.3, 2.0 Hz, 1 H), 7.56 (d, J = 2.2 Hz, 1 H), 7.36 (br. s, 1
H), 7.18 (d, J = 8.3 Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 2.35 (s, 3
H), 1.32 (s, 9 H), 1.29 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 176.8, 164.1 (t, JC,F = 35.0 Hz), 136.2, 132.7,
132.0 (t, JC,F = 3.2 Hz), 131.6 (t, JC,F = 23.4 Hz), 122.6, 117.7 (t,
JC,F = 9.4 Hz), 113.9 (t, JC,F = 252.2 Hz), 63.4, 39.8, 27.7, 19.1 (t,
JC,F = 2.6 Hz), 14.0 ppm. 19F NMR (282 MHz, CDCl3, CFCl3): δ
= –102.3 (s, 2 F) ppm. IR (neat): ν = 2967, 1767, 1746, 1691, 1513,
˜
1298, 1090 cm–1. HRMS (ESI): calcd. for C16H22F2NO3 [M + H]+
314.1568; found 314.1567.
Ethyl 2,2-Difluoro-2-(5-methoxy-2-pivalamidophenyl)acetate (2m):
Prepared following the general procedure from N-(4-meth-
oxyphenyl)pivalamide (1m) and ethyl bromodifluoroacetate. Yellow
oil (24%, 0.48 mmol scale). A 0.72:0.28 mixture of ortho/meta re-
gioisomers (based on the 19F NMR spectrum of the crude reaction
126.3 (t, JC,F = 6.1 Hz, 2 C, para), 122.6 (meta), 121.0 (t, JC,F
=
6.1 Hz, meta), 119.7 (2 C, para), 116.9 (t, JC,F = 6.6 Hz, meta),
113.2 (t, JC,F = 252.0 Hz, para), 113.0 (t, JC,F = 252.5 Hz, meta),
63.2 (meta), 63.1 (para), 39.7 (para), 39.6 (meta), 27.5 (3 C, meta),
27.4 (3 C, para), 13.8 (para and meta) ppm. 19F NMR (282 MHz,
CDCl3, CFCl3): δ = –103.9 (s, 1.68 F, para), –104.4 (s, 0.32 F, meta)
1
mixture). H NMR (300 MHz, CDCl3): δ = 8.18 (br. s, 1 H), 7.98
(d, J = 9.0 Hz, 1 H), 7.08 (d, J = 2.9 Hz, 1 H), 7.01 (dd, J = 9.0,
2.9 Hz, 1 H), 4.29 (q, J = 7.2 Hz, 2 H), 3.81 (s, 3 H), 1.31 (s, 9 H),
1.29 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
177.1, 164.5 (t, JC,F = 34.9 Hz), 156.3, 129.0 (t, JC,F = 3.2 Hz),
126.8, 124.1 (t, JC,F = 23.8 Hz), 117.2, 113.2 (t, JC,F = 253.1 Hz),
111.6 (t, JC,F = 9.0 Hz), 63.9, 55.8, 39.8, 27.5, 14.0 ppm. 19F NMR
ppm. IR (neat): ν = 3290, 2921, 1759, 1520, 1266, 1092 cm–1.
˜
HRMS (ESI): calcd. for C15H19F2NO3 [M]+ 299.1333; found
299.1330.
Ethyl 2-(4-Bromo-2-pivalamidophenyl)-2,2-difluoroacetate and Ethyl
2-(3-Bromo-5-pivalamidophenyl)-2,2-difluoroacetate (2k): Prepared
following the general procedure from N-(3-bromophenyl)pival-
amide (1k) and ethyl bromodifluoroacetate. Yellow solid (52%,
0.48 mmol scale). A 0.73:0.15:0.12 mixture of ortho/meta/para re-
gioisomers (based on the 19F NMR spectrum of the crude reaction
(282 MHz, CDCl , CFCl ): δ = –104.2 (s, 2 F) ppm. IR (neat): ν
˜
3
3
= 2967, 1767, 1683, 1510, 1286, 1089 cm–1. HRMS (ESI): calcd.
for C16H22F2NO4 [M + H]+ 330.1517; found 330.1511.
Ethyl 2-(2,4-Dipivalamidophenyl)-2,2-difluoroacetate (2n): Prepared
mixture). 1H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 8.0 Hz, following the general procedure from N,NЈ-(1,3-phenylene)bis-
0.2 H, meta), 7.69 (br. s, 0.2 H, meta), 7.62 (app. d, J = 8.7 Hz, 1.8
H, ortho), 7.69 (app. br. s, 0.7 H, ortho), 7.51 (app. d, J = 8.7 Hz,
1.7 H, ortho), 7.36 (app. t, J = 7.9 Hz, 0.2 H, meta), 7.29 (d, J =
7.9 Hz, 0.2 H, meta), 4.26 (q, J = 7.1 Hz, 2 H, ortho and meta),
1.29 (app. s, 12 H, ortho and meta), 1.27 and 1.26 [t, J = 7.2 Hz
(pivalamide) (1n) and ethyl bromodifluoroacetate. Pale brown foam
(72%, 0.48 mmol scale). A 0.84:0.16 mixture of ortho/meta re-
gioisomers (based on the 19F NMR spectrum of the crude reaction
1
mixture). H NMR (300 MHz, CDCl3): δ = 8.51 (br. s, 1 H), 8.09
(br. s, 1 H), 8.06 (d, J = 1.4 Hz, 1 H), 7.63 (dd, J = 8.7, 1.6 Hz, 1
(meta), and t, J = 7.2 Hz (ortho), 3 H] ppm. 13C NMR (75 MHz, H), 7.34 (d, J = 8.8 Hz, 1 H), 4.26 (q, J = 7.1 Hz, 2 H), 1.29 (s, 9
CDCl3): δ = 177.1 (ortho), 177.0 (meta), 164.3 (t, JC,F = 35.7 Hz,
ortho), 164.2 (t, JC,F = 35.2 Hz, meta), 140.7 (t, JC,F = 1.7 Hz, or-
tho), 138.6 (meta), 133.6 (t, JC,F = 25.6 Hz, meta), 129.4 (ortho),
H), 1.25 (t, J = 7.2 Hz, 3 H), 1.16 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 177.5, 177.4, 165.1 (t, JC,F = 35.5 Hz), 141.9,
136.1 (t, JC,F = 3.0 Hz), 127.0 (t, JC,F = 8.5 Hz), 117.6 (t, JC,F
24.4 Hz), 115.9, 115.1, 113.4 (t, JC,F = 253.4 Hz), 63.9, 39.8, 39.7,
6.1 Hz, ortho), 125.6 (meta), 122.8 (ortho), 121.1 (t, JC,F = 6.1 Hz, 27.3, 27.3, 14.0 ppm. 19F NMR (282 MHz, CDCl3, CFCl3): δ =
meta), 120.2 (meta), 119.9 (ortho), 117.0 (t, JC,F = 6.5 Hz, meta), –103.7 (s, 2 F) ppm. IR (neat): ν = 2967, 1770, 1653, 1595, 1516,
=
129.0 (meta), 128.2 (t, JC,F = 26.1 Hz, ortho), 126.4 (t, JC,F
=
˜
113.4 (t, JC,F = 251.9 Hz, ortho), 113.1 (t, JC,F = 252.4 Hz, meta),
1480, 1401, 1269, 1102 cm–1. HRMS (ESI): calcd. for
63.3 (meta), 63.2 (ortho), 39.8 (ortho), 39.7 (meta), 27.6, 13.9 ppm. C16H21F2NO4 [M + H]+ 399.2095; found 399.2097.
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43656
/KAP1
Date: 30-01-15 13:12:49
Pages: 9
Ethoxycarbonyldifluoromethylation of Electron-Rich Arenes
2,2-Difluoro-2-(2,4,6-trimethoxyphenyl)acetmorpholide (2o): Pre- European Fund for Regional Development (EFRD), Labex
pared following the general procedure from 1,3,5-trimethoxy- SynOrg (ANR-11-LABX-0029), and the Région Haute-Norman-
benzene (1d) and 2-bromo-2,2-difluoroacetmorpholide. Colorless
solid (63%, 0.48 mmol scale). Single isomer (based on the 19F
NMR spectrum of the crude reaction mixture), m.p. 120 °C. 1H
die (CRUNCh network). M.-C. B. thanks the Ministère de l’En-
seignement Supérieur et de la Recherche (MESR) for a doctoral
fellowship. A. B. thanks the Labex SynOrg (ANR-11-LABX-0029)
NMR (300 MHz, CDCl3): δ = 6.10 (s, 2 H), 3.81 (s, 3 H), 3.79 (s, for a postdoctoral fellowship. Clément Janin (INSA-Rouen) is
6 H), 3.69–3.68 (m, 2 H), 3.65–3.64 (m, 2 H), 3.49–3.46 (m, 2 H),
3.33–3.30 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.7
(t, JC,F = 29.2 Hz), 163.3 (t, JC,F = 1.1 Hz), 159.7 (t, JC,F = 2.8 Hz,
2 C), 114.0 (t, JC,F = 245.9 Hz), 103.4 (t, JC,F = 24.8 Hz), 91.3 (2
C), 66.5, 66.0, 56.2 (2 C), 55.3, 46.4, 43.0 ppm. 19F NMR
gratefully acknowledged for preliminary experiments.
[1] a) D. O’Hagan, Chem. Soc. Rev. 2008, 37, 308–319; b) S.
Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc.
Rev. 2008, 37, 320–330; c) H.-J. Böhm, D. Banner, S. Bendels,
M. Kansy, B. Kuhn, K. Müller, U. Obst-Sander, M. Stahl,
ChemBioChem 2004, 5, 637–643; d) J. Wang, M. Sánchez-Ro-
selló, J. L. Aceña, C. del Pozo, A. E. Sorochinsky, S. Fustero,
V. A. Soloshonok, H. Liu, Chem. Rev. 2014, 114, 2432–2506;
e) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881–
1886; f) R. D. Chambers, Fluorine in Organic Chemistry,
Blackwell Publishing Ltd., Oxford, UK, 2004; g) P. Kirsch,
Modern Fluoroorganic Chemistry: Synthesis Reactivity, Applica-
tions, Wiley-VCH, Weinheim, Germany, 2004; h) K. Uneyama,
Organofluorine Chemistry, Blackwell Publishing, Oxford, UK,
2006; i) J.-P. Bégué, D. Bonnet-Delpon, Chimie Bioorganique et
Médicinal du Fluor, CNRS Editions, Paris, 2005.
(282 MHz, CDCl , CFCl ): δ = –90.6 (s, 2 F) ppm. IR (neat): ν =
˜
3
3
2852, 1684, 1592, 1144 cm–1. HRMS (ESI): calcd. for
C15H19F2NO5Na [M + Na]+ 354.1129; found 354.1121 (–2.3 ppm).
N,N-Diethyl-2,2-difluoro-2-(2,4,6-trimethoxyphenyl)acetamide (2p):
Prepared following the general procedure from 1,3,5-trimethoxy-
benzene (1d) and N,N-diethyl-2-bromo-2,2-difluoroacetamide. Col-
orless solid (21%, 0.48 mmol scale). Single isomer (based on the
19F NMR spectrum of the crude reaction mixture), m.p. 135 °C.
1H NMR (300 MHz, CDCl3): δ = 6.12 (s, 2 H), 3.83 (s, 3 H), 3.79
(s, 6 H), 3.40 (q, J = 7.2 Hz, 2 H), 3.21 (q, J = 7.2 Hz, 2 H), 1.19
(t, J = 7.2 Hz, 3 H), 0.98 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 164.3 (t, JC,F = 29.2 Hz), 163.1 (t, JC,F
=
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1.1 Hz), 160.0 (t, JC,F = 2.8 Hz, 2 C), 114.7 (t, JC,F = 246.5 Hz),
104.3 (t, JC,F = 24.8 Hz), 91.4 (2 C), 56.1 (2 C), 55.3, 41.8, 40.9,
13.4, 12.2 ppm. 19F NMR (CDCl3, CFCl3, 282 MHz): δ = –90.9 (s,
2 F) ppm. IR (neat): ν = 2950, 1665, 1585, 1129 cm–1. HRMS
˜
(ESI): calcd. for C15H22F2NO4 [M + H]+ 318.1528; found 318.1523.
2,2-Difluoro-2-(2,4-dimethoxyphenyl)acetmorpholide (2q): Prepared
following the general procedure from 1,2-dimethoxybenzene (1c)
and 2-bromo-2,2-difluoroacetmorpholide except that the reaction
mixture was heated at 80 °C for 48 h instead of 16 h. Colorless oil
(18%, 0.48 mmol scale). Single isomer (based on the 19F NMR
spectrum of the crude reaction mixture). 1H NMR (300 MHz,
CDCl3): δ = 7.10 (d, J = 8.3 Hz, 1 H), 7.03 (s, 1 H), 6.90 (d, J =
8.3 Hz, 1 H), 3.91 (s, 3 H), 3.90 (s, 3 H), 3.70 (br. s, 4 H), 3.47 (br.
s, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.2 (t, JC,F
=
30.8 Hz), 151.0 (t, JC,F = 1.7 Hz), 149.2, 125.6 (t, JC,F = 25.3 Hz),
118.0 (t, JC,F = 6.1 Hz), 115.4 (t, JC,F = 249.8 Hz), 110.7, 107.9 (t,
JC,F = 5.5 Hz), 66.7, 66.3, 56.0, 55.9, 46.7, 43.4 ppm. 19F NMR
(282 MHz, CDCl , CFCl ): δ = –93.4 (s, 2 F) ppm. IR (neat): ν =
˜
3
3
2924, 1667, 1517, 1258 cm–1. HRMS (ESI): calcd. for
C14H18F2NO4 [M + H]+ 302.1204; found 302.1204.
2,2-Difluoro-2-(2-methoxy-5-pivalamidophenyl)acetmorpholide (2r):
Prepared following the general procedure from 2,2-dimethyl-4Ј-
methoxypropioanilide (1r) and 2-bromo-2,2-difluoroacetmorphol-
ide, except that the reaction mixture was heated at 80 °C for 48 h
instead of 16 h. Colorless oil (22%, 0.48 mmol scale). Single isomer
(based on the 19F NMR spectrum of the crude reaction mixture).
1H NMR (300 MHz, CDCl3): δ = 7.73–7.68 (m, 2 H), 7.50 (br. s,
1 H), 6.91 (d, J = 8.7 Hz, 1 H), 3.80 (s, 3 H), 3.68 (br. s, 4 H), 3.46
(br. s, 4 H), 1.30 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
176.7, 161.8 (t, JC,F = 30.3 Hz), 153.2 (t, JC,F = 4.5 Hz), 131.6,
124.6, 122.8 (t, JC,F = 24.2 Hz), 118.7 (t, JC,F = 7.7 Hz), 113.8 (t,
JC,F = 250.3 Hz), 112.5, 66.7, 66.3, 56.3, 46.5, 43.4, 39.4, 27.5 (3
C) ppm. 19F NMR (282 MHz, CDCl3, CFCl3): δ = –95.9 (s, 2 F)
[6] a) N. Surapanich, C. Kuhakarn, M. Pohmakotr, V. Reutrakul,
Eur. J. Org. Chem. 2012, 5943–5952; b) M.-C. Belhomme, T.
Poisson, X. Pannecoucke, J. Org. Chem. 2014, 79, 7205–7211;
c) G. Caillot, J. Dufour, M.-C. Belhomme, T. Poisson, L. Gri-
maud, X. Pannecoucke, I. Gillaizeau, Chem. Commun. 2014,
50, 5887–5890; d) M.-C. Belhomme, T. Poisson, X. Panne-
coucke, Org. Lett. 2013, 15, 3428–3431.
[7] For selected examples, see: a) X.-T. Huang, Z.-Y. Long, Q.-Y.
Chen, J. Fluorine Chem. 2001, 111, 107–113; b) S. Murakami,
H. Ishii, T. Tajima, T. Fuchigami, Tetrahedron 2006, 62, 3761–
3769; c) Y. Ohtsuka, T. Yamakawa, Tetrahedron 2011, 67,
ppm. IR (neat): ν = 2923, 1690, 1501, 1103 cm–1. HRMS (ESI):
˜
calcd. for C18H25F2N2O4 [M + H]+ 371.1782; found 371.1779.
Acknowledgments
This work was partially supported by INSA Rouen, Rouen Univer-
sity, the Centre National de la Recherche Scientifique (CNRS), the
Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O43656
/KAP1
Date: 30-01-15 13:12:49
Pages: 9
M.-C. Belhomme, A. Bayle, T. Poisson, X. Pannecoucke
FULL PAPER
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[13] A similar trend has been previously observed, see ref.[8c]
Received: December 19, 2014
Published Online: ᭿
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43656
/KAP1
Date: 30-01-15 13:12:49
Pages: 9
Ethoxycarbonyldifluoromethylation of Electron-Rich Arenes
Fluorinated Compounds
M.-C. Belhomme, A. Bayle, T. Poisson,*
X. Pannecoucke* ............................... 1–9
Copper-Catalyzed Innate Ethoxycarbon-
yldifluoromethylation of Electron-Rich
Arenes
Readily available BrCF2CO2Et is used to
introduce a fluorine-containing group into
electron-rich arenes. This radical-free trans-
formation proceeds through a CuI/CuIII cy-
cle, and was applied to a wide range of
anisole and aniline derivatives.
Keywords: Synthetic methods
/ Homo-
geneous catalysis / Aromatic substitution /
Arenes / Fluorine / Copper
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9