An efficient synthesis of (Z)-α-fluorochalcones via the palladium-catalyzed cross-coupling reaction of (Z)-α-fluorocinnamoyl chloride with boronic acids

Article abstract of DOI:10.1016/j.tet.2012.12.025

An efficient synthesis of α-fluorochalcones (1,3-diphenyl-2- fluoroprop-2-en-1-one) based on the Suzuki-Miyaura palladium-catalyzed cross-coupling reaction of arylboronic acids with α-fluorocinnamoyl chlorides in the presence of Cs₂CO₃

Full text of DOI:10.1016/j.tet.2012.12.025

Tetrahedron 69 (2013) 1735e1738
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An efficient synthesis of (Z)-a-fluorochalcones via the palladium-
catalyzed cross-coupling reaction of (Z)-
a-fluorocinnamoyl chloride
with boronic acids
,
,
Said Eddarir a b, Mohammed Kajjout a, Christian Rolando a
*
a
ꢀ
ꢁ
ꢀ
Universite de Lille 1, Sciences et Technologies, USR CNRS 3290 Miniaturisation pour la Synthese, l’Analyse & la Proteomique, 59655 Villeneuve d’Ascq Cedex, France
Universite de Cadi Ayyad, Faculte des Sciences et Techniques Gueliz, BP 549 Marrakech, Morocco
b
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 August 2012
Received in revised form 3 December 2012
Accepted 11 December 2012
Available online 19 December 2012
An efficient synthesis of
kieMiyaura palladium-catalyzed cross-coupling reaction of arylboronic acids with
chlorides in the presence of Cs2CO3 in toluene is described. This approach allows the synthesis of
fluorinated analogues of functionalized natural chalcones.
a
-fluorochalcones (1,3-diphenyl-2-fluoroprop-2-en-1-one) based on the Suzu-
-fluorocinnamoyl
a
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
a
-Fluorochalcones
Palladium
Cross-coupling
Catalysis
1. Introduction
a sequence involving Mg metal-promoted successive double
defluorination,14 by the Wittig reaction via the corresponding
a-flu-
Chalcones, or 1,3-diphenyl-2-propen-1-ones represent an impor-
tant group in the polyphenolic family, abundant in fruits, vegetables,
and various edible plants.1 During biosynthesis these compounds are
the precursors of flavonoids and isoflavonoids. Chemically, they
consist of open-chain flavonoids in which the two aromatic rings are
oro substituted ylides,15 from corresponding propargyl acetates via
a gold-catalyzed rearrangement-fluorination,16 or by nucleophilic
fluoromethylation of benzyl halides using
a-fluoro-a-(phenyl-
sulfonyl)methane.17 We previously proposed a generalmethod forthe
synthesis of chalcones based on the SuzukieMiyaura reaction either
between cinnamoyl chlorides and phenylboronic acids or between
benzoyl chlorides and phenylvinylboronic acids.18 As an extension of
this work we herein describe the synthesis of a series of chalcones
linked by a three carbons-a,b-unsaturated carbonyl system. Chal-
cones have been reported to possess multiple biological activities,
such as antioxidant,2 antimalarial,3 antibacterial,4 antileishmanial,5
anti-HIV,6 anti-inflammatory,7 and antitumoral.8 The replacement
of a hydrogen by a fluorine atom is used in drug development to alter
biological functions. Monofluoro analogues of biological active mol-
ecules have often proved to have improved properties.9 Chalcones
bearing a fluorine atom or a trifluoromethyl group on either of the
aromatic rings have been shown to have many therapeutically activ-
ities, such as inhibition of nitric oxide production,10 inhibition of 5-
lipoxygenase, and anti-carcinogenic agent,11 and anti-vascular phar-
macological properties.12 Lawrence et al. reported that chalcones with
bearing a fluorine atom in the
prop-2-en-1-one) by direct palladium-catalyzed cross-coupling re-
action of arylboronic acids with -fluorocinnamoyl chlorides. This
a-position (1,3-diphenyl-2-fluoro-
a
method will be useful for the synthesis of a wide variety of naturally
occurring chalcones, as this chemistry is compatible with the easily
deprotected MOM-protected phenol function as we have shown
during the synthesis of fluororesveratrol.19
2. Results and discussion
a fluorine atom in the
a position of the conjugated central double
bond have potent cytotoxic and tubulin inhibitory properties.13
a-
Palladium-catalyzed cross-coupling reactions have a large impact
on synthetic organic chemistry and have been applied to the syn-
thesis of various biologically active compounds20 and complex mo-
lecular structures.21 The palladium-catalyzed coupling of activated
carboxylic acid with nucleophiles is a straightforward access to
ketones. The reaction can be performed using acid chlorides,22
acid anhydrides,23 or thio-esters.24 The same acyl-palladium
Fluorochalcones were obtained from trifluoromethyl ketones via
* Corresponding author. Tel.: þ33 320434977; fax: þ33 320336136; e-mail ad-
dresses:
Christian.rolando@univ-lille1.fr,
rolando.christian@wanadoo.fr
(C. Rolando).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.025

1736
S. Eddarir et al. / Tetrahedron 69 (2013) 1735e1738
intermediates may be obtained by the carbonylation of a halide with
carbon monoxide, leading to a one-pot synthesis of ketones from an
organic halide, CO, and a nucleophile.25 To the best of our knowledge
fluoro-3-(4-methoxyphenyl)-2-propenoic acid were obtained in
63% and 59% isolated yield, respectively.
Direct conversion of (Z)-a-fluorocinnamic acids 3 into (Z) a-flu-
only a few examples of the palladium-catalyzed synthesis of
oro- -unsaturated ketones have been described in literature. The
first example, which has been described is the preparation of
fluoro- -unsaturated ketones by palladium-Cu(I) co-catalyzed
a
-flu-
orocinnamoyl chlorides 4 was achieved by the treatment of fluo-
rocinnamic acids with thionyl chloride in dichloromethane.37 Crude
acid chloride 4 was used without further purification for this step
due to partial decomposition during distillation. The next step of this
work is the SuzukieMiyaura reaction of the acids chloride 4aed with
phenylboronic acids 5aed. In our previous synthesis of chalcones we
used the protocol described by Haddach et al.38 for the palladium-
catalyzed cross-coupling of acid chlorides with arylboronic acids
based on using tetrakis(triphenylphosphine)palladium(0) as the
catalyst in toluene and cesium carbonate (Cs2CO3) as a base. We used
the very same conditions for the coupling of arylboronic acids and
a,b
a-
a,b
cross-coupling reaction of fluorovinylstannanes using an acid
chloride as the substrate.26 The second example consists in the
synthesis of a-fluoro-a,b-unsaturated ketones via cross-coupling of
1-fluorovinylstannanes with iodobenzene under a carbon monoxide
atmosphere co-catalyzed by palladium(0) and copper (I).27 Recently
Pannecoucke’s group developed a synthesis of
a-fluoro-a,b-un-
saturated ketones, via a Negishi palladium-catalyzed coupling re-
action between bromofluoroolefins and alkoxyvinylzinc species.28
In our previously work,18 we described the synthesis of chalcones
in good yields by the SuzukieMiyaura coupling reaction between
benzoyl chloride and phenylvinylboronic acid catalyzed by
(PPh3)4Pd. We first planned to extend this method to the synthesis
(Z)-a-fluorocinnamoyl chlorides (Scheme 2).
R
R
R''
R''
R'
R'
(PPh3)4Pd(0)
+
of
a-fluorochalcone. Unfortunately, no access to
a
-fluoro-2-
OH
Cl
Cs2CO3, toluene
100 °C
B
F
F
phenylvinylboronic acid is described in the literature. Phenyl-
vinylboronic acid is either commercially available or readily
obtained by the reaction of a phenylvinyl anion equivalent with
4
6
OH
O
5
O
Scheme 2. Synthesis of a-fluorochalcones.
a trialkoxyboron derivative. It is well known that
ions are highly unstable.29 To the best of our knowledge, the direct
access to -fluoro-vinylboronic by reacting an -fluorovinyl anion
with a trialkoxyboron derivative has never been described. This
instability is limited to non-stabilized -fluorovinyl anion and re-
a-fluorovinyl an-
The reaction was performed with various arylboronic acids,
which afforded the A ring of the chalcones and (Z) -fluorocinnamic
acids, which bring the B ring. The reaction was not affected by
substituents located either on the acyl chloride 4aed or on the
boronic acid 5aed (Table 1, entries 1e7). In all cases the a-fluori-
a
a
a
a
cently lithium trimethoxy(trifluorovinyl)borate has been obtained
by this strategy.30 The second approach to vinylboronic acid is based
on the reaction of a vinyl halide with a diboron derivative.31 How-
ever, the reactivity of gemvinyl dihalides including a fluorine atom is
very often different from the one of simple monovinyl halides.32
Therefore, when we reacted (Z)-2-bromo-2-fluoroethenylbenzene
with bis(pinacolato)diboron we obtained in majority the symmet-
rical duplication product (1E,3E)-2,3-difluoro-1,4-diphenyl-buta-
1,3-dienes as the major product and only traces (ca. 10%) of the
expected (E)-fluoro-2-phenylvinylboronic ester and we could not
improve this yield.33 Fortunately, the reaction of phenylboronic acid
with cinnamoyl chloride also afforded the expected chalcones but
with a lower yield.18 So we decided to explore this synthetic ap-
nated analogues of chalcones 6aeg were obtained in fair yields
(50e58%).
Table 1
Synthesis of (Z)-a-fluorochalcones by SuzukieMiyaura coupling between
(Z)- -fluorocinnamoyl chloride 4aed and phenylboronic acids 5aed
a
Entry
4
5
6
R
R0
R00
Isolated yield (%)
1
2
3
4
6
5
7
a
b
b
b
b
c
a
a
b
c
d
d
d
a
b
c
d
e
f
OMe
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
OMe
OMe
OMe
53
55
50
56
52
58
51
CHO
N(CH3)2
OMe
OMe
OMe
proach to the synthesis of
the two partners -fluorocinnamoyl chlorides and phenylboronic
acids are readily available. (Z)- -Fluorocinnamic acids were ob-
a-fluorinated analogues of chalcones as
d
g
F
a
a
tained by the WittigeHorner reaction of 2-(diethoxyphosphinyl)-2-
fluoro-acetic acid, ethyl ester 2 with the corresponding aldehydes
(Scheme 1). The condensation between benzaldehyde 1aed and
compound 2 in THF in the presence of n-butyllithium at ꢀ78 ꢁC in
We demonstrated that phenyl bearing a phenol function pro-
tected by methoxymethyl (MOM) ether group behave similarly to
methoxy groups and may be deprotected without loss of a fluorine
atom in the vinylic position in the resveratrol series.19 Therefore,
THF gave the corresponding (E)-
major product.34 The isomerization of (E)-
into (Z)- -fluorocinnamic esters was performed by heating for 1 h in
CCl4 the isomer mixture in the presence of 10% of bromine at 50 ꢁC.35
Then, the saponification of (Z)- -fluorocinnamic esters was ach-
ieved using sodium hydroxide in ethanol/water mixture, which led
the desired (Z)-
-fluorocinnamic acids.36 From the corresponding
a
-fluorocinnamic esters as the
this synthesis paves the way to a-fluorinated analogues of bioactive
a
-fluorocinnamic esters
chalcones. For example, alkoxylated and hydroxylated chalcones on
ring A or B are found in antimalarial compounds and inhibitors of
Mycobacterium tuberculosis protein tyrosine phosphatase.39 The
alkoxy substituents also serve to link the chalcone moiety to an-
other active molecule, such as dihydroartemisinin.40 Chalcones
bearing amino and fluorine groups on the phenyl rings like 6d and
6g have been described as positron emission tomography probes.41
Chalcones bearing fluorine groups on either rings, such as 6g or
methoxy groups, such as 6a, eeg are more efficient against mela-
noma cell lines.11a
a
a
a
benzaldehydes, pure (Z)-2-fluoro-3-phenyl-2-propenoic acids are
obtained in fair yields without regards of the substituent. For ex-
ample, pure (Z)-2-fluoro-3-phenyl-2-propenoic acid, and (Z)-2-
R
R
F
F
3. Conclusion
1) BuLi/-78 °C, THF
OEt
O
H
(EtO)2
+
P
2) Br2, CCl4
In conclusion, the cross-coupling reaction of arylboronic acids
OH
O
O
O
3) NaOH, H2O/EtOH
1
3
2
with (Z)-
a-fluorocinnamic acid chlorides was achieved using tet-
Scheme 1. Synthesis of fluorocinnamic acids.
rakis(triphenylphosphine)palladium(0) as the catalyst in toluene

S. Eddarir et al. / Tetrahedron 69 (2013) 1735e1738
1737
and cesium carbonate as a base to afford (Z)-
fair yields. The method was applied to a variety of
acid chlorides and boronic acids, which opens the route to a general
synthesis of (Z)- -fluoro- -unsaturated ketones bearing reactive
substituents like phenol groups. By transforming the ketone group
of a chalcone in an imine, several families of potential drugs may be
obtained, such as chalcones thiosemicarbazide derivatives, which
have been proved to be anticancer agents.42 Therefore, this general
a
-fluorochalcones in
(9.5), 105 (12.4), 77 (25.0). HRMS: calcd for C16H14OF [MþH]þ
a
-fluorocinnamic
241.1023; found 241.1027.
a
a
,b
4.2.3. 4-[(Z)-2-Fluoro-3-(4-methylphenyl)-3-oxo-1-propenyl] benz-
aldehyde (6c). 1H NMR (CDCl3):
d
¼2.20 (s, 3H), 6.86 (d,
3JHeF¼36.5 Hz,1H), 7.23 (d, 3JHeH¼7.6 Hz, 2H), 7.62 (d, 3JHeH¼7.6 Hz,
2H), 7.80 (d, 3JHeH¼7.8 Hz, 2H), 8.05 (d, 3JHeH¼7.8 Hz, 2H), 10.12 (s,
1H) ppm. 13C NMR (CDCl3):
d
¼21.7, 110.9, 118.3 (d, JCeF¼6.4 Hz),
synthesis of (Z)-
a
-fluoro-
a
,b
-unsaturated ketones paves the way to
124.2 (d, JCeF¼2.0 Hz), 123.1 (d, JCeF¼3.7 Hz), 129.8, 130.8, 130.6,
132.5, 132.8, 139.8 (d, JCeF¼2.8 Hz), 156.2 (d, JCeF¼274.6 Hz), 188.4
access new families of potentially active compounds.
(d, JCeF¼28.2 Hz), 191.7 ppm. 19F NMR (CDCl3):
d
¼ꢀ125.3 (d,
3JHeF¼36.5 Hz, 1F) ppm. MS (EI): m/z (%)¼268 (25.5, Mþ), 267
(18.5), 254 (19.5), 253 (100), 239 (17.4), 239 (14.2), 219 (9.5), 191
(9.0), 133 (13.5), 105 (11.0), 77 (12.3). HRMS: calcd for C17H14O2F
[MþH]þ 269.0972; found 269.0980.
4. Experimental
4.1. General
All commercially available products were purchased from
Aldrich (Saint-Quentin Fallavier, France) and used as received.
Deuterated solvents (99.9% or better) were purchased from Euriso-
Top (Saint-Aubin, France). For flash chromatography, Merck silica-
gel 60 (230e400 mesh ASTM) was used. The melting points were
measured on an Electrothermal (Dubuque, Iowa USA) 9100 appa-
ratus and were not corrected. NMR spectra were recorded on
a Bruker (Wissembourg, France) AM 300 spectrometer (300, 282,
and 75 MHz, for 1H, 19F, and 13C, respectively) using CDCl3 as solvent
and TMS as internal standard; chemical shifts and J values are given
in parts per million and Hertz, respectively. GC/MS were recorded
on a Thermo Fisher Polaris ion trap mass spectrometer fitted with
a 60 m 0.32 mm apolar CPSil5 column using electron ionization (EI)
at 70 eV. Fast atom bombardment (FAB) mass spectra were mea-
4.2.4. (Z)-1-(4-Dimethylaminophenyl)-2-fluoro-3-(4-methylphenyl)-
2-propen-1-one (6d). 1H NMR (CDCl3):
d
¼2.37 (s, 3H), 3.07 (s, 6H),
3
3
6.67 (d, JHeH¼9.0 Hz, 2H), 6.81 (d, JHeF¼37.5 Hz, 1H), 7.21 (d,
3JHeH¼8.1 Hz, 2H), 7.59 (d, 3JHeH¼9.0 Hz, 2H), 7.74 (d, 3JHeH¼8.0 Hz,
2H) ppm. 13C NMR (CDCl3):
d
¼21.5, 40.0, 110.6, 117.5 (d,
JCeF¼6.1 Hz), 123.55 (d, JCeF¼2.2 Hz), 129.2 (d, JCeF¼3.7), 129.5,
130.3, 130.4, 132.1, 132.2, 139.6 (d, JCeF¼2.8 Hz), 155.4 (d,
JCeF¼274.3 Hz), 185.0 (d, JCeF¼28.0 Hz) ppm. 19F NMR (CDCl3):
d
¼ꢀ121.9 (d, 3JHeF¼37.5 Hz,1F), MS (EI): m/z (%)¼284 (15.3, Mþþ1),
283 (100, Mþ), 263 (65.0), 262 (20.0), 235 (12.5), 148 (45.0), 134
(21.5), 77 (9.5) ppm. HRMS: calcd for C18H19OFN [MþH]þ 284.1451;
found 284.1455.
4.2.5. (Z)-1-(3,4-Dimethoxyphenyl)-2-fluoro-3-(4-methylphenyl)-2-
propen-1-one (6e). 1H NMR (CDCl3):
d
¼2.37 (s, 3H), 3.93 (s, 3H),
ꢀ
sured on a JEOL Mass Station 700 spectrometer at the Ecole Nor-
male Superieure (Paris, France).
3.95 (s, 3H), 6.86 (d, 3JHeF¼36.9 Hz, 1H), 6.90 (d, 3JHeH¼8.4 Hz, 1H),
ꢀ
3
3
7.22 (d, JHeH¼8.0 Hz, 2H), 7.48 (s, 1H), 7.59 (d, JHeH¼8.0 Hz, 2H),
7.62 (d, 3JHeH¼8.4 Hz, 1H) ppm. 13C NMR (CDCl3):
¼21.5, 56.0, 56.1,
d
4.2. General procedure for the preparation of
a-fluorochalcones
110.1, 111.9 (d, JCeF¼5.0 Hz), 119.2 (d, JCeF¼6.0 Hz), 124.3 (d,
JCeF¼7.5 Hz), 129.7, 130.5, 130.6, 140.2 (d, JCeF¼2.9 Hz), 149.0, 153.5,
(1.0 mmol) of -fluorocinnamoyl chloride (0.5 mmol) of aryl-
a
154.6 (d, JCeF¼272.5 Hz), 186.0 (d, JCeF¼28.4 Hz) ppm. 19F NMR
3
boronic acid, and (2.5 mmol) of anhydrous cesium carbonate were
dissolved in 5 mL of anhydrous toluene. The mixture was treated
with 5% of tetrakis(triphenylphosphine) palladium. The solution
was heated at 100 ꢁC for 12 h, diluted with ethyl acetate, and
washed successively with water, a saturated solution of sodium
bicarbonate, and brine. The solvent was evaporated and the residue
was purified by flash column chromatography using a mixture of
ethyl acetate/pentane 10/90 as eluent, to give the desired product.
(CDCl3):
d
¼ꢀ123.30 (d, JHeF¼36.8 Hz, 1F) ppm. MS (EI): m/z (%)¼
301 (20.0), 300 (100, Mþ), 285 (70.0), 280 (68.5), 269 (42.3), 237
(12.0), 181 (9.5), 209 (14.5), 166 (15.0), 165 (48.0), 137 (13.5), 121
(9.0), 77 (9.5). HRMS: calcd for C18H18O3F [MþH]þ 301.1240; found
301.1244.
4.2.6. (Z)-1-(3,4-Dimethoxyphenyl)-2-fluoro-3-phenyl-2-propen-1-
one (6f). 1H NMR (CDCl3):
d
¼3.95 (s, 3H), 3.97 (s, 3H), 6.87 (d,
3JHeF¼36.8 Hz,1H), 6.93 (d, 3JHeH¼8.4 Hz,1H), 7.22 (m, 2H), 7.40 (m,
4.2.1. (Z)-2-Fluoro-3-(4-methoxyphenyl)-1-phenyl-2-propen-1-one
3H), 7.50 (s, 1H), 7.70 (d, 3JHeH¼8.4 Hz, 1H) ppm. 13C NMR (CDCl3):
3
(6a). 1H NMR (CDCl3):
d
¼3.85 (s, 3H), 6.82 (d, JHeF¼36.3 Hz, 1H),
d
¼56.0, 56.1, 110.4, 112.3 (d, JCeF¼4.5 Hz), 119.6 (d, JCeF¼6.0 Hz),
6.93 (d, 3JHeH¼8.6 Hz, 2H), 7.50 (m, 3H), 7.65 (d, 3JHeH¼8.6 Hz, 2H),
124.7 (d, JCeF¼7.0 Hz), 129.7, 130.8, 130.9, 140.4 (d, JCeF¼2.5 Hz),
149.7, 153.6, 154.6 (d, JCeF¼273.4 Hz), 185.9 (d, JCeF¼28.4 Hz) ppm.
7.85 (d, JHeH¼7.7 Hz, 2H) ppm. 13C NMR (CDCl3):
d
¼55.9, 118.6,
3
119.4 (d, JCeF¼5.0 Hz), 127.8, 128.1 (d, JCeF¼4.3 Hz), 129.2, 129.5,
130.1, 130.5, 132.4, 153.6 (d, JCeF¼271.4 Hz), 161.4, 186.7 (d,
JCeF¼28.3 Hz) ppm. 19F NMR (CDCl3): ꢀ125.2 (d, 3JHeF¼36.4 Hz, 1F)
ppm. MS (EI): m/z (%)¼257 (20.5), 256 (100, Mþ), 255 (39.4), 237
(19.0), 236 (75.3), 225 (19.5), 208 (20.6), 193 (21.0), 193 (22.5), 165
(18.7), 105 (15.0), 77 (30.4). HRMS: calcd for C16H14O2F [MþH]þ
257.0972; found 257.0979.
19F NMR (CDCl3):
d
¼ꢀ123.8 (d, 3JHeF¼36.8 Hz 1F) ppm. MS (EI): m/z
(%)¼287 (18.5), 286 (100, Mþ), 285 (75.0), 266 (40.3), 255 (24.5),
183 (14.6), 165 (74.5), 137 (18.5), 121 (10.5), 77 (11.0). HRMS: calcd
for C17H16O3F [MþH]þ 287.1078; found 287.1080. (6a).
4.2.7. (Z)-1-(3,4-Dimethoxyphenyl)-2-fluoro-3-(4-fluorophenyl)-2-
propen-1-one (6g). 1H NMR (CDCl3):
d
3
¼3.93 (s, 3H), 3.95 (s, 3H),
3
6.83 (d, JHeF¼36.9 Hz, 1H), 6.91 (d, JHeH¼8.5 Hz, 1H), 7.15 (d,
4.2.2. (Z)-2-Fluoro-3-(4-methylphenyl)-1-phenyl-2-propen-1-one
3JHeH¼8.0 Hz, 2H), 7.48 (s, 1H), 7.63 (d, 3JHeH¼8.5 Hz, 1H), 7.68 (dd,
3
3
(6b). 1H NMR (CDCl3):
d
¼2.37 (s, 3H), 6.83 (d, JHeF¼36.6 Hz, 1H),
3JHeH¼8.6 Hz, JHeF¼5.5, 2H) ppm. 13C NMR (CDCl3):
d¼56.0, 56.1,
7.23 (d, 3JHeH¼8.2 Hz, 2H), 7.50 (m, 2H), 7.60 (d, 3JHeH¼8.2 Hz, 2H),
110.1, 110.4, 111.5, 111.9 (d, JCeF¼3.6 Hz), 115.9, 116.2, 117.6 (d,
JCeF¼5.9 Hz), 119.1, 124.4 (d, JCeF¼7.9 Hz), 128 (d, JCeF¼2.0 Hz),
132.4, 132.5, 132.6, 134.2, 149.1, 153.6, 154.7 (d, JCeF¼274.1 Hz),163.3
7.87 (m, 3H) ppm. 13C NMR (CDCl3):
d
¼21.5, 120.5 (d, JCeF¼5.9 Hz),
128.4, 128.6 (d, JCeF¼4.0 Hz), 129.3, 129.4, 129.7, 130.6, 130.7, 132.7,
136.4, 154.2 (d, JCeF¼270.8 Hz), 188.0 (d, JCeF¼28.3 Hz) ppm. 19F
(d, JCeF¼251.7 Hz), 185.5 (d, JCeF¼28.6 Hz) ppm. 19F NMR (CDCl3):
3
NMR (CDCl3):
d
¼ꢀ124.92 (d, 3JHeF¼36.5 Hz, 1F) ppm. MS (EI): m/z
d
¼ꢀ125.6 (d, JHeF¼36.8 Hz 1F), ꢀ112.4 (m, 1F) ppm. MS (EI): m/z
(%)¼240 (45, Mþ), 239 (32.5), 226 (15.3), 225 (100), 220 (15.0), 205
(%)¼305 (20.0), 304 (100, Mþ), 284 (67.5), 273 (46.0), 241 (10.5), 213

1738
S. Eddarir et al. / Tetrahedron 69 (2013) 1735e1738
11. (a) Henmi, K.; Hiwatashi, Y.; Hikita, E.; Toyama, N.; Hirano, T. Biol. Pharm. Bull.
2009, 32, 1109e1113; (b) Nakamura, C.; Kawasaki, N.; Miyataka, H.; Jayachan-
dran, E.; Kim, I. H.; Kirk, K. L.; Taguchi, T.; Takeuchi, Y.; Hori, H.; Satoh, T. Bioorg.
Med. Chem. 2002, 10, 699e706.
(14.6), 201 (9.5), 165 (63.5), 137 (16.3), 79 (9.5), 77 (9.0). HRMS:
calcd for C17H15O3F2 [MþH]þ 305.0984; found 305.0982.
12. Chiron, M.; Combeau, C.; Mailliet, P. Aventis Pharma, WO Patent 2002047604,
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This work was supported by the Conseil Regional Nord, Pas-de-
Calais, France. The NMR and Mass Spectrometry facilities used in
this study were funded by the European Community (FEDER), the
Region Nord-Pas de Calais (France), the CNRS, and the Universite de
ꢀ
ꢀ
2737e2742.
ꢀ
Lille 1, Sciences et Technologies. S.E. thanks the Universite Cadi
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Ayyad, Faculte des Sciences et Techniques Gueliz, Marrakech, Mo-
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rocco, for a sabbatical leave and the Conseil Regional Nord, Pas-de-
Calais for a position as invited professor. The authors thank Dr.
Maria van Agthoven for her help with editing this manuscript.
Supplementary data
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Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.12.025.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
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