Access to difluoromethylated alkynes through the castro-stephens reaction

Article abstract of DOI:10.1002/ejoc.201402937

An efficient synthesis of difluoromethylated alkynes is described. A panel of readily available Cu^I acetylides undergo direct difluoromethylation by using BrCF₂CO₂Et, which is an inexpensive, easy to handle, commercially available fluorinated reagent. The reaction, which is based on a Castro-Stephens transformation, proceeds smoothly under mild conditions offering a new synthetic route for the direct introduction of the difluoromethylated group into alkynes that does not involve ozone-depleting reagents. The resulting products were obtained with good yields by using CsOPiv and Cu(OAc)₂ as additives.

Full text of DOI:10.1002/ejoc.201402937

Job/Unit: O42937
/KAP1
Date: 29-09-14 16:59:24
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201402937
Access to Difluoromethylated Alkynes through the Castro–Stephens Reaction
Tatiana Besset,*[a] Thomas Poisson,*[a] and Xavier Pannecoucke[a]
Keywords: Synthetic methods / Fluorine / Alkynes / Copper
An efficient synthesis of difluoromethylated alkynes is de-
scribed. A panel of readily available CuI acetylides undergo
direct difluoromethylation by using BrCF2CO2Et, which is an
inexpensive, easy to handle, commercially available fluorin-
ated reagent. The reaction, which is based on a Castro–
Stephens transformation, proceeds smoothly under mild con-
ditions offering a new synthetic route for the direct introduc-
tion of the difluoromethylated group into alkynes that does
not involve ozone-depleting reagents. The resulting products
were obtained with good yields by using CsOPiv and
Cu(OAc)2 as additives.
moieties onto aromatic backbones, whereas the direct intro-
duction of fluorinated groups on alkenes and alkynes re-
mains scarce.
Introduction
Over the last five years, the organic chemist community
has witnessed a resurgence of interest in organofluorine
chemistry.[1] This growing interest is partly explained by the
impressive capacity of the fluorine atom to alter the chemi-
cal and physical properties of a molecule. This ability is
considered to be a real asset in the quest of new bioactive
products and, as a result, molecules containing fluorine and
fluorinated groups constitute several agrochemical and
pharmaceutical products.[2] It is therefore not surprising
that much effort has been devoted to the design of elegant
and straightforward methodologies to reach these fluorin-
ated targets. Basically, typical approaches with which to ac-
cess such fluorinated compounds rely on either the func-
tionalization of fluorinated building blocks or the introduc-
tion of fluorinated moieties on functionalized substrates.
The latter approach has recently been widely explored by
using (1) radical reactions,[3] (2) transition-metal-catalyzed
cross-coupling reaction by means of either a fluorinated or-
ganometallic species or a halogenated fluorinated species[4]
and, more recently, through (3) transition-metal-catalyzed
direct C–H bond functionalization of non-prefunction-
alized species with a fluorinated partner.[5] The latter strat-
egy mainly focused on the introduction of the fluorine atom
or the CF3 group, whereas the introduction of function-
alized fluorinated moieties remained underexplored despite
the high potential for post-functionalization of the resulting
products.[6] In addition, these reported methodologies
mostly focused on the direct introduction of fluorinated
Notably, only a few reports have described the direct tri-
fluoromethylation,
trifluoromethanesulfanylation
and
fluorination of alkynes generally by means of transition-
metal catalysis or base-promoted reactions, despite their
high synthetic value (Scheme 1).[7] In contrast, the introduc-
tion of functionalized fluorinated groups such as –CF2R
[e.g., R = CO2Et, SO2Ph, P(O)(OEt)2] is still underdevel-
oped, despite the high level of functionalization of the re-
sulting adducts.[8] For instance the synthesis of difluoro-
methylated acetylene derivatives, which have been exten-
sively studied by Hammond and co-workers,[8a,8b] required
a multistep sequence starting from terminal alkynes. How-
ever, this procedure used difluoropropargyl bromide as an
intermediate, which was itself obtained after the addition of
a lithium acetylide species to CF2Br2, an ozone-depleting
reagent that is forbidden by the Montreal protocol.[9] As
part of our ongoing research program dedicated to the de-
velopment of new methodologies with which to access
valuable fluorinated building blocks, particular attention
was paid to the synthesis of difluoromethylated scaffolds
using BrCF2CO2Et, a commercially available fluorinating
agent.[10] We recently reported the addition of BrCF2CO2Et
on alkynes, leading to fluorinated bromoalkenes, and dur-
ing the course of our investigations we have been able to
selectively obtain, depending on the reaction conditions, the
difluoromethylated alkynes albeit in low yields due to com-
petitive Glaser–Hay coupling reaction.[11] To tackle this
lack of selectivity, we envisioned that the use of a preformed
copper acetylide might offer a promising alternative for the
synthesis of such unsaturated compounds. Indeed, recent
reports using a modified version of the Stephens–Castro
reaction[12] allowed the introduction of several nucleophiles
on alkynes (pyrrolidinone, dialkyl phosphites, phosphine
boranes etc.) based on the use of these copper acetylide
[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: tatiana.besset@insa-rouen.fr
thomas.poisson@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.201402937.
Eur. J. Org. Chem. 0000, 0–0
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T. Besset, T. Poisson, X. Pannecoucke
FULL PAPER
derivatives under oxidative conditions.[13] Herein, we report the reaction time probably reduced the amount of degrada-
our contribution toward the synthesis of difluorometh- tion of the fluorinated alkynes in the reaction media. Grati-
ylated alkynes from copper acetylide derivatives and fyingly, the combination of both CsOPiv and Cu(OAc)2
BrCF2CO2Et.
turned out to be highly efficient, giving the desired product
2a in 77% isolated yield (entry 13).[15] Although their func-
tion have not yet been clearly defined, these observations
highlighted the crucial role of CsOPiv and Cu(OAc)2 as key
additives for the success of such transformations. Finally,
control experiments revealed that the exclusion of 1,10-
phenanthroline had a detrimental effect on the reaction be-
cause no product was observed (entry 14). Notably, the use
of 5 equiv. BrCF2CO2Et was required to ensure acceptable
yields; all attempts to reduce this amount were unsuccess-
ful.
Table 1. Optimization of reaction conditions.[a]
Entry Ligand[b]
Solvent[b] Base
Additive
Yield
[%][c]
Scheme 1. State of the art.
1
TMEDA
DMF
–
–
6
2
3
4
5
6
7
8
9
2,6-bipyridine DMF
–
–
–
–
–
–
–
–
–
–
–
19
25
2
18
15
26
30
12
0
35
52[e]
77[e]
–
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
DMF
pyridine
DMSO
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Results and Discussion
NaOAc
CsOAc
CsOPiv
–
–
–
–
We started our investigations with the difluorometh-
ylation of copper(I) phenylacetylide (1a) as a model sub-
strate with ethyl bromodifluoroacetate (Table 1). Pleasingly,
in the presence of N,N,NЈ,NЈ-tetramethylethylenediamine
(TMEDA) as a ligand, traces of the expected product 2a
were observed (entry 1). To enhance the conversion of Cu-
acetylide 1a into 2a, other ligands were then evaluated. 2,6-
Bipyridine was tested, affording 2a in 19% yield and 1,10-
phenanthroline appeared to be the most efficient, giving the
product in 25% yield (entries 2 and 3).[14] A survey of sol-
vents was then performed: when pyridine, which is com-
monly used as a solvent in the Castro–Stephens reaction,
was employed, the reactivity dropped drastically, whereas
the use of dimethyl sulfoxide (DMSO) gave slightly lower
yield than obtained with N,N-dimethylformamide (DMF)
(entries 4 and 5). We then studied the effect of base on the
outcome of the reaction. When the reaction was carried out
Cu(acac)2
CuBr2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
10
11
12[d] Phen
13[d] Phen
CsOPiv
–
14
–
[a] Reaction conditions: 1a (0.2 mmol), BrCF2CO2Et (5 equiv.), li-
gand (1.1 equiv.), base (1 equiv.), additive (1 equiv.), [1a]
=
0.2 molL–1, 80 °C, 16 h, air. [b] TMEDA = N,N,NЈ,NЈ-tetramethyl-
ethylenediamine, DMF = N,N-dimethylformamide, DMSO = di-
methyl sulfoxide. Phen = 1,10-Phenanthroline. [c] Yield determined
by 19F NMR spectroscopic analysis of the crude reaction mixture
by using trifluoroacetophenone or α,α,α-trifluorotoluene as an in-
ternal standard. [d] 2 h. [e] Isolated yield.
With the optimized reaction conditions in hand, we ex-
in the presence of 1 equiv. NaOAc, a lower yield was ob- amined the scope of the transformation (Scheme 2). Pleas-
tained (entry 6). CsOAc gave similar yield to that obtained ingly, the reaction proceeded smoothly, affording the de-
when the reaction was performed without base, whereas the sired products with moderate to good yields. In general, the
use of CsOPiv furnished 2a in a slightly improved 30% yield transformation turned out to be tolerant to several func-
(entries 7 and 8). To study further the reaction conditions, tional groups. Indeed, a large variety of aromatic alkynes
different copper salts were tested as additives. First, the re- were efficiently converted into the corresponding difluoro-
action was carried out in the presence of 1 equiv. of Cu- methylated products. For alkynes bearing electron-donating
(acac)2, affording the desired product in lower yield, (2b, 2c, 2d, 2e) or electron-withdrawing groups (2f, 2g, 2h)
whereas the use of CuBr2 suppressed the reaction (entries 9 on the aromatic ring, the reaction proceeded nicely and fur-
and 10). Gratifyingly, the use of 1 equiv. of Cu(OAc)2 pro- nished the fluorinated alkynes in good yields (57–78%).
vided the desired product 2a in 35% yield (entry 11). More- The substitution pattern (2b vs. 2c) and the electronic ef-
over, a reduced reaction time (2 vs. 16 h) had a beneficial fects of the substituents on the aromatic core had no signifi-
effect on the reactivity, and difluoromethylated alkyne 2a cant influence on the outcome of the reaction. Notably, the
was isolated in 52% yield (entry 12). Notably, a decrease of reaction was also compatible with the presence of a halogen
2
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Synthesis of Difluoromethylated Alkynes
Scheme 2. Scope of the difluoromethylation of copper(I) acetylides 1. [a] Reaction conditions: 1 (0.4 mmol), BrCF2CO2Et (2.0 mmol),
Phen (0.44 mmol), CsOPiv (0.4 mmol), Cu(OAc)2 (0.4 mmol), DMF (2 mL), 80 °C, 2 h, air. Isolated yields. [b] Compounds 2e and 2i
were isolated as a mixture with an inseparable impurity (20%).
atom on the aromatic core such as chlorine (2i), allowing the reaction proved to be chemoselective and functional
further synthetic functionalization. In addition, even more group tolerant, thus demonstrating the synthetic value of
challenging heteroaromatic-substituted alkynes such as this reaction.
thiophene 1j were readily converted into the corresponding
fluorinated product, albeit in moderate yield (54%). Grati-
Experimental Section
fyingly, the scope of the reaction was not limited to aro-
matic substrates and was successfully expanded to include
aliphatic alkynes 2k and 2l, thus showcasing the effective-
ness of the reaction. To assess the versatility of this method-
ology, the reaction was evaluated on the enyne derivative
General Methods: All reactions were carried out using oven-dried
glassware and magnetic stirring under an air atmosphere. Column
chromatography was performed with silica gel (0.060–0.200 nm)
unless otherwise stated. Analytical thin-layer chromatography was
1m. In this case, the expected difluoromethylated alkyne 2m performed on silica gel aluminum plates with F-254 indicator and
visualized by UV light (254 nm) and/or chemical staining with
KMnO4 solution. H NMR spectra were recorded in CDCl3 with
was isolated in moderate yield (35%), thus highlighting the
functional group tolerance and the chemoselectivity of our
developed process.
1
a Bruker DXP 300 at 300 MHz, 13C NMR spectra at 75 MHz and
19F NMR spectra at 282 MHz. Chemical shifts (δ) are quoted in
parts per million (ppm) relative to residual solvent (CHCl3: δ =
7.26 ppm for 1H, δ = 77.0 ppm for 13C or relative to external
CFCl3: δ = 0 ppm for 19F). The following abbreviations have been
used: δ (chemical shift), J (coupling constant), s (singlet), d (doub-
let), t (triplet), q (quartet), m (multiplet). High-resolution mass
spectra (HRMS) were recorded with a Waters LCT Premier, IR
spectra were recorded with a PerkinElmer Spectrum 100. All anhy-
drous solvents were dried by using standard techniques. Pyridine
was distilled from CaH2 prior to use. Anhydrous DMF and DMSO
(sealed bottle) were purchased from Acros. CuI acetylides 1a–m
were prepared according to reported procedures.[13a,13b] All the so-
lid bases: sodium acetate, cesium acetate, and cesium pivalate were
Conclusions
We have reported an easy access to difluoromethylated
alkynes by means of a modified Castro–Stephen reaction.
This method represents a straightforward alternative to the
use of CF2Br2, which is forbidden by the Montreal proto-
col. This process uses the valuable BrCF2CO2Et reagent as
the fluorinated source and allows the difluoromethylation
of aryl, heteroaryl and alkyl-substituted alkynes without the
use of ozone-depleting reagents. The resulting products
were obtained in moderate to good yields and the scope of dried with P2O5 under vacuum prior to use.
Eur. J. Org. Chem. 0000, 0–0
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T. Besset, T. Poisson, X. Pannecoucke
FULL PAPER
General Procedure for the Preparation for Alkynyl Copper Reagents
1: A terminal alkyne (5 mmol, 1 equiv.) was added dropwise to a
solution of CuI (10 mmol, 2 equiv.) in a 28% NH3 aqueous solu-
tion (25 mL) and EtOH (15 mL). The reaction mixture was stirred
for 24 h at room temperature. The solution was filtered and the
yellow precipitate was successively washed with a 10% NH3 aque-
ous solution (3ϫ 50 mL), H2O (3ϫ 50 mL), EtOH (3ϫ 50 mL),
and Et2O (3ϫ 50 mL). The yellow solid was then dried under high
vacuum overnight to furnish the desired alkynylcopper derivative
1.
2241, 1773, 1467, 1304, 1275, 1146, 1075 cm–1. HRMS (EI+): m/z
calcd. for C16H18F2O2 [M]+ 280.1275; found: 280.1290.
Ethyl 4-(Biphenyl-4-yl)-2,2-difluorobut-3-ynoate (2e): Obtained as a
yellow oil in 57% yield in a mixture with an inseparable impurity
(20%), after column chromatography (SiO2; pentane/Et2O, 100:0
to 90:10); Rf = 0.61 (pentane/Et2O, 90:10). 1H NMR (300 MHz,
CDCl3): δ = 7.70–7.34 (m, 9 H), 4.44 (q, J = 7.2 Hz, 2 H), 1.43 (t,
J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.6 (t,
J = 34.5 Hz), 143.3, 139.8, 132.8 (t, J = 2.4 Hz), 129.0, 128.1, 127.2,
127.1, 118.0 (t, J = 3.1 Hz), 104.9 (t, J = 242.4 Hz), 89.6 (t, J =
6.3 Hz), 78.9 (t, J = 38.1 Hz), 63.8, 13.9 ppm. 19F NMR (282 MHz,
General Procedure: Alkynylcopper derivative 1 (0.4 mmol, 1 equiv.),
Phen (0.44 mmol, 1.1 equiv.), Cu(OAc)2 (0.4 mmol, 1 equiv.), CsO-
Piv (0.4 mmol, 1 equiv.), and DMF (2 mL) were mixed under air
in a Schlenk flask (10 mL). Ethyl bromodifluoroacetate (2 mmol,
5 equiv.) was then added and the reactor was closed and held at
80 °C for 2 h. The reactor was then cooled to room temp. and the
products were directly purified by SiO2 column chromatography
(Caution: The products are highly volatile!).
CDCl ): δ = –89.8 ppm. IR (neat): ν = 2983, 2239, 1769, 1485,
˜
3
1274, 1140, 1075 cm–1. HRMS (EI+): m/z calcd. for C18H14F2O2
[M]+ 300.0962; found: 300.0954.
Ethyl 4-(4-Cyanophenyl)-2,2-difluorobut-3-ynoate (2f): Obtained as
a yellow oil in 57% yield, after column (SiO2; pentane/Et2O, 100:0
to 90:10); Rf = 0.32 (pentane/Et2O, 90:10). 1H NMR (300 MHz,
CDCl3): δ = 7.75–7.57 (m, 4 H), 4.41 (q, J = 7.2 Hz, 2 H), 1.39 (t,
J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.0 (t,
J = 34.0 Hz), 132.9 (t, J = 2.2 Hz), 132.2, 123.9, 117.7, 114.1, 104.5
(t, J = 243.8 Hz), 87.0 (t, J = 6.3 Hz), 81.7 (t, J = 38.3 Hz), 64.1,
13.8 ppm. 19F NMR (282 MHz, CDCl3): δ = –90.8 ppm. IR (neat):
Ethyl 2,2-Difluoro-4-phenylbut-3-ynoate (2a): Obtained as a pale-
yellow oil in 77% yield, after column chromatography (SiO2; pent-
ane/Et2O, 100:0 to 90:10); Rf = 0.19 (pentane/Et2O, 95:5). 1H NMR
(300 MHz, CDCl3): δ = 7.60–7.30 (m, 5 H), 4.41 (q, J = 7.2 Hz, 2
H), 1.39 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 161.5 (t, J = 34.5 Hz), 132.3 (t, J = 2.3 Hz), 130.5, 128.5, 119.2
(t, J = 3.0 Hz), 104.9 (t, J = 242.4 Hz), 89.6 (t, J = 6.3 Hz), 78.3
(t, J = 37.8 Hz), 63.8, 13.8 ppm. 19F NMR (282 MHz, CDCl3): δ
ν = 2994, 2237, 1765, 1471, 1275, 1141, 1069 cm–1. HRMS (EI+):
˜
m/z calcd. for C13H9F2NO2 [M]+ 249.0601; found: 249.0597.
Ethyl 2,2-Difluoro-4-[4-(trifluoromethyl)phenyl]but-3-ynoate (2g):
Obtained as a yellow oil in 62% yield, after column chromatog-
raphy (SiO2; pentane/Et2O, 100:0 to 90:10); Rf = 0.76 (pentane/
Et2O, 90:10). 1H NMR (300 MHz, CDCl3): δ = 7.74–7.46 (m, 4
H), 4.42 (q, J = 7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 161.2 (t, J = 34.1 Hz), 132.7 (t, J =
2.2 Hz), 132.2 (q, J = 32.9 Hz), 125.5 (q, J = 3.7 Hz), 123.5 (q, J
= 272.6 Hz), 123.1, 104.7 (t, J = 243.3 Hz), 87.6 (t, J = 6.3 Hz),
80.3 (t, J = 38.3 Hz), 64.0, 13.9 ppm. 19F NMR (282 MHz, CDCl3):
= –89.9 ppm. IR (neat): ν = 2987, 2242, 1772, 1491, 1446, 1273,
˜
1141, 1076 cm–1. HRMS (EI+): m/z calcd. for C12H10F2O2 [M+]
224.0649; found 224.0647.
Ethyl 2,2-Difluoro-4-(3-methylphenyl)but-3-ynoate (2b): Obtained
as a yellow oil in 78% yield, after column chromatography (SiO2;
pentane/Et2O, 100:0 to 90:10); Rf = 0.51 (pentane/Et2O, 90:10). 1H
NMR (300 MHz, CDCl3): δ = 7.35 (m, 2 H), 7.25 (m, 2 H), 4.40
(q, J = 7.0 Hz, 2 H), 2.34 (s, 3 H), 1.39 (t, J = 7.1 Hz, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 161.7 (t, J = 34.6 Hz), 138.4,
132.9 (t, J = 2.4 Hz), 131.4, 129.4 (t, J = 2.3 Hz), 128.4, 119.1 (t,
J = 2.9 Hz), 104.9 (t, J = 242.3 Hz), 89.9 (t, J = 6.4 Hz), 78.0 (t, J
= 38.0 Hz), 63.9, 21.2, 14.0 ppm. 19F NMR (282 MHz, CDCl3): δ
δ = –63.2, –90.6 ppm. IR (neat): ν = 2991, 2248, 1773, 1321, 1275,
˜
1129, 1060 cm–1. HRMS (EI+): m/z calcd. for C13H9F5O2 [M]+
292.0523; found: 292.0518.
Ethyl 2,2-Difluoro-4-(4-fluorophenyl)-but-3-ynoate (2h): Obtained
as a yellow oil in 64% yield, after column chromatography (SiO2;
pentane/Et2O, 100:0 to 90:10); Rf = 0.52 (pentane/Et2O, 90:10). 1H
NMR (300 MHz, CDCl3): δ = 7.53 (m, 2 H), 7.07 (m, 2 H), 4.40
(q, J = 7.2 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 161.6 (t, J = 34.4 Hz), 134.7 (dt, J = 8.8,
2.3 Hz), 116.4, 116.1, 115.6, 105.0 (t, J = 242.5 Hz), 88.7 (t, J =
6.3 Hz), 78.3 (t, J = 38.1 Hz), 64.0, 14.0 ppm. 19F NMR (282 MHz,
= –89.8 ppm. IR (neat): ν = 2986, 2243, 1770, 1280, 1073 cm–1.
˜
HRMS (EI+): m/z calcd. for C13H12F2O2 [M]+ 238.0805; found:
238.0800.
Ethyl 2,2-Difluoro-4-(4-methylphenyl)but-3-ynoate (2c): Obtained as
a pale-yellow oil in 69% yield, after column chromatography (SiO2;
pentane/Et2O, 100:0 to 90:10); Rf = 0.54 (pentane/Et2O, 90:10). 1H
NMR (300 MHz, CDCl3): δ = 7.39–7.03 (m, 4 H), 4.32 (q, J =
7.2 Hz, 2 H), 2.29 (s, 3 H), 1.31 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 161.6 (t, J = 34.6 Hz), 141.0, 132.2 (t, J =
2.3 Hz), 129.3, 116.2 (t, J = 2.9 Hz), 105.0 (t, J = 242.0 Hz), 90.0
(t, J = 6.4 Hz), 77.8 (t, J = 38.0 Hz), 63.7, 21.6, 13.8 ppm. 19F
CDCl ): δ = –90.0, –106.7 ppm. IR (neat): ν = 2987, 2244, 1770,
˜
3
1507, 1275, 1232, 1140, 1073, 836 cm–1. HRMS (EI+): m/z calcd.
for C12H9F3O2 [M]+ 242.0555; found: 242.0554.
Ethyl 4-(4-Chlorophenyl)-2,2-difluorobut-3-ynoate (2i): Obtained as
a yellow oil in 55% yield in a mixture with an inseparable impurity
(20%), after column chromatography (SiO2; pentane/Et2O, 100:0
to 90:10); Rf = 0.70 (pentane/Et2O, 90:10). 1H NMR (300 MHz,
CDCl3): δ = 7.48–7.46 (m, 2 H), 7.37–7.34 (m, 2 H), 4.41 (q, J =
7.2 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 161.3 (t, J = 34.4 Hz), 136.9, 133.6 (t, J = 2.3 Hz),
129.0, 117.7 (t, J = 2.9 Hz), 104.8 (t, J = 242.7 Hz), 88.3 (t, J =
6.3 Hz), 79.2 (t, J = 38.2 Hz), 63.9, 13.9 ppm. 19F NMR (282 MHz,
NMR (282 MHz, CDCl ): δ = –89.7 ppm. IR (neat): ν = 2988,
˜
3
2239, 1770, 1510, 1302, 1274, 1137, 1073 cm–1. HRMS (EI+): m/z
calcd. for C13H12F2O2 [M]+ 238.0805; found: 238.0790.
Ethyl 4-(4-tert-Butylphenyl)-2,2-difluorobut-3-ynoate (2d): Obtained
as a yellow oil in 64% yield, after column chromatography (SiO2;
pentane/Et2O, 100:0 to 90:10); Rf = 0.72 (pentane/Et2O, 90:10). 1H
NMR (300 MHz, CDCl3): δ = 7.56–7.34 (m, 4 H), 4.41 (q, J =
7.2 Hz, 2 H), 1.40 (t, J = 7.2 Hz, 3 H), 1.32 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 161.6 (t, J = 34.7 Hz), 154.1, 132.1 (t, J =
2.3 Hz), 125.6, 116.2 (t, J = 2.9 Hz), 105.0 (t, J = 242.0 Hz), 90.0
(t, J = 6.4 Hz), 77.8 (t, J = 38.1 Hz), 63.7, 34.9, 31.0, 13.8 ppm.
CDCl ): δ = –90.2 ppm. IR (neat): ν = 2987, 2243, 1768, 1490,
˜
3
1273, 1071, 828 cm–1. HRMS (EI+): m/z calcd. for C12H9ClF2O2
[M]+ 258.0259; found: 258.0274.
Ethyl 2,2-Difluoro-4-(3-thienyl)but-3-ynoate (2j): Obtained as a
19F NMR (282 MHz, CDCl ): δ = –89.7 ppm. IR (neat): ν = 2966, pale-yellow oil in 54% yield, after column chromatography (SiO2;
˜
3
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Synthesis of Difluoromethylated Alkynes
pentane/Et2O, 100:0 to 90:10); Rf = 0.60 (pentane/Et2O, 90:10). 1H
NMR (300 MHz, CDCl3): δ = 7.68 (s, 1 H), 7.32–7.31 (m, 1 H),
7.19–7.18 (m, 1 H), 4.40 (q, J = 7.2 Hz, 2 H), 1.39 (t, J = 7.2 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.7 (t, J = 34.5 Hz),
132.9 (t, J = 2.8 Hz), 129.9 (d, J = 1.7 Hz), 126.4, 118.7, 105.2 (t,
J = 242.3 Hz), 85.3 (t, J = 6.3 Hz), 78.4 (t, J = 38.1 Hz), 64.0,
14.1 ppm. 19F NMR (282 MHz, CDCl3): δ = –89.8 ppm. IR (neat):
2012, 5, 30–37; d) T. Liang, C. N. Neumann, T. Ritter, Angew.
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Chem. Rev. 2014, 114, 2432–2506.
[2]
[3]
ν = 3117, 2988, 2240, 1768, 1301, 1257, 1201, 1132, 1073, 786 cm–1.
˜
a) Q. Y. Chen, Z. Y. Yang, J. Fluorine Chem. 1985, 28, 399–
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HRMS (EI+): m/z calcd. for C10H8F2O2S [M]+ 230.0213; found:
230.0218.
Ethyl 2,2-Difluorotetradec-3-ynoate (2k): Obtained as a yellow oil
in 75% yield, after column chromatography (SiO2; pentane/Et2O,
100:0 to 90:10); Rf = 0.89 (pentane/Et2O, 90:10). 1H NMR
(300 MHz, CDCl3): δ = 4.35 (q, J = 7.2 Hz, 2 H), 2.38–2.21 (m, 2
H), 1.63–1.49 (m, 2 H), 1.43–1.13 (m, 17 H), 0.87 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.8 (t, J = 34.7 Hz),
104.4 (t, J = 241.1 Hz), 92.5 (t, J = 6.2 Hz), 70.7 (t, J = 37.7 Hz),
63.5, 31.9, 29.5, 29.4, 29.3, 29.0, 28.7, 27.4, 22.6, 18.5 (t, J =
2.3 Hz), 14.1, 13.8 ppm. 19F NMR (282 MHz, CDCl3): δ =
[4]
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–89.1 ppm. IR (neat): ν = 2926, 2856, 2254, 1773, 1466, 1295, 1228,
˜
1105, 1015 cm–1. HRMS (CI+): m/z calcd. for C16H27F2O2 [M +
H]+ 289.1979; found: 289.1978.
Ethyl 2,2-Difluoro-7-phenylhept-3-ynoate (2l): Obtained as a yellow
oil in 51% yield, after column chromatography (SiO2; pentane/
1
Et2O, 100:0 to 90:10); Rf = 0.80 (pentane/Et2O, 90:10). H NMR
(300 MHz, CDCl3): δ = 7.42–7.09 (m, 5 H), 4.38 (q, J = 7.2 Hz, 2
H), 2.73 (t, J = 7.5 Hz, 2 H), 2.37–2.20 (m, 2 H), 1.98–1.78 (m, 2
H), 1.38 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 161.8 (t, J = 34.7 Hz), 140.7, 128.5, 126.2, 104.4 (t, J = 241.4 Hz),
91.9 (t, J = 6.3 Hz), 71.3 (t, J = 37.7 Hz), 63.6, 34.5, 28.9 (t, J =
2.0 Hz), 17.8 (t, J = 2.5 Hz), 13.9 ppm. One carbon is overlapped.
[8]
19F NMR (282 MHz, CDCl ): δ = –89.1 ppm. IR (neat): ν = 2944,
˜
3
2253, 1770, 1299, 1228, 1098, 747 cm–1. HRMS (CI+): m/z calcd.
for C15H17F2O2 [M + H]+ 267.1197; found: 267.1199.
[9]
Ethyl 4-Cyclohexenyl-2,2-difluorobut-3-ynoate (2m): Obtained as a
yellow oil in 35% yield, after column chromatography (SiO2; pent-
ane/Et2O, 100:0 to 90:10); Rf = 0.63 (pentane/Et2O, 90:10). 1H
NMR (300 MHz, CDCl3): δ = 6.37 (s, 1 H), 4.37 (q, J = 7.2 Hz, 2
H), 2.21–2.06 (m, 4 H), 1.71–1.52 (m, 4 H), 1.37 (t, J = 7.2 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 161.8 (t, J = 34.9 Hz),
140.8 (t, J = 3.5 Hz), 118.0 (t, J = 3.4 Hz), 105.0 (t, J = 241.4 Hz),
91.7 (t, J = 6.6 Hz), 76.0 (t, J = 37.8 Hz), 63.6, 27.9, 25.7, 21.8,
21.1, 13.8 ppm. 19F NMR (282 MHz, CDCl3): δ = –89.2 ppm. IR
[10]
(neat): ν = 2939, 2228, 1770, 1298, 1273, 1246, 1123, 1067 cm–1.
˜
[11]
[12]
HRMS (EI+): m/z calcd. for C12H14F2O2 [M]+ 228.0962; found:
228.0967.
Supporting Information (see footnote on the first page of this arti-
1
cle): H, 13C and 19F NMR spectra.
Acknowledgments
[13]
a) K. Jouvin, R. Veillard, C. Theunissen, C. Alayrac, A.-C.
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2014, 50, 10008–10018.
This work was partially supported by INSA Rouen, Rouen Univer-
sity, the Centre National de la Recherche Scientifique (CNRS), the
European Fund for Regional Development (EFRD), Labex
SynOrg (ANR-11-LABX-0029) and the Région Haute-Normandie
(CRUNCh network).
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Eur. J. Org. Chem. 0000, 0–0
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Job/Unit: O42937
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Date: 29-09-14 16:59:24
Pages: 7
T. Besset, T. Poisson, X. Pannecoucke
FULL PAPER
Fujikawa, H. Amii, Adv. Synth. Catal. 2011, 353, 1247–1252;
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Received: July 16, 2014
Published Online: ᭿
[15] The crucial roles of Cu(OAc)2 and of carboxylate has been pre-
viously reported, see: a) L. Ackermann, Chem. Rev. 2011, 111,
6
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/KAP1
Date: 29-09-14 16:59:24
Pages: 7
Synthesis of Difluoromethylated Alkynes
Fluorinated Compounds
T. Besset,* T. Poisson,*
X. Pannecoucke ................................. 1–7
Access to Difluoromethylated Alkynes
through the Castro–Stephens Reaction
Based on a Castro–Stephens transform-
ation, a coupling reaction between copper
acetylides and inexpensive and readily
available BrCF2CO2Et was developed. The
approach offers straightforward access to a
panel of synthetically valuable aryl, het-
eroaryl and alkyl difluoromethylated al-
kynes.
Keywords: Synthetic methods / Fluorine /
Alkynes / Copper
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