Towards chemical libraries based on heterocyclic scaffolds with monofluorinated and difluoroalkyl side chains

Article abstract of DOI:10.1016/j.jfluchem.2011.03.003

The preparation of focused chemical libraries, based on five- and six-membered heteroaromatic systems with mono- and gemdifluoroalkyl side chains, is described. Four heterocyclic scaffolds with a p-bromophenyl group have been easily prepared from readily available propargylic fluorides. Starting from these scaffolds, palladium-catalyzed reactions have been performed, including by automated procedures, to prepare libraries of molecules designed for biological applications.

Full text of DOI:10.1016/j.jfluchem.2011.03.003

Journal of Fluorine Chemistry 134 (2012) 180–187
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Towards chemical libraries based on heterocyclic scaffolds with
monofluorinated and difluoroalkyl side chains
a,1
b
b
a,
Pierre Bannwarth a,1, Danielle Gree , Saibal Das , Jhillu Singh Yadav , Rene Gree
*
´
´
´
a Universite´ de Rennes 1, Laboratoire Sciences Chimiques de Rennes CNRS UMR 6226 and Laboratoire Chimie et Photonique Mole´culaires CNRS UMR 6510, Avenue du Ge´ne´ral Leclerc,
35042 Rennes Cedex, France
b Organic Chemistry Division I, Indian Institute of Chemical Technology, 500607 Hyderabad, India
A R T I C L E I N F O
A B S T R A C T
Article history:
The preparation of focused chemical libraries, based on five- and six-membered heteroaromatic systems
with mono- and gemdifluoroalkyl side chains, is described. Four heterocyclic scaffolds with a p-
bromophenyl group have been easily prepared from readily available propargylic fluorides. Starting from
these scaffolds, palladium-catalyzed reactions have been performed, including by automated
procedures, to prepare libraries of molecules designed for biological applications.
ß 2011 Elsevier B.V. All rights reserved.
Received 10 January 2011
Received in revised form 4 March 2011
Accepted 7 March 2011
Available online 15 March 2011
Keywords:
Chemical library
Pyrimidine
Pyrazole
Palladium catalysis
Fluoroalkyls
Propargylic fluorides
1. Introduction
that they can be of much interest for the preparation of various types
of 5- and 6-membered heterocycles [8]. In continuation to these
It is widely recognized that the introduction of fluorine in
organic molecules modifies in depth their physical, chemical and
biological properties and this has been already of much use in
bioorganic as well as in medicinal chemistry [1]. It is also clear that
heterocyclic molecules are very classically at the core of
pharmaceutical products [2]. More recently, due to the develop-
ment of high throughput screening methods in biochemistry and
biology, medicinal chemists have introduced chemical libraries of
molecules around so called priviledge scaffolds, which are often
natural products and/or heterocyclic compounds [3]. Therefore it
appears of much interest to develop new methodologies and novel
synthetic strategies combining fluorine and heterocyclic chemis-
tries which, further, can be applied to the preparation of chemical
libraries of new fluorinated molecules.
Several years ago we started a programme dealing with new
propargylicfluorides [4]. We haveproposed a rationalefortheir easy
synthesis, including in optically active series [5]. Then we have
developed their use in the synthesis of various types of products
such as fluorinated analogues of fatty acid metabolites [6], as well as
carbocyclic systems [7]. More recently, we have also demonstrated
studies, the goal of this publication is to demonstrate that these
approaches can be extended towards the preparation of focused
chemical libraries for selected 5- or 6-membered heterocyclic
systems with mono- or gemdifluoroalkyl side chains, using
appropriate palladium-catalyzed coupling reactions (Scheme 1).
Wewillalsodemonstratethatitispossibletopreparecorresponding
chemical libraries through automated procedures using an Auto-
mated Parallel Synthetiser [Chemspeed Accelerator1].
2. Results and discussion
The pyrimidine 2 was selected as a first example. It was easily
prepared in excellent yield by reaction of propargylic fluoride 1
with acetamidine [8b]. Then, the aromatic bromide hence
obtained, can be used for Suzuki-Miyaura type coupling
reactions [9]. Model studies were performed first with phenyl
boronic acid to optimize the reaction and to achieve the suitable
conditions which will be compatible for automated processes. It
was found that reaction of 2 with phenyl boronic acid (2 equiv.),
sodium carbonate (2 equiv.) and palladiumdichlorobistriphe-
nylphosphine (5 mol%) in a 5/1 (dioxane/water) mixture at 70 8C
for 7 h furnished 3a in 82% isolated yield. These reaction
conditions were employed for the other boronic acids, using
Automated Parallel Synthetiser, affording the desired pyrimi-
dines 3a–3f in 60–88% yields (Scheme 2 and Table 1).
* Corresponding author. Fax: +33 0223236978.
E-mail address: rene.gree@univ-rennes1.fr (R. Gre´e).
1
Fax: +33 0223236978.
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.03.003

P. Bannwarth et al. / Journal of Fluorine Chemistry 134 (2012) 180–187
181
By this route, a first focused chemical library of pyrimidines
fluorinated on the side chain could be easily obtained. Further-
more, it is worthy of note that most of the corresponding molecules
of 3 series have still available functional groups (OH, carbonyl,
vinyl and amine) which could be used for further transformations
and extension to a second generation of pyrimidines fluorinated on
side chain.
Then, pyrimidine 5 was selected as a first example for
heterocycles with a gemdifluoroalkyl side chain. This scaffold
was also easily prepared in excellent yield by the reaction of
Br
R'
Y
Y
F
F
Het
( )
Het
( )
R
R
n
n
R= H, alkyl
Y = H, F
n = 0, 1
Het : 5- or 6-membered
heteroaromatic system
Br
propargylic fluoride
4 with acetamidine [8c]. The aromatic
bromide hence obtained can be used again for Suzuki-Miyaura
type coupling reactions. Under the same reaction conditions as
previously described, the pyrimidines 6a–6f were obtained in 69–
86% yields using the Automated Parallel Synthetizer (Scheme 3 and
Table 1). Most molecules belonging to this second library of 6-
series still have the appropriate functionalities (double bond,
Y
Y
F
F
H
R
R
O
Scheme 1. Synthetic strategy towards targeted chemical libraries of heterocyclic
systems with mono- and gemdifluoroalkyl side chains.
Br
Ar'B(OH)2
Br
[ref 8b]
Me
Ar'
F
F
PdCl2(PPh3)2 (5%)
F
Me
Me
Na2CO3
N
N
N
N
O
3
dioxane/H2O,
7h, 70°C
2
1
Me
Me
Scheme 2. Synthesis of the pyrimidine chemical library with a monofluorinated alkyl side chain.
Table 1
Pyrimidines 3 and 6 with fluorinated alkyl side chains.
Entry
1
Ar0B(OH)2
Product 3 (yield %)
3a (82%)
Product 6 (yield %)
6a (84%)
B(OH)2
2
3b (60%)
6b (70%)
B(OH)2
OHC
HO
3
4
5
6
3c (85%)
3d (88%)
3e (70%)
3f (75%)
6c (86%)
6d (81%)
6e (82%)
6f (69%)
B(OH)2
B(OH)2
O
S
B(OH)2
NH
O
O
B(OH)2
Br
Ar'B(OH)2
PdCl2(PPh3)2 (5%)
Ar'
Br
F [Ref 8c]
F
F
F
F
F
nC9H19
nC9H19
Na2CO3
N
N
N
N
O
nC9H19
6
dioxane/H2O, 70°C
5
4
Me
Me
Scheme 3. Synthesis of the pyrimidine chemical library with a gemdifluoroalkyl side chain.

182
P. Bannwarth et al. / Journal of Fluorine Chemistry 134 (2012) 180–187
Ar'B(OH)2
Br
Ar'
F
F
PdCl2(PPh3)2 (10%)
[Ref 8c]
1
Me
Me
Na2CO3
N N
Me
N N
Me
dioxane/H2O, 100°C
8
7
Scheme 4. Synthesis of the pyrazole chemical library with a monofluorinated alkyl side chain.
carbonyl group, phenol, amine) to prepare new derivatives and
extend the scope of this chemical library.
5, 7 and 9) were reacted individually with tributylvinylstannane to
afford the desired molecules 11–14 in fair to excellent yields
(Scheme 6). However, as the pyrazoles were less reactive than the
corresponding pyrimidines, hence required higher catalyst loading
with longer reaction times. Here again it is important to make a
note that these reactions afforded four scaffolds with vinyl groups,
which can be used later towards various types of functionalization,
including, in particular for cross metathesis reaction [12].
Therefore, these molecules open-up the route to new chemical
libraries of heterocycles with fluorinated side chains.
In conclusion, we have developed efficient procedures for the
preparation of focused model chemical libraries of various
heterocycles with mono- or gemdifluoroalkyl side chains. The
heterocyclic scaffolds bearing an aromatic bromide are easily
prepared through the chemistry previously developed, using
propargylic fluorides as key intermediates. Palladium-catalyzed
coupling reactions can be easily performed on these scaffolds,
including automated procedures to access new chemical
libraries. Taking into account the versatility of the propargylic
systems in carbo- and heterocyclic chemistry and the number of
possible transition metal-mediated coupling reactions, this
strategy opens up the route to large libraries with a good
molecular diversity. These chemical libraries would be of
much interest for the preparation of fluorinated bioactive
Now, pyrazole 7 was selected as a first example for 5-
membered heteroaromatic derivatives. It was easily prepared by
the reaction of propargylic fluoride 1 with N-methylhydrazine,
following the literature procedure [8c] in excellent yield (Scheme
4). The aromatic bromide hence obtained was used for Suzuki-
Miyaura type coupling reactions. These pyrazoles were found to be
less reactive than previous pyrimidines and therefore higher
catalyst loadings (10 mol%) and elevated temperatures were used.
Under these conditions the pyrazoles 8a–8f were obtained in 74–
88% yields (Table 2).
Then, pyrazole 9 was selected as an example for five-membered
heterocyclic scaffold with a gemdifluoroalkyl side chain. It was
easily prepared in excellent yield by the reaction of propargylic
fluoride 4 with N-methylhydrazine [8c]. The aromatic bromide
hence obtained was also successfully used for representative
Suzuki-Miyaura type coupling reactions affording the pyrazoles
10a–10f in 76–89% yields (Scheme 5 and Table 2).
To extend the scope of these approaches it was of interest to
demonstrate the possibility of using other Pd-catalyzed reactions
and therefore we have selected the Stille cross coupling reaction
[10]. Under appropriate reaction conditions [11], all four previous
heterocycles with their mono- and gemdifluoroalkyl side chains (2,
Ar'B(OH)2
Br
Ar'
F
F
F
F
PdCl2(PPh3)2 (10%)
[Ref 8c]
4
nC9H19
nC9H19
Na2CO3
N N
Me
N N
Me
dioxane/H2O, 100°C
10
9
Scheme 5. Synthesis of the pyrazole chemical library with a gemdifluoroalkyl side chain.
Table 2
Pyrazoles 8 and 10 with fluorinated alkyl side chains.
Entry
1
Ar0B(OH)2
Product 8 (yield %)
8a (76%)
Product 10 (yield %)
10a (79%)
B(OH)2
2
3
4
5
8b (88%)
8c (82%)
8d (74%)
8f (79%)
10b (80%)
10c (85%)
10d (76%)
10f (89%)
B(OH)2
OHC
HO
B(OH)2
B(OH)2
O
B(OH)2

P. Bannwarth et al. / Journal of Fluorine Chemistry 134 (2012) 180–187
183
Scheme 6. Synthesis of styrene type derivatives through Stille cross coupling reactions.
molecules and corresponding studies are under development in
3.2. General procedure for Suzuki-Miyaura coupling reactions
our groups.
Most of Suzuki-Miyaura coupling reactions were performed on
a Chemspeed Accelerator SLT100 automated synthesizer. The
robot was equipped with a four-needle head and an array of 16
parallel 13 mL glass reactors along with Solid Dosing Unit (SDU) for
solid additions. All reactors were connected to a Huber Unistat
(heating range: ꢀ70 to 300 8C) and were equipped with a
coldfinger reflux condenser in which the temperature can be
fixed from ꢀ5 to 40 8C. The inert atmosphere in the glass reactors of
the Accelerator SLT100 was obtained by flushing with nitrogen for
at least 30 min. Before the beginning of the coupling experiments,
the reaction vessels were heated to 70 8C, evacuated for 15 min,
and then filled with nitrogen. This procedure was repeated two
times to perform the reactions under an inert atmosphere with
1.5 bar flowrate. Substrates and reagents were administrated using
SDU unit and solvents were transferred from the stock solutions
with water and dioxane into the reaction vessels. A mixture of
pyrimidine 2 (or 5) (1 mmol) in a (5/1 dioxane/water mixture,
7 mL), Dichlorobis(triphenylphosphine)-palladium(II) (5 mol%),
sodium carbonate (2 mmol) and boronic acid (2 equiv.) was
heated at 70 8C for 7 h with a 900 rpm vortex. After cooling to
room temperature, MgSO4 was added. The reaction mixture was
3. Experimental
3.1. General
All reagents were obtained commercially and used without
further purification. All reactions were carried out under a
nitrogen, or argon, atmosphere and anhydrous conditions. The
solvents used were freshly distilled under anhydrous conditions,
unless otherwise specified. The reaction mixtures were magneti-
cally stirred with Teflon stirring bars, and the temperatures were
measured externally. Reactions that require anhydrous conditions
were carried out by using oven dried (120 8C, 24 h) glassware.
Yields refer to chromatographically and spectroscopically (1H and
13C NMR) homogeneous materials, and the reactions were
monitored by thin layer chromatography (TLC), carried out on
0.25 mm Merck silica gel plates (60 F254). The eluents used were
mixtures of pentane (P) and ether (E), with detection by UV light, or
a p-anisaldehyde staining solution. Acros silica gel (60, particle size
0.040–0.063 mm) was used for column chromatography. Nuclear
magnetic resonance (NMR) spectra were recorded with Bruker
Avance 500, 400 and 300 spectrometers. 1H NMR spectra:
given in ppm relative to tetramethylsilane (TMS) [TMS,
(H) = 0.00 ppm] as internal reference. 13C NMR spectra:
(C) are
given in ppm relative to TMS [CDCl3, (C) = 77.0 ppm] as internal
reference. 19F NMR spectra:
(F) are given in ppm relative to CFCl3.
Multiplicities were designated as singlet (s), doublet (d), triplet (t),
quadruplet (q) or multiplet (m). Mass spectral analyses have been
performed on a high resolution Micromass ZABSpecTOF mass
spectrometer in electrospray mode or on a Bruker MicrO-Tof-Q 2 in
d
(H) are
filtered through a pad of celite, washed with CH2Cl2 and
concentrated under vacuum. The product was purified by silica
gel chromatography using pentane/ether (9/1) as eluent.
d
d
d
d
3.3. Spectral and analytical data for pyrimidines 3 and 6
3.3.1. Pyrimidines 3
3.3.1.1. Synthesis of 4-(biphenyl-4-yl)-6-(1-fluoroethyl)-2-methyl-
pyrimidine 3a. The reaction was performed using pyrimidine 2
´
APCI mode, at the ‘‘Centre Regional de Mesures Physiques’’ Rennes.

184
P. Bannwarth et al. / Journal of Fluorine Chemistry 134 (2012) 180–187
according to the general procedure. A purification on silica gel
pyrimidine 3e as an oil (70% yield). 1H NMR (CDCl3, 300 MHz):
d
(eluent: pentane/ether, 9/1) afforded pyrimidine 3a as an oil (82%
(ppm) 8.25–8.13 (m, 2H); 7.77–7.57 (m, 5H); 7.43–7.30 (m, 2H);
7.07 (broad s, 1H); 5.63 (dq, JHF = 48.1 Hz, J = 6.5 Hz, 1H); 3.08 (s,
3H); 2.79 (s, 3H); 1.72 (dd, JHF = 24.5 Hz, J = 6.5 Hz, 3H). 13C NMR
yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 8.27–8.14 (m, 2H); 7.80–
7.69 (m, 3H); 7.69–7.59 (m, 2H); 7.54–7.33 (m, 3H); 5.64 (dq,
JHF = 48.1 Hz, J = 6.5 Hz, 1H); 2.80 (s, 3H); 1.76 (dd, JHF = 24.5 Hz,
(CDCl3, 75 MHz): d (ppm) 169.8 (d, JCF = 24.8 Hz); 167.8 (d,
J = 6.5 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
d
(ppm) 169.8 (d,
JCF = 2.9 Hz); 164.5 (d, JCF = 1.4 Hz); 142.4; 137.2; 136.6; 135.9;
128.4; 127.9; 127.3; 120.9; 108.4 (d, JCF = 8.1 Hz); 90.5 (d,
JCF = 172.0 Hz); 39.5; 26.1; 21.4 (d, JCF = 22.5 Hz). 19F NMR (CDCl3,
JCF = 24.7 Hz); 167.9 (d, JCF = 2.9 Hz); 164.6 (d, JCF = 1.5 Hz); 143.6;
140.2; 135.8; 128.9; 127.9; 127.8; 127.7; 127.6; 127.1; 108.3 (d,
JCF = 8.0 Hz); 90.5 (d, JCF = 171.9 Hz); 26.2; 21.4 (d, JCF = 22.5 Hz).
282 MHz):
d
(ppm) ꢀ183.43 (dq, J = 48.1 Hz, J = 24.8 Hz). HRMS
19F NMR (CDCl3, 376 MHz):
J = 24.5 Hz). HRMS (ESI) calcd for C19H17N2FNa [M+Na]+ m/
z = 315.1273, found 315.1271.
d
(ppm) ꢀ183.41 (dq, J = 48.1 Hz,
(ESI) calcd for C20H20FN3O2SNa [M+Na]+ m/z = 408.1152, found
408.1151.
3.3.1.6. Synthesis of 1-(40-(6-(1-fluoroethyl)-2-methylpyrimidin-4-
yl)biphenyl-4-yl)ethanone 3f. The reaction was performed using
pyrimidine 2 according to the general procedure. A purification on
silica gel (eluent: pentane/ether, 9/1) afforded pyrimidine 3f as an
3.3.1.2. Synthesis of 4-(1-fluoroethyl)-2-methyl-6-(40-vinylbiphenyl-
4-yl)pyrimidine 3b. The reaction was performed using pyrimidine
2 according to the general procedure. A purification on silica gel
(eluent: pentane/ether, 9/1) afforded pyrimidine 3b as an oil (60%
oil (75% yield). 1H NMR (CDCl3, 400 MHz):
d (ppm) 8.18–8.03 (m,
yield). 1H NMR (CDCl3, 300 MHz):
d
(ppm) 8.26–8.15 (m, 2H); 7.80–
2H); 7.97–7.85 (m, 3H); 7.69–7.53 (m, 4H); 5.53 (dq, JHF = 48.1 Hz,
J = 6.5 Hz, 1H); 2.70 (s, 3H); 2.51 (s, 3H); 1.63 (dd, JHF = 24.5 Hz,
7.69 (m, 3H); 7.67–7.58 (m, 2H); 7.57–7.45 (m, 2H); 6.77 (dd,
J = 17.5 Hz, J = 11.0 Hz, 1H); 5.82 (dd, J = 17.5 Hz, J = 0.7 Hz, 1H);
5.64 (dq, JHF = 48.1 Hz, J = 6.5 Hz, 1H); 5.31 (dd, J = 11.0 Hz,
J = 0.7 Hz, 1H); 2.81 (s, 3H); 1.73 (dd, JHF = 24.5 Hz, J = 6.5 Hz,
J = 6.5 Hz, 1H). 13C NMR (CDCl3, 100 MHz):
d (ppm) 197.8; 169.9 (d,
JCF = 24.0 Hz); 167.9 (d, JCF = 2.9 Hz); 164.4 (d, JCF = 1.4 Hz); 144.7;
142.2; 136.7; 136.2; 129.0; 127.9; 127.7; 127.2; 108.5 (d,
JCF = 6.7 Hz); 90.4 (d, JCF = 172.1 Hz); 26.7; 26.1; 21.4 (d,
3H). 13C NMR (CDCl3, 75 MHz):
d (ppm) 169.8 (d, JCF = 24.8 Hz);
167.9 (d, JCF = 2.9 Hz); 164.6 (d, JCF = 1.6 Hz); 143.1; 139;4; 137.2;
136.3; 135.8; 127.8; 127.4; 127.3; 127.2; 126.7; 114.3; 108.3
(JCF = 8.0 Hz); 90.5 (JCF = 171.8 Hz); 26.1; 21.4 (JCF = 22.6 Hz). 19F
JCF = 23.0 Hz). 19F NMR (CDCl3, 282 MHz):
J = 48.1 Hz, J = 24.5 Hz). HRMS (ESI) calcd for C21H19N2OFNa
[M+Na]+ m/z = 357.1379, found 357.1383.
d
(ppm) ꢀ183.35 (dq,
NMR (CDCl3, 282 MHz):
J = 24.5 Hz). HRMS (ESI) calcd for C21H19N2FNa [M+Na]+ m/
z = 341.1430, found 341.1431.
d
(ppm) ꢀ183.44 (dq, J = 48.1 Hz,
3.3.2. Pyrimidines 6
3.3.2.1. Synthesis
of
4-(biphenyl-4-yl)-6-(1,1-difluorodecyl)-2-
3.3.1.3. Synthesis of 40-(6-(1-fluoroethyl)-2-methylpyrimidin-4-
yl)biphenyl-3-carbaldehyde 3c. The reaction was performed using
pyrimidine 2 according to the general procedure. A purification on
silica gel (eluent: pentane/ether, 9/1) afforded pyrimidine 3c as an
methylpyrimidine 6a. The reaction was performed using pyrimi-
dine 5 according to the general procedure. A purification on silica
gel (eluent: pentane/ether, 9/1) afforded pyrimidine 6a as an oil
(84% yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 8.29–8.17 (m, 2H);
oil (85% yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 10.00 (s, 1H);
7.85 (s, 1H); 7.81–7.71 (m, 2H); 7.71–7.61 (m, 2H); 7.55–7.45 (m,
2H); 7.45–7.35 (m, 1H); 3.11 (s, 3H); 2.47–2.22 (m, 2H); 1.60–1.45
(m, 2H); 1.44–1.26 (m, 12H); 0.90 (broad t, J = 7.0 Hz, 3H). 13C NMR
8.21–8.10 (m, 2H); 8.05 (broad s, 1H); 7.88–7.73 (m, 2H); 7.72–
7.59 (m, 3H); 7.59–7.48 (m, 1H); 5.57 (dq, JHF = 48.1 Hz, J = 6.5 Hz,
1H); 2.73 (s, 3H); 1.67 (dd, JHF = 24.5 Hz, J = 6.5 Hz, 3H). 13C NMR
(CDCl3, 75 MHz):
d (ppm) 168.8; 165.2; 163.4 (t, JCF = 29.6 Hz);
144.0; 140.0; 135.3; 128.9; 128.0; 127.8; 127.6; 127.1; 121.1 (t,
JCF = 242.9 Hz); 119.3; 115.2; 114.2; 109.1 (t, JCF = 4.6 Hz); 36.0 (t,
JCF = 24.6 Hz); 31.9; 29.4; 29.36; 29.30; 29.2; 26.3; 22.7; 21.9 (t,
(CDCl3, 75 MHz):
d (ppm) 192.1; 169.9 (d, JCF = 24.7 Hz); 167.9 (d,
JCF = 2.9 Hz); 164.3 (d, JCF = 1.6 Hz); 142.0; 141.1; 137.0; 136.5;
133.0; 129.6; 129.2; 128.0; 127.8; 127.6; 108.4 (d, JCF = 8.1 Hz);
90.5 (d, JCF = 171.9 Hz); 26.1; 21.4 (d, JCF = 22.5 Hz). 19F NMR (CDCl3,
JCF = 4.1 Hz); 14.1. 19F NMR (CDCl3, 282 MHz):
d
(ppm) ꢀ101.84 (t,
J = 17.2 Hz). HRMS (ESI) calcd for C27H32N2F2Na [M+Na]+ m/
z = 445.2431, found 445.2435.
376 MHz):
d
(ppm) ꢀ183.26 (dq, J = 48.1 Hz, J = 24.5 Hz). HRMS
(ESI) calcd for C20H17FN2ONa [M+Na]+ m/z = 343.1217, found
343.1217.
3.3.2.2. Synthesis of 4-(1,1-difluorodecyl)-2-methyl-6-(40-vinylbi-
phenyl-4-yl)pyrimidine 6b. The reaction was performed using
pyrimidine 5 according to the general procedure. A purification
on silica gel (eluent: pentane/ether, 9/1) afforded pyrimidine 6b
3.3.1.4. Synthesis of 40-(6-(1-fluoroethyl)-2-methylpyrimidin-4-
yl)biphenyl-3-ol 3d. The reaction was performed using pyrimidine
2 according to the general procedure. A purification on silica gel
(eluent: pentane/ether, 9/1) afforded pyrimidine 3d as an oil (88%
(70% yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 8.26–8.18 (m, 2H);
yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 8.17–8.07 (m, 2H);7.73
7.82 (s, 1H); 7.80–7.72 (m, 2H); 7.68–7.60 (m, 2H); 7.57–7.49 (m,
2H); 6.78 (dd, J = 17.6 Hz, J = 10.9 Hz, 1H); 5.83 (dd, J = 17.6 Hz,
J = 0.3 Hz, 1H); 5.32 (dd, J = 10.9 Hz, J = 0.3 Hz, 1H); 2.86 (s, 3H);
2.43–2.17 (m, 2H); 1.57–1.43 (m, 2H); 1.42–1.16 (m, 12H); 0.88 (t,
(s, 1H);7.68–7.62 (m, 2H); 7.38 (broad s, 1H); 7.33–7.25 (m, 1H);
7.19–7.09 (m, 1H); 7.04–6.96 (m, 1H); 6.89–6.81 (m, 2H); 5.64 (dq,
JHF = 48.1 Hz, J = 6.5 Hz, 1H); 2.81 (s, 3H); 1.72 (dd, JHF = 24.5 Hz,
J = 6.6 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
J = 6.9 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
d (ppm) 168.8; 165.2;
d (ppm) 169.9 (d,
163.3 (t, JCF = 29.4 Hz); 143.5; 139.3; 137.3; 136.2; 135.4; 127.8;
127.4; 127.2; 126.8; 121.1 (t, JCF = 242.4 Hz); 114.4; 109.1 (t,
JCF = 4.5 Hz); 36.0 (t, JCF = 24.5 Hz); 31.8; 29.4; 29.3; 29.27; 29.24;
JCF = 24.9 Hz); 167.9 (d, JCF = 2.8 Hz); 165.1 (d, JCF = 1.6 Hz); 153.3;
143.4; 141.7; 135.7; 130.1; 127.9; 127.7; 119.4; 115.0; 114.2;
108.9 (d, JCF = 8.1 Hz); 90.3 (d, JCF = 172.2 Hz); 25.8; 21.4 (d,
26.3; 22.7; 21.9 (t, JCF = 3.9 Hz); 14.1. 19F NMR (CDCl3, 282 MHz):
d
JCF = 22.7 Hz). 19F NMR (CDCl3, 282 MHz):
d
(ppm) ꢀ183.30 (dq,
(ppm) ꢀ102.01 (t, J = 17.1 Hz). HRMS (ESI) calcd for C29H34F2N2Na
J = 48.9 Hz, J = 24.5 Hz). HRMS (ESI) calcd for C19H17N2OFNa
[M+Na]+ m/z = 331.1223, found 331.1224.
[M+Na]+ m/z = 471.2582, found 471.2579.
3.3.2.3. Synthesis of 40-(6-(1,1-difluorodecyl)-2-methylpyrimidin-
4-yl)biphenyl-3-carbaldehyde 6c. The reaction was performed
using pyrimidine 5 according to the general procedure. A
purification on silica gel (eluent: pentane/ether, 9/1) afforded
3.3.1.5. Synthesis of N-(40-(6-(1-fluoroethyl)-2-methylpyrimidin-4-
yl)biphenyl-4-yl)methanesulfonamide 3e. The reaction was per-
formed using pyrimidine 2 according to the general procedure.
A purification on silica gel (eluent: pentane/ether, 9/1) afforded

P. Bannwarth et al. / Journal of Fluorine Chemistry 134 (2012) 180–187
185
pyrimidine 6c (86% yield). 1H NMR (CDCl3, 400 MHz):
d
(ppm)
under reduced pressure to obtain a solid, which was then purified
by chromatography on silica gel (eluent: pentane/ether, 98/2)
affording pyrazole 7 as a crystalline product Mp:74 8C (123.8 mg,
10.09 (s, 1H); 8.26–8.11 (m, 2H); 8.17–8.12 (m, 1H); 7.93–7.84
(m, 2H); 7.81 (broad s, 1H); 7.79–7.72 (m, 2H); 7.66–7.59 (m,
1H); 2.84 (s, 3H); 2.42–2.20 (m, 2H); 1.53–1.41 (m, 2H); 1.39–
1.13 (m, 12H); 0.86 (broad t, J = 7.0 Hz, 3H). 13C NMR (CDCl3,
78%). 1H NMR (300 MHz, CDCl3):
d (ppm) 7.70–7.64 (m, 2H); 7.57–
7.45 (m, 2H); 6.64 (d, JHF = 2.7 Hz, 1H); 5.73 (dq, JHF = 49.9 Hz,
J = 6.5 Hz, 1H); 4.01 (d, JHF = 1.0 Hz, 3H); 1.82 (dd, JHF = 22.9, 6.5 Hz,
3H). 13C NMR (75 MHz, CDCl3):
d (ppm) 148.9 (d, JCF = 2.0 Hz); 142.6
100 MHz):
d (ppm) 192.03; 168.8; 164.9; 163.5 (t, JCF = 29.7 Hz);
142.3; 141.0; 137.0; 136.1; 132.9; 129.6; 129.3; 128.0; 127.9;
127.6; 121.1 (t, JCF = 242.6 Hz); 109.1 (t, JCF = 4.5 Hz); 35.9 (t,
(d, JCF = 20.5 Hz); 132.1; 131.7; 127.0; 121.5; 101.9 (d, JCF = 3.5 Hz);
81.7 (d, JCF = 164.7 Hz); 37.2 (d, JCF = 2.0 Hz); 19.6 (d, JCF = 23.6 Hz).
J
CF = 35.8 Hz); 31.8; 29.4; 29.3; 29.25; 29.24; 26.2; 22.6; 21.9 (t,
JCF = 3.9 Hz); 14.1. 19F NMR (CDCl3, 376 MHz):
d
(ppm) ꢀ101.73 (t,
19F NMR (282 MHz, CDCl3):
d
(ppm) ꢀ164.93 (dqd, J = 49.9 Hz,
J = 17.1 Hz). HRMS (ESI) calcd for C28H32F2N2ONa [M+Na]+ m/
z = 473.2375, found 473.2375.
J = 22.9 Hz, J = 1.3 Hz). HRMS (ESI) calcd for C12H12N2F79BrNa
[M+Na]+ m/z = 305.0066, found 305.0066.
3.3.2.4. Synthesis of 40-(6-(1,1-difluorodecyl)-2-methylpyrimidin-4-
yl)biphenyl-3-ol 6d. The reaction was performed using pyrimidine
5 according to the general procedure. A purification on silica gel
(eluent: pentane/ether, 9/1) afforded pyrimidine 6d (81% yield). 1H
3.4.2. Pyrazoles 8
3.4.2.1. General procedure for Suzuki-Miyaura coupling reactions for
pyrazoles. A mixture of pyrazole 7 or 9 (1.0 equiv.), Dichlorobis(-
triphenylphosphine)-palladium(II) (10 mol%), sodium carbonate
(2.0 equiv.) and boronic acid (2.0 equiv.) in a 5:1 mixture of
dioxane and water was stirred at 100 8C for 24 h. After cooling to
room temperature, the solution was diluted with CH2Cl2 and then
dried over anhydrous MgSO4. The reaction mixture was filtered
through a pad of celite and concentrated under vacuum. The
product was purified by silica gel chromatography using pentane/
ether (9/1) as eluent.
NMR (CDCl3, 300 MHz):
d (ppm) 8.20–8.10 (m, 2H); 7.83 (s, 1H);
7.69–7.60 (m, 2H); 7.37–7.25 (m, 1H); 7.23–7.13 (m, 2H); 7.05–
6.97 (m, 1H); 6.94–6.84 (m, 1H); 2.91 (s, 3H); 2.45–2.22 (m, 2H);
1.59–1.46 (m, 2H); 1.44–1.16 (m, 12H); 0.90 (broad t, J = 6.9 Hz,
3H). 13C NMR (CDCl3, 75 MHz):
d (ppm) 168.9; 165.7; 163.5 (t,
JCF = 29.5 Hz); 156.4; 143.8; 141.5; 135.2; 130.1; 128.7; 127.9;
127.7; 127.1; 121.0 (t, JCF = 242.9 Hz); 119.3; 115.2; 114.2; 109.7 (t,
JCF = 4.9 Hz); 36.1 (t, JCF = 24.5 Hz); 31.9; 29.4; 29.3; 29.28; 29.24;
26.0; 22.7; 21.9 (t, JCF = 4.0 Hz); 14.1. 19F NMR (CDCl3, 282 MHz):
d
3.4.2.2. Synthesis of 4-(biphenyl-4-yl)-5-(1-fluoroethyl)-1-methyl-
1H-pyrazole 8a. The reaction was performed using pyrazole 7
according to the general procedure. A purification on silica gel
(eluent: pentane/ether, 9/1) afforded pyrazole 8a (76% yield) Mp:
(ppm) ꢀ101.71 (t, J = 17.2 Hz). HRMS (ESI) calcd for C27H32F2N2ONa
[M+Na]+ m/z = 461.2375, found 461.2373.
3.3.2.5. Synthesis of N-(40-(6-(1,1-difluorodecyl)-2-methylpyrimidin-
4-yl)biphenyl-4-yl)methanesulfonamide 6e. The reaction was per-
formed using pyrimidine 5 according to the general procedure. A
purification on silica gel (eluent: pentane/ether, 9/1) afforded
102 8C. 1H NMR (300 MHz, CDCl3):
d (ppm) 7.90–7.64 (m, 4H); 7.50–
7.36 (m, 5H); 6.64 (d, JHF = 2.4 Hz, 1H); 5.75 (dq, JHF = 50.0,
J = 6.5 Hz, 1H); 4.01 (d, JHF = 1.0 Hz, 3H); 1.83 (dd, JHF = 22.9, 6.5 Hz,
3H). 13C NMR (75 MHz, CDCl3):
d (ppm) 149.7 (d, JCF = 2.2 Hz); 142.4
pyrimidine 6e (82% yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 8.25–
(d, JCF = 20.4 Hz);140.8; 140.4; 132.2; 128.7; 127.3; 127.2; 126.9;
125.8; 102.0 (d, JCF = 3.5 Hz); 81.8 (d, JCF = 164.5 Hz); 37.1 (d,
8.14 (m, 2H); 7.80 (s, 1H); 7.75–7.58 (m, 4H); 7.42–7.32 (m, 2H);
7.30 (broad s, 1H); 3.09 (s, 3H); 2.84 (s, 3H); 2.42–2.17 (m, 2H);
1.55–1.42 (m, 2H); 1.41–1.14 (m, 12H); 0.87 (broad t, J = 6.9 Hz,
JCF = 2.1 Hz); 19.6 (d, JCF = 23.7 Hz). 19F NMR (282 MHz, CDCl3):
d
3H). 13C NMR (CDCl3, 75 MHz):
d
(ppm) 168.8; 165.1; 163.4 (t,
(ppm) ꢀ164.68 (dqd, J = 50.0 Hz, J = 22.9 Hz, J = 1.6 Hz). HRMS (ESI)
calcd for C18H17N2FNa [M+Na]+ m/z = 303.1273, found 303.1275.
JCF = 29.9 Hz); 142.8; 137.0; 136.7; 135.5; 128.4; 127.9; 127.3;
121.1 (t, JCF = 242.4 Hz); 120.9; 109.1 (t, JCF = 4.9 Hz); 39.4; 36.0 (t,
JCF = 24.5 Hz); 31.8; 29.4; 29.3; 29.26; 29.23; 26.2; 22.6; 21.9 (t,
3.4.2.3. Synthesis of 5-(1-fluoroethyl)-1-methyl-4-(40-vinylbiphenyl-
4-yl)-1H-pyrazole 8b. The reaction was performed using pyrazole 7
according to the general procedure. A purification on silica gel
(eluent: pentane/ether, 9/1) afforded pyrazole 8b (88% yield) Mp:
JCF = 3.9 Hz); 14.1. 19F NMR (CDCl3, 282 MHz):
d
(ppm) ꢀ101.73 (t,
J = 17.1 Hz). HRMS (ESI) calcd for C28H35F2N2O2SNa [M+Na]+ m/
z = 538.2316, found 538.2316.
104 8C. 1H NMR (300 MHz, CDCl3):
d (ppm) 7.90–7.40 (m, 8H); 6.78
3.3.2.6. Synthesis of 1-(40-(6-(1,1-difluorodecyl)-2-methylpyrimidin-
4-yl)biphenyl-4-yl)ethanone 6f. The reaction was performed using
pyrimidine 5 according to the general procedure. A purification on
silica gel (eluent: pentane/ether, 9/1) afforded pyrimidine 6f (69%
(dd, J = 17.6, 10.9 Hz, 1H); 6.64 (d, JHF = 2.5 Hz, 1H); 5.82 (dd,
J = 17.6, 0.8 Hz, 1H); 5.76 (dq, JHF = 50.0, 6.5 Hz, 1H); 5.28 (dd,
J = 10.9, 0.8 Hz, 1H); 4.01 (d, JHF = 0.9 Hz, 3H); 1.83 (dd, JHF = 22.9,
6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d (ppm) 149.6 (d,
yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 8.28–8.12 (m, 2H); 8.06–
JCF = 2.0 Hz); 142.4 (d, JCF = 20.4 Hz); 140.1, 139.9; 136.6; 136.4;
132.2; 127.1; 127.0; 126.6; 125.8; 113.9, 102.0 (d, JCF = 3.5 Hz);
81.8 (d, JCF = 164.4 Hz); 37.1 (d, JCF = 2.1 Hz); 19.6 (d, JCF = 23.7 Hz).
7.93 (m, 2H); 7.78 (s, 1H); 7.74–7.58 (m, 4H); 2.80 (s, 3H); 2.57 (s,
3H); 2.42–2.15 (m, 2H); 1.54–1.41 (m, 2H); 1.40–1.10 (m, 12H);
19F NMR (282 MHz, CDCl3):
J = 22.9 Hz, J = 1.6 Hz). HRMS (ESI) calcd for C20H19N2FNa [M+Na]+
m/z = 329.1430, found 329.1430.
d
(ppm) ꢀ164.69 (dqd, J = 50.0 Hz,
0.83 (broad t, J = 6.8 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
d (ppm)
197.6; 168.9; 164.9; 163.3 (t, JCF = 29.7 Hz); 144.5; 142.5; 136.4;
136.3; 129.0; 127.9; 127.8; 127.3; 119.5 (t, JCF = 242.5 Hz); 109.2 (t,
JCF = 4.5 Hz); 35.9 (t, JCF = 24.6 Hz); 31.8; 29.4; 29.3; 29.26; 29.23;
26.7; 26.3; 22.6; 21.9 (t, JCF = 4.0 Hz); 14.1. 19F NMR (CDCl3,
3.4.2.4. Synthesis of 40-(5-(1-fluoroethyl)-1-methyl-1H-pyrazol-4-
yl)biphenyl-3-carbaldehyde 8c. The reaction was performed using
pyrazole 7 according to the general procedure. A purification on
silica gel (eluent: pentane/ether, 9/1) afforded pyrazole 8c (82%
282 MHz):
d
(ppm) ꢀ101.97 (t, J = 17.2 Hz). HRMS (ESI) calcd for
C29H34F2N2ONa [M+Na]+ m/z = 487.2531, found 487.2528.
yield) Mp: 88 8C. 1H NMR (300 MHz, CDCl3):
d (ppm) 10.10 (s, 1H);
3.4. Spectral and analytical data for pyrazoles 8 and 10
8.20–7.60 (m, 8H); 6.65 (d, JHF = 2.4 Hz, 1H); 5.74 (dq, JHF = 49.9,
6.6 Hz, 1H); 4.00 (d, JHF = 1.0 Hz, 3H); 1.83 (dd, JHF = 22.9, 6.5 Hz,
3.4.1. Pyrazole 7
3H).13C NMR (75 MHz, CDCl3):
d (ppm) 192.4; 149.4 (d, JCF = 2.1 Hz);
A solution of 1 (157.0 mg, 0.41 mmol) and methylhydrazine
(0.45 mmol, 1.1 equiv.) in EtOH (1 mL) was stirred under argon at
room temperature for 1 h. The mixture was then concentrated
142.5 (d, JCF = 20.5 Hz); 141.7; 138.7; 136.9; 132.9; 132.8; 129.5;
128.6; 127.9; 127.3; 126.0; 102.1 (d, JCF = 3.4 Hz); 81.7 (d,

186
P. Bannwarth et al. / Journal of Fluorine Chemistry 134 (2012) 180–187
JCF = 164.6 Hz); 37.1 (d, JCF = 2.0 Hz); 19.6 (d, JCF = 23.6 Hz). 19F NMR
(282 MHz, CDCl3):
J = 1.5 Hz). HRMS (ESI) calcd for C19H17N2OFNa [M+Na]+ m/
z = 331.1223, found 331.1224.
3.4.3.3. Synthesis of 40-(5-(1,1-difluorodecyl)-1-methyl-1H-pyrazol-
3-yl)biphenyl-3-carbaldehyde 10c. The reaction was performed
using pyrazole 9 according to the general procedure. A purification
on silica gel (eluent: pentane/ether, 9/1) afforded pyrazole 10c
d
(ppm) ꢀ164.70 (dqd, J = 50.0 Hz, J = 22.9 Hz,
(85% yield) Mp: 58 8C. 1H NMR (300 MHz, CDCl3):
d (ppm) 10.12 (s,
3.4.2.5. Synthesis of 40-(5-(1-fluoroethyl)-1-methyl-1H-pyrazol-4-
yl)biphenyl-3-ol 8d. The reaction was performed using pyrazole
7 according to the general procedure. A purification on silica gel
(eluent: pentane/ether, 9/1) afforded pyrazole 8d as an oil (74%
d (ppm) 7.80–6.75 (m, 8H); 6.59
(d, JHF = 2.5 Hz, 1H); 5.70 (dq, JHF = 49.8, 6.5 Hz, 1H); 3.99 (d,
JHF = 0.8 Hz, 3H); 1.80 (dd, JHF = 23.0, 6.5 Hz, 3H).13C NMR (75 MHz,
1H); 8.16–7.60 (m, 8H); 6.72 (t, JHF = 1.0 Hz, 1H); 4.07 (t,
JHF = 0.9 Hz, 3H); 2.45–2.18 (m, 2H); 1.80–1.45 (m, 2H); 1.40–
1.15 (m, 12H); 0.90 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d
(ppm) 192.3; 149.2; 141.7; 139.2 (t, JCF = 30.5 Hz); 139.0; 136.9;
132.8; 132.5; 129.5; 128.7; 127.9; 127.4; 126.0; 118.8 (t,
JCF = 237.8 Hz); 103.6 (t, JCF = 4.4 Hz); 38.7 (t, JCF = 3.2 Hz); 37.2
(t, JCF = 25.2 Hz); 31.8; 29.4; 29.3; 29.2; 22.6; 22.1 (t, JCF = 3.8 Hz);
yield). 1H NMR (300 MHz, CDCl3):
CDCl3):
d
(ppm) 156.1; 150.1 (d, JCF = 2.0 Hz); 142.9 (d,
14.1. 19F NMR (282 MHz, CDCl3):
HRMS (ESI) calcd for C27H32N2OF2Na [M+Na]+ m/z = 461.2380,
d
(ppm) ꢀ92.88 (t, J = 16.6 Hz).
JCF = 20.4 Hz); 142.4; 140.4; 131.5; 129.9; 127.4; 126.1; 119.4;
114.5; 114.1; 102.4 (d, JCF = 3.3 Hz); 81.7 (d, JCF = 164.9 Hz); 36.8
found 461.2380.
(d, JCF = 2.1 Hz); 19.6 (d, JCF = 23.5 Hz). 19F NMR (282 MHz, CDCl3):
(ppm) ꢀ165.32 (dqd, J = 49.9 Hz, J = 23.0 Hz, J = 1.3 Hz).
d
3.4.3.4. Synthesis of 40-(5-(1,1-difluorodecyl)-1-methyl-1H-pyrazol-
3-yl)biphenyl-3-ol 10d. The reaction was performed using pyrazole
9 according to the general procedure. A purification on silica gel
(eluent: pentane/ether, 9/1) afforded pyrazole 10d as an oil (76%
3.4.2.6. Synthesis of 1-(40-(5-(1-fluoroethyl)-1-methyl-1H-pyrazol-4-
yl)biphenyl-4-yl)ethanone 8f. The reaction was performed using
pyrazole 7 according to the general procedure. A purification on
silica gel (eluent: pentane/ether, 9/1) afforded pyrazole 8f (79%
yield). 1H NMR (300 MHz, CDCl3):
(t, JHF = 1.0 Hz, 1H); 4.07 (t, JHF = 0.8 Hz, 3H); 2.40–2.05 (m, 2H);
1.80–1.45 (m, 2H); 1.40–1.15 (m, 12H); 0.90 (t, J = 6.9 Hz, 3H). 13
NMR (75 MHz, CDCl3): (ppm) 156.3; 149.7; 142.2; 140.5; 139.4 (t,
d (ppm) 7.80–6.80 (m, 8H); 6.68
yield) Mp: 142 8C. 1H NMR (300 MHz, CDCl3):
8H); 6.65 (d, JHF = 2.6 Hz, 1H); 5.75 (dq, JHF = 49.9, 6.5 Hz, 1H); 4.00
(d, JHF = 0.9 Hz, 3H); 2.66 (s, 3H); 1.83 (dd, JHF = 22.9, 6.5 Hz, 3H).13
NMR (75 MHz, CDCl3): (ppm) 197.8; 149.4 (d, JCF = 2.0 Hz); 145.3;
d
(ppm) 8.10–7.60 (m,
C
d
C
JCF = 30.7 Hz); 131.5; 129.9; 127.4; 126.1; 119.2; 118.8 (t,
JCF = 237.7 Hz); 114.5; 114.1; 103.7 (t, JCF = 4.4 Hz); 38.5 (t,
JCF = 3.2 Hz); 37.2 (t, JCF = 25.1 Hz); 31.9; 29.4; 29.3; 29.2; 29.1;
22.6; 22.1 (t, JCF = 3.8 Hz,); 14.1. 19F NMR (282 MHz, CDCl3):
d (ppm)
d
142.6 (d, JCF = 20.5 Hz); 138.9; 135.8; 133.1; 128.9; 127.5; 127.0;
125.9; 102.1 (d, JCF = 3.4 Hz); 81.7 (d, JCF = 164.7 Hz); 37.2
(d, JCF = 2.1 Hz); 26.7, 19.6 (d, JCF = 23.7 Hz). 19F NMR (282 MHz,
ꢀ92.96 (t, J = 16.6 Hz). HRMS (APCI) calcd for C26H32N2OF2[M]+ m/
CDCl3):
d
(ppm) ꢀ164.80 (dqd, J = 49.9 Hz, J = 23.0 Hz, J = 1.3 Hz).
z = 426.2477, found 426.2478.
HRMS (ESI) calcd for C20H19N2OFNa [M+Na]+ m/z = 345.1379, found
345.1377.
3.4.3.5. Synthesis of 1-(40-(5-(1,1-difluorodecyl)-1-methyl-1H-pyr-
azol-3-yl)biphenyl-4-yl)ethanone 10f. The reaction was per-
formed using pyrazole 9 according to the general procedure. A
purification on silica gel (eluent: pentane/ether, 9/1) afforded
3.4.3. Pyrazoles 10
pyrazole 10f (89% yield) Mp: 126 8C. 1H NMR (300 MHz, CDCl3):
d
3.4.3.1. Synthesis of 3-(biphenyl-4-yl)-5-(1,1-difluorodecyl)-1-meth-
yl-1H-pyrazole 10a. The reaction was performed using pyrazole 9
according to the general procedure. A purification on silica gel
(eluent: pentane/ether, 9/1) afforded pyrazole 10a (79% yield) Mp:
52 8C. 1H NMR (300 MHz, CDCl3):
7.62 (m, 4H); 7.50–7.29 (m, 3H); 6.70 (t, JHF = 1.0 Hz, 1H); 4.06 (t,
JHF = 0.9 Hz, 3H); 2.40–2.15 (m, 2H), 1.80–1.45 (m, 2H); 1.40–1.15
(m, 12H); 0.90 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d (ppm)
149.5; 140.7; 139.5 (t, JCF = 30.6 Hz); 131.7; 128.8; 127.4; 127.3;
126.9; 125.8; 122.0; 116.4 (t, JCF = 237.7 Hz); 103.5 (t, JCF = 4.3 Hz);
38.6 (t, JCF = 3.2 Hz); 37.2 (t, JCF = 25.2 Hz); 31.8; 29.4; 29.3; 29.2;
22.6; 22.1 (t, JCF = 3.8 Hz); 14.1. 19F NMR (282 MHz, CDCl3):
d (ppm)
(ppm) 8.10–7.60 (m, 8H); 6.72 (t, JHF = 1.0 Hz, 1H); 4.07 (t,
JHF = 0.9 Hz, 3H); 2.66 (s, 3H); 2.45–2.19 (m, 2H); 1.80–1.45 (m,
2H); 1.40–1.15 (m 12H); 0.90 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz,
d (ppm) 7.90–7.84 (m, 2H); 7.67–
CDCl3):
d (ppm) 197.7; 149.2; 145.3; 139.3 (t, JCF = 30.5 Hz);
139.2; 135.9; 132.7; 128.9; 127.5; 127.0; 127.9; 126.0; 118.8 (t,
JCF = 237.8 Hz); 103.6 (t, JCF = 4.4 Hz); 38.7 (t, JCF = 3.2 Hz); 37.2 (t,
JCF = 25.2 Hz); 31.8; 29.4; 29.3; 29.2; 29.1; 26.6; 22.6; 22.1 (t,
JCF = 3.8 Hz); 14.1. 19F NMR (282 MHz, CDCl3):
J = 16.6 Hz). HRMS (ESI) calcd for C28H34N2OF2Na [M+Na]+ m/
z = 475.2537, found 475.2535.
d
(ppm) ꢀ92.88 (t,
ꢀ92.82 (t, J = 16.5 Hz). HRMS (ESI) calcd for C26H32N2F2Na [M+Na]+
3.5. Syntheses of styrene type derivatives through Stille cross coupling
reactions
m/z = 433.2431, found 433.2434.
3.4.3.2. Synthesis of 5-(1,1-difluorodecyl)-1-methyl-3-(40-vinylbi-
phenyl-4-yl)-1H-pyrazole 10b. The reaction was performed using
pyrazole 9 according to the general procedure. A purification on
silica gel (eluent: pentane/ether, 9/1) afforded pyrazole 10b (80%
3.5.1. Pyrimidine 11
3.5.1.1. Synthesis of 4-(1-fluoroethyl)-2-methyl-6-(4-vinylphenyl)-
pyrimidine 11. A mixture of pyrimidine 2 (0.67 mmol, 1 equiv.),
vinyl tributyltin (1.35 mmol, 2 equiv.) and PdCl2(PPh3)3 (5 mol%)
in dioxane (10 mL) was stirred at 100 8C overnight under argon.
The mixture was concentrated under reduced pressure and the
crude product was purified by chromatography on silica gel (eluent
Pentane/Et2O, 95/5, then 9/1) affording 11 as a yellow oil
yield) Mp: 84 8C. 1H NMR (300 MHz, CDCl3):
d (ppm) 7.90–7.45 (m,
8H); 6.78 (dd, J = 17.6, 10.9 Hz, 1H); 6.70 (t, JHF = 1.0 Hz, 1H); 5.82
(dd, J = 17.6, 0.9 Hz, 1H); 5.29 (dd, J = 10.9, 0.9 Hz, 1H); 4.06 (t,
JHF = 0.9 Hz, 3H); 2.45–2.19 (m, 2H); 1.80–1.45 (m, 2H); 1.40–1.15
(m, 12H); 0.90 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d (ppm)
149.2; 140.1; 140.0; 139.1 (t, JCF = 30.5 Hz); 136.7; 136.4; 131.8;
127.1; 127.0; 126.7; 125.9; 118.8 (t, JCF = 237.7 Hz); 113.9; 103.5
(t, JCF = 4.5 Hz); 38.6 (t, JCF = 3.1 Hz); 37.2 (t, JCF = 25.2 Hz); 31.9;
29.4; 29.3; 29.2; 29.1; 22.6; 22.1 (t, JCF = 3.7 Hz); 14.1. 19F NMR
(156.0 mg, 95% yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 8.13–
8.05 (m, 2H); 7.67 (s, 1H); 7.57–7.47 (m, 2H); 6.76 (dd, J = 17.6 Hz,
J = 10.9 Hz, 1H); 5.86 (dd, J = 17.6 Hz, J = 0.6 Hz, 1H); 5.61 (dq,
JHF = 48.1 Hz, J = 6.5 Hz, 1H); 5.35 (dd, J = 10.9 Hz, J = 0.6 Hz, 1H);
2.77 (s, 3H); 1.70 (dd, JHF = 24.5 Hz, J = 6.5 Hz, 3H). 13C NMR (CDCl3,
(282 MHz, CDCl3):
[M+H]+ calculated for C28H35N2F2 m/z = 437.2768, found
d
(ppm) ꢀ92.83 (t, J = 16.6 Hz). HRMS (m/z):
75 MHz):
d (ppm) 169.7 (d, JCF = 24.7 Hz); 167.8 (d, JCF = 2.9 Hz);
164.5 (d, JCF = 1.6 Hz); 140.1; 136.2; 136.1; 127.5; 126.7; 115.5;
437.2771.

P. Bannwarth et al. / Journal of Fluorine Chemistry 134 (2012) 180–187
187
108.2 (d, JCF = 8.0 Hz); 90.5 (d, JCF = 171.8 Hz); 26.2; 21.4 (d,
JCF = 22.5 Hz). 19F NMR (CDCl3, 282 MHz):
J = 48.1 Hz, J = 24.5 Hz). HRMS (ESI) calcd for C15H15FN2Na [M+Na]+
m/z = 265.11170, found 265.1119.
crude product was purified by chromatography on silica gel (eluent
pentane/ether, 95/5, then 9/1) affording 14 as a yellow oil (146 mg,
61% yield). 1H NMR (300 MHz, CDCl3):
d (ppm) 7.80–7.40 (m, 4H),
d
(ppm) ꢀ183.61 (dq,
6.68 (dd, J = 17.6, 10.9 Hz, 1H), 6.64 (t, JHF = 1.1 Hz, 1H), 5.78 (dd,
J = 17.6, 0.9 Hz, 1H), 5.27 (dd, J = 10.9, 0.9 Hz, 1H) 4.03 (t,
JHF = 1.0 Hz, 3H), 2.45–2.19 (m, 2H), 1.80–1.45 (m, 2H,), 1.40–
3.5.2. Pyrimidine 12
1.15 (m, 12H), 0.92 (t, J = 6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d
3.5.2.1. Synthesis of 4-(1,1-difluorodecyl)-2-methyl-6-(4-vinylphe-
nyl)pyrimidine 12. A mixture of pyrimidine 5 (0.20 mmol, 1 equiv.),
vinyl tributyltin (0.31 mmol, 1.5 equiv.) and PdCl2(PPh3)2 (5 mol%)
in dioxane (3 mL) was stirred at 100 8C for 20 h under argon. The
mixture was concentrated under reduced pressure and the crude
product was purified by chromatography on silica gel (eluent
pentane/Et2O, 98/2) affording 12 as a pale yellow oil (62.6 mg, 84%
(ppm) 149.5, 139.1 (t, JCF = 30.5 Hz), 137.1, 136.5, 132.2, 126.5,
125.6, 118.8 (t, JCF = 237.7 Hz), 113.8, 103.5 (t, JCF = 4.5 Hz), 38.6 (t,
JCF = 3.1 Hz), 37.2 (t, JCF = 25.2 Hz), 31.9, 29.4, 29.3, 29.2, 29.1, 22.7,
22.1 (t, JCF = 3.6 Hz), 14.1. 19F NMR (282 MHz, CDCl3):
d (ppm)
ꢀ92.87 (t, J = 16.6 Hz). HRMS (APCI) calcd for C22H30N2F2[M]+ m/
z = 360.2372, found 360.2379.
yield). 1H NMR (CDCl3, 300 MHz):
d (ppm) 8.18–8.03 (m, 2H); 7.77
(s, 1H); 7.60–7.46 (m, 2H); 6.77 (dd, J = 17.6 Hz, J = 10.9 Hz, 1H);
5.87 (d, J = 17.6 Hz, 1H); 5.37 (d, J = 10.9 Hz, 1H); 2.83 (s, 3H); 2.42–
2.16 (m, 2H); 1.55–1.40 (m, 2H); 1.37–1.18 (m, 12H); 0.87 (t,
Acknowledgments
This research has been performed as part of the Indo-French
‘‘Joint Laboratory for Sustainable Chemistry at Interfaces’’. We
thank CNRS, CSIR, and University of Rennes 1 for support of this
research. We thank Ministere de l’Education Nationale et de la
Recherche for a fellowship to P.B. We thank CRMPO (Rennes) for
the mass spectral studies.
J = 6.8 Hz, 3H). 13C NMR (CDCl3, 75 MHz):
d (ppm) 168.7; 165.1;
163.3 (t, JCF = 29.6 Hz); 140.4; 136.0; 135.7; 127.5; 126.8; 121.1 (t,
JCF = 242.6 Hz); 115.7; 109.0 (t, JCF = 4.7 Hz); 35.9 (t, JCF = 24.6 Hz);
31.8; 29.4; 29.3; 29.26; 29.23; 26.2; 22.6; 21.9 (t, JCF = 3.9 Hz);
`
14.1. 19F NMR (CDCl3, 282 MHz):
HRMS (ESI) calcd for C23H30F2N2Na [M+Na]+ m/z = 395.22748,
d
(ppm) ꢀ101.93 (t, J = 17.1 Hz).
found 395.2277.
References
3.5.3. Pyrazole 13
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1H-pyrazole 13. A mixture of pyrazole 7 (0.67 mmol, 1 equiv.),
vinyl tributyltin (1.35 mmol, 2 equiv.) and PdCl2(PPh3)3 (10 mol%)
in dioxane (10 mL) was stirred at 100 8C during 24 h under argon.
The mixture was concentrated under reduced pressure and the
crude product was purified by chromatography on silica gel (eluent
Pentane/ether 95/5, then 9/1) affording 13 as a yellow oil (136 mg,
(b) J.T. Welch, S. Eswarakrishnan, Fluorine in Bioorganic Chemistry, Wiley
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88% yield). 1H NMR (300 MHz, CDCl3):
d (ppm) 7.90–7.40 (m, 4H),
6.78 (dd, J = 17.6, 10.9 Hz, 1H), 6.64 (d, JHF = 2.5 Hz, 1H), 5.82 (dd,
J = 17.6, 0.8 Hz, 1H) 5.76 (dq, JHF = 50.0 Hz, J = 6.5 Hz, 1H), 5.28 (dd,
J = 10.9, J = 0.8 Hz, 1H) 4.01 (d, J = 0.9 Hz, 3H), 1.83 (dd, JHF = 22.9,
J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCl3):
d (ppm) 149.6 (d,
JCF = 2.0 Hz), 142.4 (d, JCF = 20.4 Hz), 140.1, 139.9, 136.6, 136.4,
132.2, 127.1, 127.0, 126.6, 125.8, 113.9, 102.0 (d, JCF = 3.5 Hz), 81.8
(d, JCF = 164.4 Hz), 37.1 (d, JCF = 2.1 Hz), 19.6 (d, JCF = 23.7 Hz). 19F
´
´
[5] M. Prakesch, E. Kerouredan, D. Gree, R. Gree, J. De Chancie, K.N. Houk, J. Fluorine
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Tetrahedron: Asymmetry 17 (2006) 2306, and references cited therein.
NMR (282 MHz, CDCl3):
J = 22.9 Hz, J = 1.6 Hz). HRMS (ESI) calcd for C14H15N2FNa
[M+Na]+ m/z = 253.1117, found 253.1116.
d
(ppm) ꢀ164.69 (dqd, J = 50.0 Hz,
´
´
[7] (a) D. Gree, R. Gree, Tetrahedron Lett. 48 (2007) 5435;
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´
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3.5.4. Pyrazole 14
3.5.4.1. Synthesis of 5-(1,1-difluorodecyl)-1-methyl-3-(4-vinylphe-
nyl)-1H-pyrazole 14. A mixture of pyrazole 9 (0.67 mmol, 1 equiv.),
vinyl tributyltin (1.35 mmol, 2 equiv.) and PdCl2(PPh3)3 (10 mol%)
in dioxane (10 mL) was stirred at 100 8C during 24 h under argon.
The mixture was concentrated under reduced pressure and the
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