Synthesis of tetrasubstituted α-fluoroenones

Article abstract of DOI:10.1016/j.tet.2009.05.065

We reported the synthesis of tetrasubstituted α-fluoroenones from tetrasubstituted gem-bromofluoroolefins in good yields. These compounds are scarcely studied in the literature, due to difficulty of synthesis, whereas they could serve as intermediates in the synthesis of biological relevant molecules and could also be envisioned to design new constrained peptidomimetics.

Full text of DOI:10.1016/j.tet.2009.05.065

Tetrahedron 65 (2009) 6034–6038
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of tetrasubstituted a-fluoroenones
*
Guillaume Dutheuil, Samuel Couve-Bonnaire, Xavier Pannecoucke
COBRA, CNRS, UMR 6014 & FR 3038, INSA de ROUEN, IRCOF, rue Tesnie`re BP 08, Mont-Saint-Aignan, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 April 2009
Received in revised form 20 May 2009
Accepted 26 May 2009
Available online 29 May 2009
We reported the synthesis of tetrasubstituted
a-fluoroenones from tetrasubstituted gem-bromo-
fluoroolefins in good yields. These compounds are scarcely studied in the literature, due to difficulty of
synthesis, whereas they could serve as intermediates in the synthesis of biological relevant molecules
and could also be envisioned to design new constrained peptidomimetics.
Ó 2009 Elsevier Ltd. All rights reserved.
R2
1. Introduction
R1
H
F
R1
H
Br
F
1/
R1
H
Br
up to 98% yield
R2
ClZn OEt
[Pd], THF, 10 °C
+
(Z)
The fluorine atom in organic chemistry is increasingly exploited
in several fields (pharmacy, materials.) since its use usually in-
volved new relevant properties and functionalities.1 Indeed, the
introduction of one or several fluorine atoms on a compound alters
its chemical, physical and biological properties compared to non-
fluorinated derivatives with often an improved therapeutic profile.2
In our laboratory, we are developing new methodologies towards
fluorinated fine chemicals and in particular for the development of
(Z )
F
O
(E,Z) mixture
2/ hydrolysis
TRANSOID precursor
up to 99% yield
R2
O
1/
R1
ClZn OEt
R2
(E)
[Pd], THF, reflux
2/ hydrolysis
H
CISOID precursor
F
up to 83% yield
new fluoropeptidomimetics bearing
a fluoroolefin moiety as
Scheme 2. Negishi reaction with trisubstituted gem-bromofluoroolefins.
peptide bond mimic (Scheme 1).3 Indeed, some computational
studies showed that these moieties share geometric and electronic
similarities.4
At 10 ꢀC, only the E isomer of the (E,Z) mixture of substrate
reacted to give stereospecifically transoid precursor in high yields.
At the same time the Z isomer substrate was recovered also in high
yields. Then, this Z substrate was submitted to the Negishi reaction
in refluxing condition to give cisoid precursors in good yields. This
reaction is very efficient and the stereodifferentiation operating
with the reaction temperature was possible whatever the nature of
R1 group (aliphatic, aromatic, with functionality such as cyano,
nitro,.) and R2 group.6
Here we report an extension of this method to tetrasubstituted
substrates with emphasis to the synthesis of new fluorinated
pseudopeptides where the native peptide bond has been replaced
by a fluoroolefin moiety (Scheme 3). The tetrasubstituted fluoro-
compounds can also have other relevant application as nucleo-
sides,8 factorXa inhibitors,9 ..
Dipeptide Mimics
R
∗
F
HOOC
R1
H
F
R1
H
R1
H
F
H
R2
O
R2
∗
Br
H2N
O
R
∗
O
HOOC
N
H
R2
∗
H2N
Scheme 1. General route envisioned to fluorinated pseudopeptides.
In this context, from gem-bromofluoroolefins,5 we recently de-
scribed new interesting synthesis of vinylic fluoride scaffolds via
a
Negishi coupling reaction mediated by palladium catalyst
(Scheme 2).6 The products obtained can serve as precursors for
fluoropeptidomimetics synthesis.7
fluorinated
R1
R2
F
R1
R2
Br
F
peptidomimetics
Negishi
coupling
R3
biologically
active
O
compounds
* Corresponding author. Tel.: þ33 2 35 52 24 27; fax: þ33 2 35 52 29 62.
E-mail address: xavier.pannecoucke@insa-rouen.fr (X. Pannecoucke).
Scheme 3. Tetrasubstituted a-fluoroenones and applications.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.065

G. Dutheuil et al. / Tetrahedron 65 (2009) 6034–6038
6035
Table 2
Moreover, it has to be noted that the synthesis of
a-fluo-
Reactivity of tetrasubstituted bromofluoroolefins under Negishi coupling reaction
conditions
roenone moiety is rare in the literature as well as its applications
whereas this functionality can be easily chemically modify
(asymmetric reductive amination or other specific reactions
of ketone moiety) towards interesting molecules such as
peptidomimetics.
Entry
Substrate (E/Z ratio)
Br
Isolated yield (%)
Products (E/Z ratio)
O
F
F
1
84
2. Results and discussion
1a (62/38)
2a (26/74)
We began the study with the
a-ethoxyvinylzinc chloride as
organozinc derivative using the experimental conditions already
described: 2 equiv of organozinc with 5% and 10% of Pd(OAc)2 and
PPh3, respectively, as a catalytic system (Table 1).6
O
F
F
Br
2
3
77
75
Table 1
1b (nd)a
Influence of the temperature on the Negishi coupling reaction of 1a
2b (37/63)
O
Br
O
[Pd]
hydrolysis
BnN
Br
+
OEt
BnN
F
THF
ClZn OEt
F
1c
1a
F
F
F
2c
2a
62/38: E,Z ratio
Monitoring by19F NMR
Ph
Ph
Entry
Temperature (ꢀC)
Reaction time (min)
Conversion (%)
E/Z ratio
F
F
1
2
65
40
15
15
60
5
60
5
60
15
60
15
150
150
150
100
85
100
72
100
80
100
65
90
30
76
26
30/70
26/74
29/71
5/95
15/85
14/86
18/82
15/85
20/80
15/85
21/79
23/77
35/65
Br
O
4
88
65
Ph
Ph
3
4
5
6
20
5
1d
Br
2d
O
F
F
ꢁ5
ꢁ20
5
OTBDPS
1e (56/44)
OTBDPS
2eb (41/59)
7
8
ꢁ40
ꢁ78
15
a
Not determined.
b
Reaction conducted with 3 equiv of organozinc derivative.
First, we investigated the role of the temperature on the re-
action aiming at doing efficient stereodifferentiation as already
observed in the case of trisubstituted gem-bromofluoroolefins.
reaction mixture. Then, the mixture was hydrolyzed and stirred
for 15 min by an aqueous solution of HCl (1 M). Table 2 showed
the results obtained with different tetrasubstituted gem-bromo-
Whatever the temperature used in the Negishi coupling with
a
-
fluoroolefins with a-ethoxyvinylzinc chloride.
ethoxyvinylzinc chloride, the kinetic control was ineffective. Ac-
tually, by monitoring the reaction by 19F NMR, we can see, in all
cases, that the first isomer of the E,Z mixture to react was the E
isomer, but unfortunately, quickly followed by the Z-isomer,
which restricted and prohibited the stereodifferentiation. By
running the reaction at 40 or 65 ꢀC (entries 1 and 2), the kinetic
was better but the E,Z ratio was lower than at room temperature.
On the contrary, reaction carried out at low temperature (entries
5–8) revealed to be incomplete without any gain in selectivity.
The more surprising was that, starting from a 62/38 E,Z mixture of
substrate, with 100% conversion, we ended up with a 15/85 E,Z
mixture of enol ether (entry 3). Meaning probably that on the
opposite to the observation made for trisubstituted bromo-
fluoroolefins,6 the tetrasubstituted fluorinated double bond
isomerizes partially during the catalytic process for compound 1a.
The better compromise results/experimental procedure was for
reaction conducted at room temperature. It has to be noted that
we have also changed the reaction time and the number of
equivalent (organozinc, substrate and catalyst) without any ben-
efit for selectivity. So the experimental conditions used for the
study were 2 equiv of organozinc with 5% and 10% of Pd(OAc)2
and PPh3, respectively, as catalytic system at room temperature.
The reaction was controlled by monitoring 19F NMR signal of the
Reaction yields were good for all substrates (65–88%), i.e., ali-
phatic (linear or cyclic) or aromatic molecules. Despite no ster-
eodifferentiation was possible, an interesting feature is the
possible separation of the E/Z products starting from a non-sep-
arable E/Z mixture of tetrasubstituted gem-bromofluoroolefin.
Depending on the substrate, partial isomerization occurred
sometimes during the hydrolysis step, probably through a ther-
modynamic equilibrium of the tetrasubstituted
acidic medium.
a-fluoroenones in
The reaction could lead to a fluorinated proline analogue (entry
5). This molecule is very relevant and can serve as intermediate for
fluorinated proline-containing peptidomimetic as well as DPPIV or
DPPII inhibitor precursors.10
To extend the scope of the reaction, we then did the reaction
with various organozinc derivatives (Table 3).
In that case, results are good with the possible separation of E/Z
isomers of product 4. Unfortunately, the E/Z products 3 and 5
proved to be unseparable at this stage. The E/Z ratio with 2-phenyl-
1-ethoxyvinylzinc chloride was quite high: 4/96. This result can be
explained by isomerization of the double bond under harsher hy-
drolysis conditions needed in that case because of the conjugation
of phenyl group with the enol moiety of the intermediate (E/Z ratio
of enol before hydrolysis: 36/64).

6036
G. Dutheuil et al. / Tetrahedron 65 (2009) 6034–6038
spectrometer. Absorption bands are reported in cmꢁ1. Electrospray
ionization (ESI) mass spectrometry (MS) experiments were per-
formed on a Bruker-Esquire mass spectrometer. Electronic impact
(EId70 eV), chemical ionization (CId200 eV) or high-resolution
MS experiments were recorded on a JEOL AX 500 mass spectrom-
eter using a mass resolution of 5000. Elemental analyses were
performed on a CE Instruments EA 110 CHNS-O instrument. Melt-
ing points were measured by Koffler bench and are uncorrected.
Table 3
Reactivity of 1a under Negishi coupling reaction condition using different organo-
zinc derivatives
O
R1
1) [Pd], THF, rt, 1h
Br
F
R1
+
2/ hydrolysis
ClZn OR
F
1a (62/38: E,Z ratio)
R1
OR
4.2. General procedure for the preparation of fluorinated
methylketones from mixtures of tetrasubstituted
bromofluoroolefins (Table 2)
Entry
Isolated yield
Products (E/Z ratio)
ClZn
ClZn
O
F
To a mixture of potassium tert-butoxide (2 equiv), ethylvinylether
(2 equiv) in anhydrous THF (5 mL/mmol of t-BuOK) at ꢁ78 ꢀC under
argon was added dropwise n-BuLi in hexanes (1.6 M, 2 equiv). The
mixture was stirred for 30 min at ꢁ78 ꢀC and then a solution of dry
zinc chloride (4 equiv) in THF (4 mL/mmol of ZnCl2) was added
dropwise. After 10 min, the cooling bath was removed and the so-
lution was allowed to warm to room temperature for 30 min. The
mixture was then added slowly to a solution of palladium diacetate
(0.05 equiv), triphenylphosphine (0.1 equiv) and mixture of tetra-
substituted bromofluoroolefins (1 equiv) in anhydrous THF (10 mL/
mmol of bromofluoroolefin) at room temperature under argon. The
mixture was stirred for 1 h. After the reaction was completed, con-
trolled by monitoring 19F NMR signal of the reaction mixture, HCl aq
(1 N) was added and the mixture was stirred for 15 min. The mixture
was then extracted with Et2O (ꢂ3), washed with brine and the
combined organic layers were dried over MgSO4. After filtration and
concentration under reduced pressure, the residue was purified by
chromatography on silica gel (eluent: cyclohexane/AcOEt), affording
tetrasubstituted fluorinated methylketones.
Ph
1
65
OEt
3 (4/96)a
O
F
Et
2
62
79
ClZn
ClZn
OEt
4 (27/73)a
O
F
O
O
O
3
5 (29/71)
a
Hydrolysis with HCl 6 M at 70 ꢀC.
4.2.1. (Z)- and (E)-1-Fluoro-1-(2,3-dihydronaphthalen-4(1H)-
ylidene)propan-2-one: 74/26 (2a)
3. Conclusion
Orange oil, Rf 0.3 (2% AcOEt in cyclohexane). 1H NMR (300 MHz,
CDCl3) d 7.8–7.7 (0.7H, m, HZ), 7.5–7.4 (0.3H, m, HE), 7.2–7.1 (3H, m),
To resume, we extended the scope of the Negishi type reaction
to tetrasubstituted gem-bromofluoroolefin with success in terms of
yield. Unfortunately, no stereodifferentiation was possible during
the coupling process but the (E,Z) mixture of products obtained was
often separable by column chromatography. The fluorocompounds
synthesized can have different relevant uses and current researches
are done towards the synthesis of dipeptidic analogues containing
proline derivatives.
3.0–2.9 (2H, m), 2.7 (1.5H, t, 4JH–F¼6.2 Hz, HZ), 2.6–2.5 (0.5H, m, HE),
2.3 (2.2H, d, 4JH–F¼6.2 Hz, HZ), 2.2 (0.8H, d, 4JH–F¼5.1 Hz, HE), 1.7–1.5
(2H, m, H4). 19F NMR dec (282.5 MHz, CDCl3)
d
ꢁ117.3 (0.3F, FE),
2
ꢁ123.2 (0.7F, FZ). 13C NMR (75.5 MHz, CDCl3)
d
1
195.2 (d, JC–F
¼
2
41 Hz, CZ), 193.1 (d, JC–F¼40 Hz, CE), 150.5 (d, JC–F¼261 Hz, CZ),
1
2
149.8 (d, JC–F¼261 Hz, CE), 141.6 (CZ), 141.1 (CE), 136.2 (d, JC–F
¼
2
12 Hz, CZ), 134.9 (d, JC–F¼14 Hz, CE), 130.9 (CE), 130.6 (CZ), 130.4–
125.2, 30.4 (CZ), 29.9 (CE), 28.6 (CZ), 28.4 (CE), 26.4 (CZ), 26.4 (CE),
22.6 (CE), 22.6 (CZ). MS (EI) 204 (Mþ), 199 (MþꢁCH3), 176 (MþꢁCO),
161 (MþꢁCH3CO), 146, 43 (CH3COþ). IR (neat) 3061, 2937, 1712,
1689, 1596, 1453, 1357, 1287, 1252, 1984, 763.
4. Experimental section
4.1. General methods
4.2.2. (Z)- and (E)-3-Fluoro-4-(naphthalen-6-yl)pent-3-en-2-one:
63/37 (2b)
Experiments involving organometallics were carried out under
argon atmosphere. All moisture-sensitive reactants were handled
under argon atmosphere. Low temperature experiments were
carried out by cooling down the flasks with a acetone bathfrozen by
dry-ice. The flasks were equipped with septum caps. THF was dis-
tilled before using from sodium benzophenone ketyl under nitro-
gen atmosphere. TLC was performed on Merck 60F-250 silica gel
plates, using UV light as a visualizing agent and an ethanolic so-
lution of phosphomolybdic acid and heat as developing agents.
Flash column chromatography purifications were carried out using
silica gel (70–230 mesh). 1H NMR, 13C NMR and 19F NMR (CFCl3 as
external reference) were recorded at 300.13, 75.47 and 282.40 MHz,
respectively, on a Bruker DXP 300. Abbreviations used for peak
multiplicity are s: singlet, b: broad singlet, d: doublet, t: triplet, q:
quadriplet, m: multiplet. J was used to indicate coupling constant in
hertz. IR spectra were recorded on a Perkin–Elmer 500 FT-IR
Yellow oil, Rf 0.3 (2% AcOEt in cyclohexane). 1H NMR (300 MHz,
CDCl3)
d
7.8–7.7 (4H, m), 7.4–7.2(3H, m), 2.4(1.9H, d, 4JH–F¼3.8 Hz,HZ),
2.3 (1.1H, d, 4JH–F¼5.9 Hz, HZ), 2.1 (1.1H, d, 4JH–F¼4.6 Hz, HE), 2.0 (1.9H,
d, 4JH–F¼3.8, HE). 19F NMR dec (282.5 MHz, CDCl3)
ꢁ119.6 (0.4F, FE),
d
ꢁ122.4 (0.6F, FZ). 13C NMR (75.5 MHz, CDCl3)
d
195.4 (d, 2JC–F¼41 Hz,
2
1
CZ), 192.2 (d, JC–F¼34 Hz, CE), 151.7 (d, JC–F¼255 Hz, CE), 150.6 (d,
1JC–F¼255 Hz, CZ), 136.1–126.1 (10CAromZ&E),131.7 (d, 2JC–F¼11 Hz, CZ),
130.5 (d, 2JC–F¼10 Hz, CE), 28.9 (CE), 28.6 (CZ), 20.1 (CE), 18.5 (CZ). MS
(EI) 228 (Mþ), 213 (MþꢁCH3), 183, 165, 43 (CH3COþ). IR (neat) 3057,
3017, 2924,1697,1613,1422,1358,1254,1120, 962, 859, 819, 748, 588,
477. Anal. CalcdforC15H13FO:C,78.93;H, 5.74.Found:C,78.85;H, 5.61.
4.2.3. 1-(1-Benzylpiperidin-4-ylidene)-1-fluoropropan-2-one (2c)
Note: quenching with NaHCO3 5% aq instead of HCl. Brown oil, Rf 0.3
(20% AcOEt in cyclohexane). 1H NMR (300 MHz, CDCl3)
d 7.2–7.1 (5H,

G. Dutheuil et al. / Tetrahedron 65 (2009) 6034–6038
6037
4
m), 3.4 (2H, s), 2.9–2.8 (2H, m), 2.4–2.3 (6H, m), 2.2 (3H, d, JH–F
¼
4.9 Hz, HZ), 3.8 (0.2H, d, 4JH–F¼4.1 Hz, HE), 3.0–2.9 (1.8H, m, HZ), 2.8
5.6 Hz). 19F NMR dec (282.5 MHz, CDCl3)
d
ꢁ126.7. 13C NMR
(0.2H, m, HE), 2.7–2.5 (2H, m), 1.8–1.5 (2H,m). 19F NMR (282.5 MHz,
2
(75.5 MHz, CDCl3)
d
195.0 (d, JC–F¼40 Hz), 149.0 (d, 1JC–F¼249 Hz),
CDCl3)
CDCl3)
d
ꢁ118.6 (0.1F, m, FE), ꢁ125.2 (0.9F, m, FZ). 13C NMR (75.5 MHz,
138.5, 131.4 (d, 2JC–F¼14 Hz), 129.5, 128.7, 127.5, 63.7, 54.2, 53.6, 28.6,
d
194.8 (d, JC–F¼32 Hz), 157.0 (d, 1JC–F¼278 Hz), 141.9, 134.2,
2
27.2 (d, JC–F¼2 Hz). MS (EI) 247 (Mþ), 227, 204 (MþꢁCH3CO), 91
131.2, 130.9–125.6 (8C), 113.9 (d, 2JC–F¼11 Hz), 47.6 (CE), 47.4 (CZ), 30.6
(CZ), 30.2 (CE), 26.8 (CZ), 26.3 (CE), 23.0 (CE), 22.8(CZ). MS (EI) 280 (Mþ),
189 (MþꢁCH2Ph), 146, 91 (PhCHþ2 ). IR (neat) 3062, 3029, 2936, 2869,
1727,1694,1582,1495,1454,1308,1289,1184,1101,1029,764, 743, 697.
Anal. Calcd for C19H17FO: C, 81.40; H, 6.11. Found: C, 81.49; H, 6.28.
3
(PhCHþ2 ), 43 (CH3COþ). IR (neat) 3028, 2907, 2801, 2760, 1701, 1639,
1454, 1422, 1358, 1280, 1214, 1100, 970, 741, 698, 585. Anal. Calcd for
C15H18FNO: C, 72.85; H, 7.34; N, 5.66. Found: C, 72.41; H, 7.19; N, 5.55.
4.2.4. 1-(1,5-Diphenyl-3-pentylidene)-1-fluoropropan-2-one (2d)
Yellow oil, Rf 0.3 (2% AcOEt in cyclohexane). 1H NMR (300 MHz,
4.4. Preparation of fluorinated propylketone 4 (Table 3)
CDCl3) d 7.3–7.0 (10H, m), 2.8–2.5 (6H, m), 2.5–2.3 (2H, m), 2.1 (3H,
d, 4JH–F¼5.6 Hz). 19F NMR dec (282.5 MHz, CDCl3)
d
ꢁ123.5. 13C NMR
To a mixture of potassium tert-butoxide (4 equiv), butenylethyl-
ether (4 equiv) in anhydrous THF (5 mL/mmol of t-BuOK) at ꢁ78 ꢀC
under argon was added dropwise n-BuLi in hexanes (1.6 M, 4 equiv).
The mixture was stirred for 30 min at ꢁ78 ꢀC and then a solution of
dry zinc chloride (8 equiv) in THF (4 mL/mmol of ZnCl2) was added
dropwise. After 10 min, the cooling bath was removed and the so-
lution was allowed to warm to room temperature for 30 min. The
mixture was then added slowly to a solution of palladium diacetate
(0.05 equiv), triphenylphosphine (0.1 equiv) and mixture of tetra-
substituted bromofluoroolefin (1 equiv) in anhydrous THF (10 mL/
mmol of bromofluoroolefin) at room temperature under argon. The
mixture was stirred for 1 h. After the reaction was completed, con-
trolled by monitoring 19F NMR signal of the reaction mixture, HCl aq
(1 N) was added and the mixturewas stirred for 15 min. The mixture
was then extracted with Et2O (ꢂ3), washed with brine and the
combined organic layers were dried over MgSO4. After filtration and
concentration under reduced pressure, the residue was purified by
chromatography on silica gel (eluent: cyclohexane/AcOEt), affording
the mixture of fluorinated propylketones.
(75.5 MHz, CDCl3)
d
194.2 (d, 2JC–F¼41 Hz), 152.2 (d, 1JC–F¼252 Hz),
2
141.8–141.4 (2C), 134.6 (d, JC–F¼12 Hz), 129.0–128.8 (4C), 126.7–
126.5 (2C), 35.1 (d, 4JC–F¼4 Hz), 34.2 (d, 4JC–F¼2 Hz), 33.3 (d, 3JC–F
¼
3
3
8 Hz), 32.9 (d, JC–F¼3 Hz), 28.4 (d, JC–F¼2 Hz). MS (EI) 296 (Mþ),
281 (MþꢁCH3), 191 (MþꢁPhCH2CH2), 91 (PhCH2þ), 43 (CH3COþ). IR
(neat) 3085, 3062, 3027, 2928, 2861, 1698, 1633, 1604, 1495, 1454,
1350, 1267, 1221, 1178, 1099, 1074, 749, 699, 581, 550. Anal. Calcd for
C20H21FO: C, 81.05; H, 7.14. Found: C, 80.86; H, 6.93.
4.2.5. (Z)- and (E)-1-[2-(tert-Butyldiphenylsilyloxymethyl)-
cyclopentylidene]-1-fluoropropan-2-one: 59/41 (2e)
Yellow oil, Rf 0.4 (2% AcOEt in cyclohexane). 1H NMR (300 MHz,
CDCl3)
d 7.6–7.5 (4H, m), 7.3–7.2 (6H, m), 3.7–3.4 (2.6H, br m), 3.1–
3.0 (0.6H, m, HZ), 2.6 (1H, m, HZ), 2.4 (1H, m, HE), 2.1 (3H, d, 4JH–F
¼
5.3 Hz, H15), 1.9–1.6 (4H, br m), 1.0 (9H, s). 19F NMR (282.5 MHz,
CDCl3)
(75.5 MHz, CDCl3)
d
ꢁ119.2 (0.4F, m, FE), ꢁ123.6 (0.6F, m, FZ). 13C NMR
d
192.2 (d, 2JC–F¼41 Hz, CZ), 191.7 (d, 2JC–F¼40 Hz,
CE), 148.6 (d, 1JC–F¼251 Hz, CZ), 148.5 (d, 1JC–F¼251 Hz, CE), 139.3 (d,
2JC–F¼14 Hz, CE), 138.5 (d, 2JC–F¼13 Hz, CZ), 134.6 (2C), 132.6, 128.6–
128.5 (2C), 126.6–126.5 (2C), 63.3 (CE), 62.8 (CZ), 44.8 (CZ), 43.3 (CE),
30.3 (CZ), 29.3 (CE), 28.7 (CE), 27.5 (CZ), 26.3, 25.8, 23.8 (CZ), 21.7 (CE),
18.2. MS (EI) 353 (Mþꢁt-Bu), 201, 199 (MþꢁTBDPS), 181, 135, 91, 77
(Phþ), 57 (t-Buþ). IR (neat) 3072, 2968, 2930, 1702, 1638, 1477, 1428,
1382, 1277, 1089, 1049, 881, 703, 505. Anal. Calcd for C25H31FO2Si: C,
73.13; H, 7.61. Found: C, 73.48; H, 7.25.
4.4.1. (Z) and (E) 1-Fluoro-1-(2,3-dihydronaphthalen-4(1H)-
ylidene)pentan-2-one: 73/27 (4)
Yellow oil, Rf 0.5 (5% AcOEt in cyclohexane). 1H NMR (300 MHz,
CDCl3) d 7.8–7.7 (0.7H, m, HZ), 7.4–7.3 (0.3H, m, HE), 7.2–7.0 (3H, m),
3.0 (1.4H, td, 3JH–H¼6.7 Hz, 4JH–F¼2.7 Hz, HZ), 2.7–2.5 (4.6H, m), 1.8–
1.7 (2H, m), 1.7–1.5 (2H, m), 0.9–0.8 (3H, m). 19F NMR (282.5 MHz,
CDCl3)
(75.5 MHz, CDCl3)
d
ꢁ119.4 (0.3F, m, FE), ꢁ125.8 (0.7F, m, FZ). 13C NMR
4.3. Preparation of fluorinated benzylketone 3 (Table 3)
d
197.7 (d, 2JC–F¼39 Hz, CZ), 195.4 (d, 2JC–F¼37 Hz,
CE),150.6 (d, 1JC–F¼253 Hz, CE),149.8 (d, 1JC–F¼261 Hz, CZ),141.5 (CZ),
140.8 (d, J¼4 Hz, CE), 131.1, 130.4 (d, J¼18 Hz, CZ), 130.1 (CE), 129.4
(CE),129.2 (CZ),128.7 (CZ),127.7 (CE),127.6 (d, 2JC–F¼4 Hz),126.0 (CZ),
125.2 (CE), 42.4(CE), 42.2 (CZ), 30.4 (CZ), 29.9 (CE), 26.3 (CZ), 25.4 (d,
3JC–F¼9 Hz, CE), 22.6 (CZ), 21.2 (CE), 17.2 (CE), 17.1 (CZ), 13.9. MS (EI)
232 (Mþ), 203 (MþꢁCH3CH2), 189 (MþꢁCH3CH2CH2), 146, 141, 133.
IR (neat) 3063, 3021, 2961, 2874, 1692, 1608, 1585, 1482, 1454, 1308,
1196,1101,1023, 764, 744. Anal. Calcd for C15H17FO: C, 77.56; H, 7.38.
Found: C, 77.96; H, 7.46.
To a mixture of potassium tert-butoxide (4 equiv), 1-(2-ethoxy-
vinyl)benzene (4 equiv) in anhydrous THF (5 mL/mmol of t-BuOK) at
ꢁ78 ꢀC under argon was added dropwise n-BuLi in hexanes (1.6 M,
4 equiv). The mixture was stirred for 30 min at ꢁ78 ꢀC and then
a solution of dry zinc chloride (8 equiv) in THF (4 mL/mmol of ZnCl2)
was added dropwise. After 10 min, the cooling bath was removed
and the solution was allowed to warm to room temperature for
30 min. The mixture was then added slowly to a solution of palla-
dium diacetate (0.05 equiv), triphenylphosphine (0.1 equiv) and
mixture of tetrasubstituted bromofluoroolefin (1 equiv) in anhy-
drous THF (10 mL/mmol of bromofluoroolefin) at room temperature
under argon. The mixture was stirred for 1 h. After the coupling re-
action was completed, controlled by monitoring 19F NMR signal of
the reaction mixture, HCl aq (6 N) was added and the mixture was
stirred at 70 ꢀC for another hour. After cooling to room temperature,
the mixture was then extracted with Et2O (ꢂ3), washed with brine
and the combined organic layers were dried over MgSO4. After fil-
tration and concentration under reduced pressure, the residue was
purified by chromatography on silica gel (eluent: 2% AcOEt in cy-
clohexane), affording the mixture of fluorinated benzylketones.
4.5. Preparation of fluorinated dihydrodioxines 5 (Table 3)
To 1,4-diox-2-ene (4 equiv) in anhydrous THF (5 mL/mmol of enol
ether) at ꢁ30 ꢀC under argon was added dropwise t-BuLi in hexanes
(1.6 M, 4 equiv). The mixture was stirred for 1 h at ꢁ20 ꢀC and then
a solution of dry zinc chloride (8 equiv) in THF (4 mL/mmol of ZnCl2)
was added dropwise at ꢁ20 ꢀC. After 10 min, the cooling bath was
removed and the solution was allowed to warm to room temperature
for 30 min. The mixture was then added slowly to a solution of pal-
ladium diacetate (0.05 equiv), triphenylphosphine (0.1 equiv) and
mixture of tetrasubstituted bromofluoroolefin (1 equiv) in anhydrous
THF (10 mL/mmol of bromofluoroolefin) at room temperature under
argon. The mixture wasstirred for 1 h. After the coupling reactionwas
completed, controlled by monitoring 19F NMR signal of the reaction
mixture, NH4Cl aq (satd) was added and the mixture was stirred for
5 min. The mixture was then extracted with Et2O (ꢂ3), washed with
4.3.1. (Z) and (E) 1-Fluoro-1-(2,3-dihydronaphthalen-4(1H)-
ylidene)-3-phenylpropan-2-one: 88/12 (3)
Yellow oil, Rf 0.5 (5% AcOEt in cyclohexane). 1H NMR (300 MHz,
4
CDCl3)
d
7.8 (0.9H, m, HZ), 7.4–7.0 (8.1H, m), 3.9 (1.8H, d, JH–F
¼

6038
G. Dutheuil et al. / Tetrahedron 65 (2009) 6034–6038
brine and the combined organic layers were dried over MgSO4. After
filtration and concentration under reduced pressure, the residue was
purified by chromatography on basic alumina (eluent: cyclohexane),
affording the mixture of fluorinated dihydrodioxines.
References and notes
1. (a) Kirsch, P. In Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004;
(b) Chambers, R. D. In Fluorine in Organic Chemistry; Oxford: Blackwell, 2004;
(c) Chimie bioorganique et me´dicinale du fluor; Be´gue´, J.-P., Bonnet-Delpon, D.,
Eds.; CNRS Editions: Paris, 2005; or Bioorganic and Medicinal Chemistry of
Fluorine; John Wiley & Sons: 2008; (d) Ameduri, B.; Boutevin, B. Well-archi-
tectured Fluoropolymers: Synthesis, Properties and Applications; Elsevier:
Amsterdam, 2004; (e) Thayer, A. Chem. Eng. News 2006, 84, 15–24.
2. (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320–330; (b) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359–4369; (c) Shah, P.;
Westwell, A. D. J. Enzyme Inhib. Med. Chem. 2007, 22, 527–540; (d) Kirk, K. L. J.
Fluorine Chem. 2006, 127, 1013–1029; (e) Special issue of J. Fluorine Chem. 2008,
129, 725–888.
4.5.1. (Z) and (E) 5-(Fluoro(2,3-dihydronaphthalen-4(1H)-
ylidene)methyl)–2,3–dihydro-1,4-dioxene: 69/31 (5)
Yellow oil, Rf 0.3 (cyclohexane, aluminium oxide neutral). 1H NMR
(300 MHz, CDCl3)
d 7.8–7.7 (0.7H, m, HZ), 7.3 (0.3H, m, HE), 7.2–7.0
4
4
(3H, m), 6.3 (0.7H, d, JH–F¼1.0 Hz, HZ), 6.2 (0.3H, d, JH–F¼2.6 Hz,
HE), 4.1–4.0 (4H, m), 2.7 (1.4H, m, HZ), 2.6 (0.6H, m, HE), 2.5 (2H, m),
1.8–1.6 (2H, m). 19F NMR (282.5 MHz, CDCl3)
d
ꢁ108.3 (0.3F, m, FE),
1
3. (a) Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Org. Biomol. Chem. 2007, 5,
1151–1157.
ꢁ117.7 (0.7F, m, FZ). 13C NMR (75.5 MHz, CDCl3)
d
151.1 (d, JC–F
¼
4. (a) Urban, J. J.; Tillman, B. G.; Cronin, W. A. J. Phys. Chem. A 2006, 110,11120–11129;
(b) Cieplak, P.; Kollman, P. A.; Radomski, J. P. Molecular Design of Fluorine-Con-
taining Peptide Mimetics. In Biomedical Frontiers of Fluorine Chemistry; Ojima, I.,
McCarthy, J. R., Welch, J. T., Eds.; ACS Symposium Series 639, American Chemical
Society: Washington, DC, 1996; pp 143–156; (c) Abraham, R. J.; Ellison, S. L. R.;
Schonholzer, P.; Thomas, W. A. Tetrahedron 1986, 42, 2101–2110.
5. Lei, X.; Dutheuil, G.; Pannecoucke, X.; Quirion, J.-C. Org. Lett. 2004, 6, 2101–2104.
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46, 1290–1292; (b) Pierry, C.; Zoute, L.; Jubault, P.; Pfund, E.; Lequeux, T.; Cahard,
D.; Couve-Bonnaire, S.; Pannecoucke, X. Tetrahedron Lett. 2009, 50, 264–266.
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L.; Doughan, B.; Su, T.; Kanter, J.; Woolfrey, J.; Wong, P.; Huang, B.; Tran, K.;
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Zhu, B.-Y. Bioorg. Med. Chem. Lett. 2002, 12, 1511–1515.
241 Hz, CE), 150.7 (d, 1JC–F¼248 Hz, CZ), 139.5 (d, J¼6 Hz, CZ), 138.6
(CE), 133.0 (d, J¼6 Hz, CE), 132.8 (CZ), 131.6 (d, 2JC–F¼34 Hz, CE), 131.4
2
(d, JC–F¼34 Hz, CZ), 130.5–130.3 (2C), 130.0 (d, J¼16 Hz, CZ), 129.2,
128.6 (d, J¼32 Hz, CE), 127.6 (CZ), 127.4 (CE), 126.0 (CZ), 125.4 (CE),
2
2
119.7 (d, JC–F¼24 Hz, CE), 117.0 (d, JC–F¼9 Hz, CZ), 64.6, 64.5, 64.4,
64.2, 30.5, 27.4 (CZ), 24.6 (d, 3JC–F¼6 Hz, CE), 24.0 (CZ), 22.8 (CE). MS
(EI) 246 (Mþ), 187, 159, 146, 141, 133. IR (neat) 3098, 3062, 2933,
2874, 1727, 1651, 1484, 1454, 1314, 1263, 1159, 1097, 1050, 919, 764.
Anal. Calcd for C15H15FO2: C, 73.15; H, 6.14. Found: C, 72.27; H, 5.75.
Acknowledgements
10. (a) Welch, J. T.; Lin, J. Tetrahedron 1996, 52, 291–304; (b) Zhao, K.; Lim, D. S.;
Funaki, T.; Welch, J. T. Bioorg. Med. Chem. 2003, 11, 207–215; (c) Van der Veken,
The authors want to thank the ministry of Education and Re-
search (doctoral fellowship to G.D.) and the region Haute-Nor-
mandie for financial support.
´
P.; Senten, K.; Kertesz, I.; De Meester, I.; Lambeir, A.-M.; Maes, M.-B.; Scharpe,
S.; Haemers, A.; Augustyns, K. J. Med. Chem. 2005, 48, 1768–1780.