Pyrazoles with a "click" 4-[N-(4-fluorobutyl)-1,2,3-triazole] substituent in position 3 are nanomolar CB1 receptor ligands

Article abstract of DOI:10.1016/j.jfluchem.2014.07.010

Replacement of the 3-carbonylaminopiperidine substitutent with a "click" 4-[N-(4-fluorobutyl)-(1,2,3-triazolyl)] group in Rimonabant-type pyrazoles produced a novel class of nanomolar CB₁ receptor ligands. Molecule 1d is the most promising lead

Full text of DOI:10.1016/j.jfluchem.2014.07.010

Journal of Fluorine Chemistry 167 (2014) 184–191
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Pyrazoles with a ‘‘click’’ 4-[N-(4-fluorobutyl)-1,2,3-triazole]
substituent in position 3 are nanomolar CB receptor ligands
1
a,b,1
a,1
a
a
Rita Distinto
, Chiara Zanato , Serena Montanari , Maria Grazia Cascio ,
b,c
a
a,d,
Paolo Lazzari , Roger Pertwee , Matteo Zanda
*
a
Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill AB25 2ZD, Scotland, UK
Neuroscienze PharmaNess Scarl, Parco Scientifico della Sardegna, Edificio 5, Loc. Piscinamanna, 09010 Pula, CA, Italy
KemoTech s.r.l., Parco Scientifico della Sardegna, Edificio 3, Loc. Piscinamanna, 09010 Pula, CA, Italy
C.N.R.-I.C.R.M., via Mancinelli 7, 20131 Milano, Italy
b
c
d
A R T I C L E I N F O
A B S T R A C T
Article history:
Replacement of the 3-carbonylaminopiperidine substitutent with a ‘‘click’’ 4-[N-(4-fluorobutyl)-(1,2,3-
Received 2 May 2014
triazolyl)] group in Rimonabant-type pyrazoles produced a novel class of nanomolar CB
ligands. Molecule 1d is the most promising lead with a K = 23 nM for CB , which is very close to that
displayed by Rimonabant (SR141716), and fairly good CB /CB selectivity (K CB /K CB = 35.5), thus
representing a promising candidate for [ F]radiolabeling and PET Imaging studies of the CB receptor.
1
receptor
Received in revised form 11 July 2014
Accepted 12 July 2014
Available online 21 July 2014
i
1
1
2
i
2
i
1
1
8
1
ß 2014 Elsevier B.V. All rights reserved.
Keywords:
Cannabinoids
PET imaging
Fluorine
Sonogashira reaction
‘
‘Click’’ chemistry
1
. Introduction
included severe depression and suicidal thoughts. Since the
1
relationship between (a) the CB receptors’ functional modification,
Cannabinoid receptors are members of the large family of G-
density and distribution, and (b) the onset of a pathological state is
still not well understood, the development of radio-ligands suitable
protein coupled receptors (GPCRs) [1]. Two types of cannabinoid
receptor have been discovered so far, CB and CB [2], and both of
them have been extensively studied. CB receptors are localised
predominantly in the brain [2] whereas CB receptors are more
abundant in peripheral nervous system (PNS) cells [3], although
some studies have shown the presence of CB in the PNS [4] and of
CB in the central nervous system, albeit in low density [5]. CB
1
2
1
for in vivo PET functional imaging of CB receptors remains an
1
important area of research in medicine and drug development. To
date, a few radiotracers [13] based on the structure of SR141716
(Rimonabant) [12] have been synthesised and tested in vivo but most
of them afforded unsatisfactory brain imaging results due to their
poor ability to cross the blood-brain barrier (BBB). A handful of
2
1
2
1
receptors have been associated with a number of disorders,
including depression [6], anxiety [7], stress [8], schizophrenia [9],
chronic pain [10] and obesity [11]. For this reason, several
cannabinoid ligands were developed as drug candidates. Among
these ligands, a prominent position is occupied by SR141716
radiolabelled CB
clinical trials in humans [15]. In this paper we describe the synthesis
of a conceptually new class of high-affinity CB ligands 1, bearing a
‘‘click’’ N-(4-fluorobutyl)-1,2,3-triazolyl function in position 3 of a
pyrazolyl ring, as candidate PET tracers. Furthermore, we synthesised
the 4-iodo-1,2,3-triazolyl analogue 10 which might be developed into
a theranostic or a multi-modal imaging tool by radioiodination.
1
PET ligands [14] have also been submitted to
1
(Rimonabant) [12], which is a pyrazole-core inverse agonist
discovered by Sanofi-Synthelabo (now Sanofi-Aventis) in 1994,
marketed in Europe as an anti-obesity drug but subsequently
withdrawn from the market owing to its side-effects, which
2. Results and discussion
2.1. Ligands design
*
Corresponding author at: Kosterlitz Centre for Therapeutics, Institute of
Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, UK.
Extensive theoretical and experimental structure-activity rela-
tionship studies have been performed on Rimonabant analogues for
E-mail address: m.zanda@abdn.ac.uk (M. Zanda).
1
These two authors contributed equally.
http://dx.doi.org/10.1016/j.jfluchem.2014.07.010
0022-1139/ß 2014 Elsevier B.V. All rights reserved.

R. Distinto et al. / Journal of Fluorine Chemistry 167 (2014) 184–191
185
(
b)
(
a)
1
Fig. 1. (a) Rimonabant’s pharmacophore. (b) Proposed binding mode of compounds 1 to CB .
identifying a general pharmacophore. Hydrophobic interactions
between ligands and CB receptor were deemed to be essential. In
via a palladium-catalysed cross coupling reactions, into the
desired target pyrazoles 1a–e.
1
fact, the two aromatic rings in positions 1 and 5 of the pyrazole ring
interact favourably with the residues Trp279/Phe200/Trp356 and
Tyr275/Trp255/Phe278 respectively, and likewise the aminopiper-
idine cyclohexyl with the cavity constituted by Val196/Phe170/
Leu387 and Met384 [16] (Fig. 1a). Moreover, the hydrogen bond
between the ligand’s amidic oxygen and the receptor residue Lys192
plays a crucial role in the binding, favouring the inverse agonism of
Rimonabant.
The synthesis started from 2 (Scheme 2), which was condensed
with diethyl oxalate in the presence of sodium ethylate to give, in
85% yield, the 1,3-diketoester
3 as a tautomeric mixture,
predominantly containing the alkenylidene structure. Subsequent-
ly, tricarbonyl compound 3 and 2,4-dichlorophenylhydrazine were
heated in ethanol [18] to afford the pyrazole 4 in rather modest
yield (32%). The latter was regioselectively brominated, [19]
employing NBS as bromine source, to afford the corresponding
bromothiophene 5 in good yield (83%). The following conversion
was accomplished through a DIBAL-H hydride reduction, providing
the aldehyde 6 which was homologated under Bestmann-Ohira
alkynylation conditions [20] to generate the alkyne 7 in a moderate
yield (55%). Finally, the key triazole 8 was achieved by means of a
copper-catalyzed azide-alkyne cycloaddition protocol [21] in an
acceptable 55% yield.
With the intermediate 8 in hand, compounds 1a–c were
obtained by means of a palladium-catalysed Suzuki–Miyaura cross
coupling [22] using the respective commercially available boronic
acids, while compounds 1d–e were synthesised employing a
copper-palladium catalysed Sonogashira cross coupling [23] using
the appropriate alkyne (Scheme 3).
With that in mind, we decided to replace the carbonyl-
aminopiperidine residue in position 3 with a 4-(1,2,3-triazolyl)
2
function, since either of the triazolyl sp nitrogen atoms could act
as hydrogen bond acceptor with Lys192. The 1,2,3-triazole would
carry a N-(4-fluorobutyl) group, which should be readily amenable
18
to [ F]radiofluorination and could be accommodated in the
lipophilic Val196/Phe170/Leu387/Met384 pocket. Finally, we
planned to replace the 4-chlorophenyl group in 5-position with
a 5-substituted 2-thiophenyl residue, which was previously shown
to be a very advantageous structural modification leading to high-
affinity CB
.2. Synthesis of 1,2,3-triazolyl compounds 1
The synthesis of target compounds 1 envisaged the use of a
1
ligands, such as NESS125A [17].
2
2.3. Synthesis of 5-iodo-1,2,3-triazolyl compound 10
key intermediate 8 (Scheme 1) which was obtained in a few
synthetic steps from commercially available reagents such as
diethyl oxalate, 1-(thiophen-2-yl) propan-1-one 2, and 2,4-
dichlorophenylhydrazine hydrochloride, and directly converted
The synthesis of 4-iodo-1,2,3-triazolyl derivative 10 (Scheme
4) started from the intermediate 7 that was iodinated in a good
yield (74%) using 4-iodomorpholine as iodine source. Next, a
Scheme 1. Retro-synthesis of 1,2,3-triazolyl analogues 1a–e.

1
86
R. Distinto et al. / Journal of Fluorine Chemistry 167 (2014) 184–191
Scheme 2. Synthesis of key intermediate 8. Reagents and conditions: (i) diethyl oxalate, EtONa/EtOH, r.t., overnight, (85%); (ii) 2,4-dichlorophenylhydrazine hydrochloride,
EtOH, reflux, overnight, (32%); (iii) NBS, CH CN, from 0 8C to r.t., overnight, (83%); (iv) DIBAL-H, DCM, -78 8C, 4 h, (55%); (v) dimethyl 1-diazo-2-oxopropylphosphonate, K CO
MeOH, r.t., overnight, (55%); and (vi) 1-azido-4-fluorobutane, CuI, sodium ascorbate, tert-BuOH/H O, r.t, overnight, (55%).
3
2
3
,
2
copper-catalysed azide-iodoalkyne cycloaddition [24] afforded
the desired compound 10 in moderate yield (43%).
Compound 1d stands out for its high CB
was comparable to that displayed by Rimonabant
SR141716). Moreover, 1d showed fairly good CB /CB
selectivity (K CB /K CB = 35.5). All the other compounds
showed K CB one order of magnitude higher than that of 1d,
and low to moderate CB /CB selectivity. Compound 1d is
1
affinity, which
(
1
2
2.4. Biological tests
i
2
i
1
i
1
3
We next performed [ H]CP55940 displacement binding assays
with membranes obtained from hCB and hCB CHO cells using
methods we have described previously [25]. Results are summarised
1
2
1
2
therefore the most promising candidate for further develop-
ment, including its possible use as a PET tracer for imaging the
in Table 1 (affinity to CB
1
and CB
2
are expressed as K
i
values).
1
CB receptor in vivo.
Table 1
Compound
hCB
1
CHO cells
hCB
2
CHO cells
a,d
b
b
a,d
b
K
i
(95% CL )
% Maximum displacement (95% CL )
K
i
(95% CL )
% Maximum
b
displacement (95% CL )
3
3
1
1
1
1
1
8
1
a
b
c
200 (94.9–420)
76.5 (66.3–86.7)
85.1 (66.5–103)
80.0 (65.9–94.1)
75.6 (62.0–89.2)
58.8 (43.2–74.5)
100 (81.0–120)
71.8 (65.6–77.9)
90.2 (85.0–95.3)
2.36 ꢀ 10 (641–8.70 ꢀ 10 )
73.3 (47.3–99.2)
97.5 (82.6–112)
55.6 (41.8–69.5)
74.5 (55.0–94.0)
3
3
3
353 (103–1.20 ꢀ 10 )
1.70 ꢀ 10 (953–3.02 ꢀ 10 )
f
3
119 (40.2–353)
471 (95.1–2.33 ꢀ 10 )
3
d
e
23.4 (6.80–80.0)
164 (32.5–825)
312 (113–862)
422 (235–757)
830 (281–2.45 ꢀ 10 )
c
c
n.a.
n.a.
3
3
1.02 ꢀ 10 (603–1.72 ꢀ 10 )
92.0 (79.7–104)
c
c
0
n.a.
n.a.
e
3
3 g
SR141716
18.7 (11.1–31.4)
1.40 ꢀ 10 (500–3.70 ꢀ 10 )
92.4 (70.4–114)
a
nM.
b
CL, confidence limits.
c
d
e
f
Plateau could not be reached.
n = 4, unless otherwise indicated.
n = 14.
n = 12.
n = 2.
g

R. Distinto et al. / Journal of Fluorine Chemistry 167 (2014) 184–191
187
Scheme 3. Synthesis of analogues 1a–e. Reagents and conditions: (i) phenylboronic acid, Pd(PPh
Na CO , DME, r.t., overnight, (35%); (iii) 1-cyclohexen-1-yl-boronic acid, Pd(PPh , Na CO , DME, r.t., overnight, (75%); (iv) 1-pentyne, Pd(PPh
20%); and (v) cyclopropylacetylene, Pd(PPh , DIPEA, CuI, 80 8C, 20 h, (25%).
3
)
4
, Na
2
CO
3
, DME, r.t., overnight, (35%); (ii) 2-thienylboronic acid, Pd(PPh
3 4
) ,
2
3
3
)
4
2
3
3 4
) , DIPEA, CuI, 80 8C, 20 h,
(
3 4
)
Scheme 4. Synthesis of iodinated analogue 10. Reagents and conditions: (i) 4-iodomorpholine, CuI, THF, r.t. 1 h, (74%); and (ii) 1-azido-4-fluorobutane, CuI, TEA, THF, r.t, 72 h,
43%).
(
3
. Conclusions
in the same range as that displayed by Rimonabant (SR141716),
and fairly good CB /CB selectivity (K CB approx.36-fold lower
than K CB ).
1
2
i
1
In Rimonabant-type pyrazoles, replacement of the 3-carbo-
i
2
nylaminopiperidine substitutent with a ‘‘click’’ [4-(1,2,3-triazo-
lyl)] group carrying a N-(4-fluorobutyl) function produced a novel
class of nanomolar CB
1
receptor ligands displaying nanomolar
4. Experimental
4.1. General information
affinity for the CB receptor. This may be explained by the
1
capacity of the 1,2,3-triazole ring to mimic Rimonabant’s 3-
carboxamide residue and behave as hydrogen-bond acceptor
1
13
19
with Lys192 of the CB
promising candidate for [ F]radiolabeling and PET Imaging
1
studies of the CB receptor, as it displayed a K = 23 nM for the CB ,
1
receptor. Molecule 1d is a particularly
H (400.13 MHz), C (100.58 MHz) and F (376.45 MHz) NMR
1
8
1
spectra were recorded on a Bruker ADVANCE III spectrometer. H
NMR chemical shifts are reported relative to TMS, and the solvent
1
i

1
88
R. Distinto et al. / Journal of Fluorine Chemistry 167 (2014) 184–191
resonance was employed as the internal standard (CDCl
3
,
d
= 7.26).
C NMR spectra were recorded with complete proton decoupling,
and the chemical shifts are reported relative to TMS with the
chromatography (Hexane/EtOAc 8:2). A final recrystallization
13
(Hexane/EtOAc 7:3) gave compound 4 (2.01 g, 32%) as a white
1
solid. Rf 0.30 (Hexane/EtOAc 8:2); H NMR (400 MHz, CDCl
3
)
d
:
1
9
solvent resonance as the internal standard (CDCl
3
,
d
= 77.0).
F
1.45 (t, 3H, J = 7.1 Hz), 2.46 (s, 3H), 4.47 (q, 2H, J = 7.1 Hz), 6.92 (dd,
1H, J = 1.2, 3.6 Hz), 7.02 (dd, 1H, J = 3.6, 5.1 Hz), 7.33 (dd, 1H, J = 2.2,
8.5 Hz), 7.38 (dd, 1H, J = 1.2, 5.1 Hz), 7.40 (d, 1H, J = 8.5 Hz), 7.46 (d,
NMR spectra were recorded with complete proton decoupling. The
following abbreviations are used to describe spin multiplicity:
s = singlet, d = doublet, t = triplet, m = multiplet, dd = doublet-
1
3
1H, J = 2.2 Hz); C NMR (100 MHz, CDCl
3
) d: 9.9, 14.5, 61.0, 120.0,
doublet, dt = doublet-triplet, q = quartet. All chemical shifts (d)
127.2, 127.7, 127.8, 128.6, 128.9, 130.0, 131.0, 133.9, 136.0, 136.3,
35
are expressed in parts per million and coupling constant (J) are
given in Hertz. LC–MS experiments were performed on an Agilent
Technologies 1200 Series HPLC system equipped with a DAD and a
137.8, 142.9, 162.7; MS (ESI), calculated m/z C17
H
14 Cl
2
N
2
O
2
S:
+
+
381.0 [M+H] , 383.0 [M+2+H] , found m/z (relative intensity):
+
+
381.0 [M+H] (100), 383.0 [M+2+H] (70).
6
120 MS detector composed by a ESI ionisation source and a Single
Quadrupole mass selective detector using an Analytical C18 RP
˚
4.4. Ethyl 5-(5-bromothiophen-2-yl)-1-(2,4-dichlorophenyl)-4-
column (Phenomenex Luna, C18, 250 mm ꢀ 4.60 mm, 5
m
, 100 A).
methyl-1H-pyrazole-3-carboxylate (5)
HPLC purifications were performed on the Agilent 1200 system
using a semi preparative C18 RP column (Phenomenex Luna,
˚
m, 100 A). All reactions were carried out in
Compound 4 (2.21 g, 1.31 mmol) was dissolved in acetonitrile
(4.5 mL) and the solution was cooled to 0 8C. NBS (0.39 g,
2.23 mmol) was added in small portions, than the mixture was
2
50 mm ꢀ 10.00 mm, 5
oven- or flame-dried glassware under nitrogen atmosphere, unless
stated otherwise. All commercially available reagents were used as
received. Reactions were magnetically stirred and monitored by
TLC on silica gel (60 F254 pre-coated glass plates, 0.25 mm
thickness). Visualisation was accomplished by irradiation with a
UV lamp and/or staining with a ceric ammonium molibdate or
2 2 3
stirred overnight at r.t. A saturated solution of Na S O (5 mL) was
added and the solvent was removed under reduced pressure. The
resulting mixture was extracted with EtOAc, the organic layers
4
were washed with water, brine, dried over MgSO , filtered and the
solvent was evaporated under reduced pressure. The crude
product was purified by flash chromatography (Hexane/EtOAc
4
KMnO solution. Flash chromatography was performed on silica
˚
gel (60 A, particle size 0.040–0.062 mm). Yields refer to chromato-
graphically and spectroscopically pure compounds, unless stated
otherwise. Abbreviations used: DCM for dichloromethane, EtOAc
8:2) to give compound 5 (510 mg, 83%) as a pale yellow solid. Rf
1
0.38 (Hexane/EtOAc 8:2); H NMR (400 MHz, CDCl
3
)
d
: 1.40 (t, 3H,
J = 7.1 Hz), 2.41 (s, 3H), 4.43 (q, 2H, J = 7.1 Hz), 6.63 (d, 1H,
J = 3.9 Hz), 6.94 (d, 1H, J = 3.9 Hz), 7.33 (d, 1H, J = 2.0 Hz), 7.35 (d,
2
for ethyl acetate, Et O for diethyl ether, NBS for N-bromosucci-
1
3
nimide, DIBAL-H for diisobutylaluminium hydride, DME for
dimethoxyethane, DIPEA N,N-Diisopropylethylamine, THF for
1H, J = 0.4 Hz), 7.45 (dd, 1H, J = 0.4, 2.0 Hz); C NMR (100 MHz,
CDCl : 10.1, 14.6, 61.2, 115.1, 120.5, 128.0, 129.4, 130.3, 130.3,
3
) d
tetrahydrofuran, MeOH for methanol and TEA for triethylamine.
131.0, 133.9, 134.1, 135.8, 136.7, 137.0, 142.8, 162.6; MS (ESI),
3
78 35
+
[
H]CP55940 displacement binding assays with membranes
and hCB CHO cells using methods were
performed as described previously [25].
calculated m/z
C
17
H
13 Br Cl
2
N
2
O
2
S: 458.9 [M+H] , 460.9
+
+
obtained from hCB
1
2
[M+2+H] , found m/z (relative intensity): 458.9 [M+H] (65),
+
460.9 [M+2+H] (100).
4.2. Ethyl-3-methyl-2,4-dioxo-4-(thiophen-2-yl)butanoate (3)
4.5. 5-(5-Bromothiophen-2-yl)-3-(2,4-dichlorophenyl)-5-
methylcyclopenta-1,4-dienecarbaldehyde (6)
Under a nitrogen atmosphere, sodium (0.86 g, 37.50 mmol) was
added in small portions to dry ethanol (25 mL) and stirred at room
temperature until all the sodium was dissolved. Diethyl oxalate
Ester 5 (0.2 g, 0.43 mmol) was dissolved in anhydrous
dichloromethane (2 mL) and the mixture was cooled to ꢁ78 8C.
DIBAL-H (0.5 mL) was added drop wise over 45 min and the
mixture was stirred for 4 h at ꢁ78 8C. MeOH (0.5 mL) was added
and the solvent was removed under reduced pressure. The
resulting mixture was extracted with EtOAc, the organic layers
(7.6 mL, 56.30 mmol) was then added, followed by dropwise
addition of a solution of commercially available 1-(thiophen-2-yl)
propan-1-one 2 (2.63 g, 18.65 mmol) in dry ethanol (26 mL). The
mixture was stirred at room temperature for 18 h, than slowly
poured into a mixture of ice and aqueous 1 N HCl. The resulting
4
were washed with brine, dried over MgSO , filtered and the solvent
mixture was extracted with Et
2
O, the organic layers were dried
was evaporated under reduced pressure. The crude product was
purified by flash chromatography (Hexane/EtOAc 5:5) to give
over MgSO , filtered and the solvent was evaporated under
4
reduced pressure. The crude product was purified by flash
aldehyde 6 (0.45 g, 55%) as a white solid. Rf 0.50 (Hexane/EtOAc
1
chromatography (Hexane/EtOAc 8:2) to give compound 3 (3.8 g,
5:5); H NMR (400 MHz, CDCl
3
)
d
: 2.36 (s, 3H), 6.58 (d, 1H,
1
8
5%) as a white solid. Rf 0.57 (Hexane/EtOAc 8:2); H NMR
J = 3.9 Hz), 6.90 (d, 1H, J = 3.9 Hz), 7.29 (d, 1H, J = 0.5 Hz), 7.30 (d,
1H, J = 2.0 Hz), 7.46 (dd, 1H, J = 0.5, 2.0 Hz), 10.0 (s, 1H); MS (ESI),
(
400 MHz, CDCl
3
)
d: 1.24 (t, 3H, J = 7.1 Hz), 1.45 (d, 3H, J = 7.0 Hz),
7
8
35
+
4
.25 (q, 2H, J = 7.1 Hz), 4.70 (q, 1H, J = 7.0 Hz), 7.37 (t, 1H,
calculated m/z
C
15
H
9
Br Cl
2
N
2
OS: 414.9 [M+H] , 416.9
1
3
+
+
J = 8.4 Hz), 7.37 (d, 1H, J = 8.4 Hz), 7.51 (d, 1H, J = 8.4 Hz);
C
[M+2+H] , found m/z (relative intensity): 414.9 [M+H] (55),
+
NMR (100 MHz, CDCl
3
)
d
: 13.4, 14.0, 52.6, 63.1, 128.6, 133.5, 135.3,
42.4, 160.4, 187.5, 190.1; MS (ESI), calculated m/z C11 S:
41.0 [M+H] , 263.0 [M+Na] , found m/z (relative intensity): 241.0
416.9 [M+2+H] (100).
1
2
12 4
H O
+
+
4.6. 2-Bromo-5-(5-(2,4-dichlorophenyl)-3-ethynyl-2-
+
+
[
M+H] (100), 263.0 [M+Na] (40).
methylcyclopenta-1,3-dienyl) thiophene (7)
4.3. Ethyl 5-(thiophen-2-yl)-1-(2,4-dichlorophenyl)-4-methyl-1H-
2 3
K CO (0.11 g, 0.86 mmol) and dimethyl 1-diazo-2-oxopropyl-
pyrazole-3-carboxylate (4)
phosphonate (0.09 g, 0.52 mmol) were added to an ice cold
solution of aldehyde 6 (0.45 g, 1.09 mmol) in MeOH (0.5 mL). After
5 min the ice bath was removed and the reaction was allowed to
warm to r.t. and stirred for additional 12 h. Rochelle salt (2 mL) and
The
a,g-diketoester 3 (4.63 g, 20.51 mmol) was dissolved in
absolute EtOH (36 mL) and 2,4-dichlorophenylhydrazine hydro-
chloride (4.38 g, 20.51 mmol) was added in one portion, then the
mixture was refluxed overnight. The solvent was removed under
reduced pressured and the crude product was purified by flash
Et
brine, dried over MgSO
under reduced pressure. The crude product was purified by flash
2
O (2 mL) were added. The organic layers were washed with
4
, filtered and the solvent was evaporated

R. Distinto et al. / Journal of Fluorine Chemistry 167 (2014) 184–191
189
chromatography (Hexane/EtOAc 7:3) to give alkyne 7 (0.15 g, 55%)
as a white solid. Rf 0.82 (Hexane/EtOAc 7:3); H NMR (400 MHz,
NMR (400 MHz, CDCl
3
)
d
: 1.67–1.90 (m, 2H), 2.07–2.22 (m, 2H),
1
2.63 (s, 3H), 4.52 (dt, 2H, JH-F = 47.2 Hz, JH-H = 5.7 Hz), 4.52 (t, 2H,
J = 6.9 Hz), 6.88 (d, 1H, J = 3.8 Hz), 7.22 (d, 1H, J = 3.8 Hz), 7.30–7.46
(m, 6H), 7.51 (d, 1H, J = 2.2 Hz), 7.56 (d, 1H, J = 2.2 Hz), 7.98 (s, 1H);
CDCl
H, J = 3.9 Hz), 7.36 (d, 2H, J = 1.3 Hz), 7.50 (t, 1H, J = 1.3 Hz);
NMR (100 MHz, CDCl : 9.4, 75.0, 81.4, 114.5, 120.1, 127.9, 128.4,
30.1, 130.2, 130.7, 130.9, 133.7, 135.2, 135.8, 136.3, 136.4; MS
3
) d: 2.28 (s, 3H), 3.31 (s, 1H), 6.62 (d, 1H, J = 3.9 Hz), 6.96 (d,
1
3
1
C
1
9
13
3
)
d
F NMR (376.45 MHz, CDCl
3
)
d
: ꢁ219.3 (s, 1F); C NMR (100 MHz,
1
CDCl ) d: 10.3, 26.5 (d, JC-F = 4.1 Hz), 27.3 (d, JC-F = 20.1 Hz), 49.8,
3
78
35
+
(ESI), calculated m/z C16
H
9
Br Cl
2
N
2
S: 410.9 [M+H] , 412.9
83.2 (d, JC-F = 165.7 Hz), 121.2, 123.1, 125.8, 127.9, 128.0, 128.3,
129.0, 129.2, 129.7, 130.2, 130.4, 131.1, 133.6, 134.0, 135.9, 136.5,
136.8, 137.3, 142.5, 143.9, 146.2; MS (ESI), calculated m/z
+
+
+
[
M+2+H] , 432.9 [M+Na] , 434.9 [M+2+Na] , found m/z (relative
+
+
+
intensity): 410.9 [M+H] (35), 412.9 [M+2+H] (70), 432.9 [M+Na]
+
35
+
+
(
55), 434.9 [M+2+Na] (100).
.7. 1-Azido-4-fluorobutane
NaN (0.25 g, 3.96 mmol) was added to a stirred solution of 1-
C
(
26
H
22 Cl
2
FN
relative intensity): 526.1 [M+H] (100), 528.1 [M+2+H] (70);
HRMS calcd. for C26 FN S: 526.1030, found: 526.1026.
5
S: 526.1 [M+H] , 528.1 [M+2+H] , found m/z
+
+
4
H23Cl
2
5
3
4.11. 4-(1-(2,4-Dichlorophenyl)-4-methyl-5-(5-phenylthiophen-2-
bromo-4-fluorobutane (0.5 g, 2.61 mmol) in 40 mL of water/
acetone (1:4). The resulting suspension was stirred at r.t. for
yl)-1H-pyrazol-3-yl)-1-(4-fluorobutyl)-1H-1,2,3-triazole (1b)
2
4 h. The mixture was extracted with DCM, dried over MgSO
4
,
Starting from 8 and 2-thienylboronic acid, compound 1b
filtered and the solvent was evaporated under reduced pressure. 1-
Azido-4-fluorobutane was obtained (300 mg, 76%) as a yellow oil
and was used without further purification. H NMR (400 MHz,
(48 mg, 35%) was obtained as yellow oil. Rf 0.31 (Hexane/EtOAc
1
6:4); H NMR (400 MHz, CDCl
3
)
d
: 1.71–1.79 (m, 1H), 1.79–1.86 (m,
1
1H), 2.10–2.20 (m, 2H), 2.62 (s, 3H), 4.52 (dt, 2H, JH-F = 47.2 Hz, JH-
= 5.7 Hz), 4.52 (t, 2H, J = 7.0 Hz), 6.81 (d, 1H, J = 3.8 Hz), 7.04 (dd,
1H, J = 3.6, 5.1 Hz,) 7.08 (d, 1H, J = 3.8 Hz), 7.17 (dd, 1H J = 1.1,
.6 Hz), 7.26 (dd, 1H, J = 1.1, 5.1 Hz), 7.38 (dd, 1H, J = 2.2, 8.4), 7.45
CDCl
3
)
d
: 1.71–1.79 (m, 1H), 1.79–1.87 (m, 1H), 1.89–1.99 (m, 2H),
H
3
.39 (t, 2H, J = 6.5 Hz), 4.42 (dt, 2H, JH-F = 47.3 Hz, JH-H = 5.7 Hz).
3
1
9
4
1
.8. 4-(5-(5-Bromothiophen-2-yl)-1-(2,4-dichlorophenyl)-4-methyl-
(d, 1H, J = 8.4 Hz), 7.52 (d, 1H, J = 2.2 Hz), 8.00 (s, 1H); F NMR
1
3
H-pyrazol-3-yl)-1-(4-fluorobenzyl)-1H-1,2,3-triazole (8)
(376.45 MHz, CDCl
: 10.2, 26.5 (d, JC-F = 4.2 Hz), 27.3 (d, JC-F = 20.1 Hz), 49.8, 83.2 (d,
C-F = 165.7 Hz), 115.5, 120.7, 123.6, 124.2, 125.0, 127.9 (2C), 129.0,
3
)
d
: ꢁ219.3 (s, 1F); C NMR (100 MHz, CDCl
3
)
d
J
Sodium ascorbate (0.08 g, 0.38 mmol) and copper sulphate
(
1
0.02 g, 0.07 mmol) were added to a solution of alkyne 7 (0.80 g,
.94 mmol) and 1-azido-4-fluorobutane (0.34 g, 2.11 mmol) in
tert-butanol/water (50 mL, 4:1). The mixture was stirred at r.t. for
4 h. A saturated aqueous solution of ammonium chloride (20 mL)
was added and the aqueous layer was extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO , filtered
130.2, 131.1, 134.0, 136.0, 136.3, 136.5, 137.1, 139.3, 142.4, 143.9,
3
5
+
146.1; MS (ESI), calculated m/z C24
H
20 Cl
2
FN
5
S
2
: 532.1 [M+H] ,
+
+
534.1 [M+2+H] , found m/z (relative intensity): 532.1 [M+H]
+
2
(100), 534.1 [M+2+H] (75); HRMS calcd. for C24
532.0594, found: 532.0588.
2 5 2
H21Cl FN S :
4
and the solvent was evaporated under reduced pressure. The crude
product was purified by flash chromatography (Hexane/EtOAc 6:4)
4.12. 4-(5-(5-Cyclohexenylthiophen-2-yl)-1-(2,4-dichlorophenyl)-4-
methyl-1H-pyrazol-3-yl)-1-(4-fluorobutyl)-1H-1,2,3-triazole (1c)
to give triazole 8 (0.12 g, 55%) as a white solid. Rf 0.24 (Hexane/
1
EtOAc 6:4); H NMR (400 MHz, CDCl
3
)
d
: 1.60–1.68 (m, 1H), 1.69–
Starting from 8 and 1-cyclohexen-1-yl-boronic acid, compound
1
.76 (m, 1H), 1.99–2.09 (m, 2H), 2.47 (s, 3H), 4.41 (dt, 2H, JH-
= 47.2 Hz, JH-H = 5.7 Hz), 4.41 (t, 2H, J = 7.0 Hz), 6.60 (d, 1H,
1c (15 mg, 75%) was obtained as yellow oil. Rf 0.36 (Hexane/EtOAc
1
F
6:4); H NMR (400 MHz, CDCl
3
)
d
: 1.58–1.71 (m, 4H), 1.71–1.84 (m,
J = 3.9 Hz), 6.89 (d, 1H, J = 3.9 Hz), 7.25–7.32 (m, 2H), 7.42 (d, 1H,
4H), 2.16–2.23 (m, 2H), 2.34–2.40 (m, 2H), 2.58 (s, 3H), 4.51 (t, 2H,
J = 7.0 Hz), 4.51 (dt, 2H, JH-F = 47.2 Hz, JH-H = 5.7 Hz), 6.15–6.18 (m,
1H), 6.73 (d, 1H, J = 3.8 Hz), 6.82 (d, 1H, J = 3.8 Hz), 7.34 (dd, 1H,
J = 2.2, 8.5 Hz), 7.40 (d, 1H, J = 8.5 Hz), 7.50 (d, 1H, J = 2.2 Hz), 7.98
19
J = 2.1 Hz), 7.88 (s, 1H); F NMR (376.45 MHz, CDCl
3
)
d
: ꢁ219.3 (s,
: 10.3, 26.7 (d, JC-F = 4.1 Hz), 26.7
d, JC-F = 20.1 Hz), 50.0, 83.3 (d, JC-F = 165.5 Hz), 114.5, 121.3, 128.1,
28.9, 130.3, 130.4, 131.2, 134.1, 136.2, 136.3, 140.2, 142.4, 144.1, 147.0,
13
1
3
F); C NMR (100 MHz, CDCl ) d
(
1
9
13
1
(s,1H); F NMR (376.45 MHz, CDCl
3
)
d
: ꢁ219.3 (s, 1F); C NMR
79
35
+
150.5; MS (ESI), calculated m/z C20
H
17 Br Cl
2
+
FN
5
S: 528.0 [M+H] ,
(100 MHz, CDCl ) d: 10.2, 22.0, 22.6, 25.6, 26.5 (d, JC-F = 4.0 Hz),
3
+
+
530.0 [M+2+H] , 550.0 [M+Na] , 552.0 [M+2+Na] , found m/z (relative
27.4 (d, JC-F = 22.0 Hz), 29.7, 49.8, 83.2 (d, JC-F = 165.7 Hz), 115.2,
121.1, 125.2, 126.3, 127.8, 128.1, 128.5, 130.1, 130.3, 130.7,
131.1, 134.0, 135.7, 136.6, 142.0, 143.8, 149.0; MS (ESI),
+
+
+
intensity): 528.0 [M+H] (30), 530.0 [M+2+H] (65), 550.0 [M+Na] (52),
+
552.0 [M+2+Na] (100); HRMS calcd. for C20
2 5
H18BrCl FN S: 527.9822
3
5
+
and 529.9799, found: 527.9813 and 529.9787.
calculated m/z C26
H
26 Cl
2
FN
5
S: 530.1 [M+H] , 532.1 [M+2+H],
+
found m/z (relative intensity): 530.1 [M+H] (100), 532.1
4.9. Suzuki–Miyaura cross coupling: general procedure
[M+2+H] (70); HRMS calcd. for C26
30.1343.
2 5
H27Cl FN S: 530.1333, found:
5
A mixture of alkyne 8 (0.18 mmol), Pd(PPh
appropriate boronic acid (0.28 mmol) and aqueous Na
0.23 mmol) in DME (2 mL), was heated to reflux and stirred
overnight. The reaction was cooled down to r.t., poured into water,
extracted with DCM, dried over MgSO , filtered and the solvent
was evaporated under reduced pressure. The crude product was
purified by flash chromatography (Hexane/EtOAc 6:4) to give the
desired compound 1a–c.
3
)
4
(0.09 mmol), the
2
CO
3
4.13. Sonogashira reaction: general procedure
3 4
A mixture of alkyne 8 (0.09 mmol), Pd(PPh ) (0.003 mmol),
DIPEA (1 mL) and the appropriate alkyne (0.19 mmol of either
1-pentyne or cyclopropylacetylene) was stirred at 40 8C for
20 min. CuI (0.006 mmol) was added and the reaction was stirred
at 80 8C overnight. The mixture was cooled down to r.t., diluted
(
4
4
with EtOAc (1 mL), dried over MgSO , filtered and the solvent was
0
4
1
.10. 4-(5-(2,2 -bithiophen-5-yl)-1-(2,4-dichlorophenyl)-4-methyl-
evaporated under reduced pressure. The crude product was
purified first by HPLC (Semi-preparative C18 Luna column,
H-pyrazol-3-yl)-1-(4-fluorobutyl)-1H-1,2,3-triazole (1a)
2 3
Eluent: A: H O, Eluent B: CH CN; in isocratic condition Eluent A:
Starting from 8 and phenylboronic acid, compound 1a (46 mg,
20% and Eluent B: 80%, 5 mL/min) to give the desired compound
1d–e.
1
3
5%) was obtained as yellow oil. Rf 0.36 (Hexane/EtOAc 6:4);
H

1
90
R. Distinto et al. / Journal of Fluorine Chemistry 167 (2014) 184–191
4
.14. 4-(1-(2,4-Dichlophenyl)-4-methyl-5-(5-(pent-1-
(d, 1H, J = 3.9 Hz), 6.83 (d, 1H, J = 3.9 Hz), 7.25 (m, 2H), 7.38 (m,
7
9
35
+
ynyl)thiophen-2-yl)-1H-pyrazol-3-yl)-1-(4-fluorobutyl)-1H-1,2,3-
1H); MS (ESI), calculated m/z C16
H
8
Br Cl
2
IN
2
S: 536.8 [M+H] ,
+
+
+
triazole (1d)
538.8 [M+2+H] , 558.8 [M+Na] , 560.8 [M+2+Na] , found m/z
+
+
(
relative intensity): 536.8 [M+H] (20), 538.8 [M+2+H] (50), 558.8
+
+
Starting from 8 and 1-pentyne, compound 1d (50 mg, 20%) was
[M+Na] (70), 560.8 [M+2+Na] (100).
obtained as a yellow oil after an HPLC purification (Semi-
preparative C18 Luna column, Eluent A: H
in isocratic condition Eluent A: 20% and Eluent B: 80%, 5 mL/min,
retention time: 8.9 min). Rf 0.24 (Hexane/EtOAc 6:4); H NMR
2
O, Eluent B: CH
3
CN;
4.18. 4-[5-(5-Bromothiophen-2-yl)-1-(2,4-dichlorophenyl)-4-
methyl-1H-pyrazol-3-yl]-1-(4-fluorobutyl)-5-iodo-1H-1,2,3-triazole
(10)
1
(400 MHz, CDCl
3
)
d
: 1.02 (t, 3H, J = 7.4 Hz), 1.52–1.66 (m, 2H),
1
2
.68–1.75 (m, 1H), 1.75–1.85 (m, 1H), 2.04–2.19 (m, 2H), 2.39 (t,
H, J = 7.1 Hz), 2.55 (s, 3H), 4.48 (t, 2H, J = 7.0 Hz), 4.49 (dt, 2H, JH-
= 47.2 Hz, JH-H = 5.7 Hz), 6.77 (d, 1H, J = 3.8 Hz), 6.99 (d, 1H,
1-Azido-4-fluorobutane (400 mg, 0.37 mmol,) CuI (40 mg,
0.19 mmol) and TEA (10 mL, 0.74 mmol) were added to a solution
of propargyl iodide 9 (200 mg, 0.37 mmol) in THF (5 mL). The
reaction was stirred at r.t. for 72 h, then quenched with a 10%
F
J = 3.8 Hz), 7.33 (dd, 1H, J = 2.1, 8.4 Hz), 7.38 (d, 1H, J = 8.4 Hz), 7.48
19
(d, 1H, J = 2.1 Hz), 7.96 (s, 1H); F NMR (376.45 MHz, CDCl
3
)
d
:
aqueous solution of NH
under reduced pressure. The residue was diluted with Et
washed with water, dried over MgSO , filtered and the solvent was
4
OH (10 mL) and the solvent was removed
13
ꢁ
219.3 (s, 1F); C NMR (100 MHz, CDCl
3
)
d
: 10.3, 13.7, 21.8, 22.1,
2
O,
2
6.5 (d, JC-F = 4.2 Hz), 27.3 (d, JC-F = 20.1 Hz), 29.8, 50.0, 73.3, 83.3
4
(
1
d, JC-F = 165.7 Hz), 96.6, 115.6, 116.5, 121.3, 126.4, 128.1, 130.4,
evaporated under reduced pressure. The crude product was
purified by flash chromatography (Hexane/EtOAc 4:1) to give
31.1, 131.2, 134.1, 136.1, 136.3, 137.0, 142.4, 144.0; MS (ESI),
3
5
+
calculated m/z C25
found m/z (relative intensity): 516.1 [M+H] (100), 518.1 [M+2+H]
H
24 Cl
2
FN
5
S: 516.1 [M+H] , 518.1 [M+2+H],
the triazole 10 (100 mg, 42%) as a white solid. Rf 0.52 (Hexane/
+
1
EtOAc 4:1); H NMR (400 MHz, CDCl
3
)
d
: 1.70–1.79 (m, 1H), 1.79–
(
75); HRMS calcd. for C25
H
25Cl
2
FN
5
S: 516.1186, found: 516.1176.
1.87 (m, 1H), 2.05–2.19 (m, 2H), 2.41 (s, 3H), 4.50 (dt, 2H, JH-
= 5.8 Hz, JC-F = 47.2 Hz), 4.54 (t, 2H, J = 7.1 Hz), 6.66 (d, 1H,
J = 3.9 Hz), 6.96 (d, 1H, J = 3.9 Hz), 7.30–7.38 (m, 2H), 7.50 (d,
H
4
.15. 4-(5–(5-(2-cyclopropylethynyl)thiophen-2-yl]-1-(2,4-
1
9
13
dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1-(4-fluorobutyl)-1H-
1H, J = 1.9 Hz); F NMR (376.45 MHz, CDCl
NMR (100 MHz, CDCl : 10.1, 26.0 (d, JC-F = 4.4 Hz), 27.3 (d,
C-F = 20.3 Hz), 50.3, 78.0, 83.1 (d, JC-F = 165.8 Hz), 114.4, 116.9, 127.9,
3
)
d: ꢁ219.3 (s, 1F);
C
1
,2,3-triazole (1e)
3
) d
J
Starting from 8 and cyclopropylacetylene, compound 1e
128.7, 130.1, 130.3, 130.9, 131.2, 133.9, 135.9, 136.0, 136.2, 143.1,
79
35
+
(
40 mg, 25%) was obtained as a yellow oil after an HPLC
purification (Semi-preparative C18 Luna column, Eluent: A: H O,
Eluent B: CH CN; in isocratic condition Eluent A: 20% and Eluent B:
0%, 5 mL/min, Retention time: 12.0 min). Rf 0.24 (Hexane/EtOAc
145.1; MS (ESI), calculated m/z C20
H
16 Br Cl
2
FIN
5
S: 653.9 [M+H] ,
+
+
2
655.9 [M+2+H] , found m/z (relative intensity): 653.9 [M+H] (75),
+
3
2 5
655.9 [M+2+H] (100); HRMS calcd. for C20H17BrCl FIN S: 653.8788
8
6
2
2
and 655.8765, found: 653.8784 and 655.8757.
1
3
:4); H NMR (400 MHz, CDCl ) d: 0.77–0.86 (m, 2H), 0.87–0.94 (m,
H), 1.41–1.54 (m, 1H), 1.70–1.77 (m, 1H), 1.77–1.85 (m, 1H),
.08–2.19 (m, 2H), 2.56 (s, 3H), 4.51 (t, 2H, J = 7.0 Hz), 4.51 (dt, 2H,
Acknowledgments
J
H-F = 47.2 Hz, JH-H = 5.7 Hz), 6.69 (d, 1H, J = 3.9 Hz), 6.98 (d, 1H,
J = 3.9 Hz), 7.33–7.41 (m, 2H), 7.51 (d, 1H, J = 2.0 Hz), 7.98 (s, 1H);
We thank the European Commission for financial support
(Industry Academia Partnerships and Pathways project ‘‘PET
BRAIN’’, Contract No 251482) and the EPSRC National Mass
Spectrometry Service Centre (Swansea, UK), for performing HRMS
analyses.
1
9
13
F NMR (376.45 MHz, CDCl
100 MHz, CDCl
: ꢁ1.47, 8.50, 8.68 (2C), 26.5 (d, JC-F = 4.1 Hz),
7.0 (d, JC-F = 19.2 Hz), 46.1, 49.8, 68.0, 83.2 (d, JC-F = 165.5 Hz),
3
)
d
: ꢁ219.3 (s, 1F);
C NMR
(
3
) d
2
9
1
C
0.2, 115.6, 118.7, 121.1, 126.1, 126.7, 127.9, 128.5, 129.5, 130.1,
31.2, 133.9, 135.9, 137.6, 143.4; MS (ESI), calculated m/z
References
3
5
+
25
H
22 Cl
2
FN
5
S: 514.1 [M+H] , 516.1 [M+2+H], found m/z
+
(
relative intensity): 514.1 [M+H] (100), 516.1 [M+2+H] (75);
[1] (a) R.G. Pertwee, A.C. Howlett, M.E. Abood, S.P.H. Alexander, V. Di Marzo, M.R.
Elphick, P.J. Greasley, H.S. Hansen, G. Kunos, K. Mackie, R. Mechoulam, R.A. Ross,
Pharmacol. Rev. 62 (2010) 588–631;
HRMS calcd. for C25
.16. 4-Iodomorpholine
To a solution of iodine (4 g, 31.5 mmol) in MeOH (63 mL)
2 5
H23Cl FN S: 514.1030, found: 514.1020.
(b) S. Munro, K.L. Thomas, M. Abu-Shaar, Nature 365 (1993) 61–65.
4
[2] M. Herkenham, A.B. Lynn, M.D. Little, M.R. Johnson, L.S. Melvin, B.R. de Costa, K.C.
Rice, Proc. Natl. Acad. Sci. U. S. A. 87 (1990) 1932–1936.
[3] G. Griffin, S.R. Fernando, R.A. Ross, N.G. McKay, M.L.J. Ashford, D. Shire, J.W.
Huffman, S. Yu, J.A.H. Lainton, R.G. Pertwee, Eur. J. Pharmacol. 339 (1997) 53–61.
morpholine (2.75 mL, 31.5 mmol) was added drop wise and the
mixture was stirred for 1 h. The precipitate formed was collected
[4] R.G. Pertwee, Life Sci. 65 (1999) 597–605.
[
[
5] J.C. Ashton, D. Friberg, C.L. Darlington, P.F. Smith, Neurosci. Lett. 396 (2006) 113–116.
6] J. Horder, M. Browning, M. Di Simplicio, P.J. Cowen, C.J. Harmer, J. Psychophar-
macol. 26 (2012) 125–132.
by filtration, dried under vacuum and used crude, without further
1
purification. Rf 0.32 (DCM/MeOH 95:5); H NMR (400 MHz, CDCl
3
)
[7] G. Kunos, D. Osei-Hyiaman, S. B a´ tkai, K.A. Sharkey, A. Makriyannis, Trends
Pharmacol. Sci. 30 (2009) 1–7.
d
: 2.89–3.00 (m, 2H), 3.69–3.77 (m, 2H).
[
[
8] E. Kirilly, X. Gonda, G. Bagdy, Acta Physiol. 205 (2012) 41–60.
9] B.-C. Ho, T.H. Wassink, S. Ziebell, N.C. Andreasen, Schizophr. Res. 128 (2011) 66–
75.
4.17. 5-(5-Bromothiophen-2-yl)-1-(2,4-dichlorophenyl)-3-
[
[
10] B. Costa, A.E. Trovato, M. Colleoni, G. Giagnoni, E. Zarini, T. Croci, Pain 116 (2005) 52–61.
11] P. Gazzerro, M.G. Caruso, M. Notarnicola, G. Misciagna, V. Guerra, C. Laezza, M.
Bifulco, Int. J. Obes. 31 (2006) 908–912.
(iodoethynyl)-4-methyl-1H-pyrazole (9)
CuI (20.0 mg, 0.07 mmol) and 4-iodomorpholine (340 mg,
.56 mmol) were added to a solution of alkyne 7 (590 mg,
.43 mmol) in THF (4 mL). The reaction mixture was stirred at
room temperature for 1 h. The mixture was filtered on a neutral
alumina pad and the solvent was evaporated under reduced
pressure. The iodinated derivative 9 was obtained (570 mg, 74%) as
[12] M. Rinaldi-Carmona, F. Barth, M. H e´ aulme, D. Shire, B. Calandra, C. Congy, S.
Martinez, J. Maruani, G. N e´ liat, D. Caput, P. Ferrara, P. Soubri e´ , J.C. Breli e` re, G. Le
Fur, FEBS Lett. 350 (1994) 240–244.
1
1
[
13] (a) S.J. Gatley, A.N. Gifford, N.D. Volkow, R. Lan, A. Makriyannis, Eur. J. Pharmacol.
07 (1996) 331–338;
3
(b) S.J. Gatley, R. Lan, N.D. Volkow, N. Pappas, P. King, C.T. Wong, A.N. Gifford, B.
Pyatt, S.L. Dewey, A. Makriyannis, J. Neurochem. 70 (1998) 417–423.
[
14] (a) H.D. Burns, K.V. Laere, S. Sanabria-Boh o´ rquez, T.G. Hamill, G. Bormans, W. Eng, R.
Gibson, C. Ryan, B. Connolly, S. Patel, S. Krause, A. Vanko, A. Van Hecken, P. Dupont, I.
De Lepeleire, P. Rothenberg, S.A. Stoch, J. Cote, W.K. Hagmann, J.P. Jewell, L.S. Lin,
a yellow oil and was used without further purification. Rf 0.84
1
(
Hexane/EtOAc 7:3); H NMR (400 MHz, CDCl
3
)
d
: 2.16 (s, 3H), 6.51

R. Distinto et al. / Journal of Fluorine Chemistry 167 (2014) 184–191
191
P. Liu, M.T. Goulet, K. Gottesdiener, J.A. Wagner, J. de Hoon, L. Mortelmans, T.M. Fong,
R.J. Hargreaves, Proc. Natl. Acad. Sci. U. S. A. 104 (2007) 9800–9805;
[19] (a) C.-L. Tai, M.-S. Hung, V.D. Pawar, S.-L. Tseng, J.-S. Song, W.-P. Hsieh, H.-H. Chiu,
H.-C. Wu, M.-T. Hsieh, C.-W. Kuo, C.-C. Hsieh, J.-P. Tsao, Y.-S. Chao, K.-S. Shia, Org.
Biomol. Chem. 6 (2008) 447–450;
(b) F. Yasuno, A.K. Brown, S.S. Zoghbi, J.H. Krushinski, E. Chernet, J. Tauscher, J.M.
Schaus, L.A. Phebus, A.K. Chesterfield, C.C. Felder, R.L. Gladding, J. Hong, C. Halldin,
V.W. Pike, R.B. Innis, Neuropsychopharmacology 33 (2008) 259–269;
(b) S.-L. Tseng, M.-S. Hung, C.-P. Chang, J.-S. Song, C.-L. Tai, H.-H. Chiu, W.-P.
Hsieh, Y. Lin, W.-L. Chung, C.-W. Kuo, C.-H. Wu, C.-M. Chu, Y.-S. Tung, Y.-S. Chao,
K.-S. Shia, J. Med. Chem. 51 (2008) 5397–5412.
(c) G.E. Terry, J. Hirvonen, J.-S. Liow, S.S. Zoghbi, R. Gladding, J.T. Tauscher, J.M.
Schaus, L. Phebus, C.C. Felder, C.L. Morse, S.R. Donohue, V.W. Pike, C. Halldin, R.B.
Innis, J. Nucl. Med. 51 (2010) 112–120;
[20] (a) S. Ohira, Synth. Commun. 19 (1989) 561–564;
(b) S. M u¨ ller, B. Liepold, G.J. Roth, H.J. Bestmann, Synlett (1996) 521–522.
[21] F. Himo, T. Lovell, R. Hilgraf, V.V. Rostovtsev, L. Noodleman, K.B. Sharpless, V.V.
Fokin, J. Am. Chem. Soc. 127 (2005) 210–216.
(
d) S.R. Donohue, V.W. Pike, S.J. Finnema, P. Truong, J. Andersson, B. Guly a´ s, C.
Halldin, J. Med. Chem. 51 (2008) 5608–5616.
[
[
[
15] Retrieved from: http://clinicaltrials.gov/ (27.06.12).
[22] N. Miyaura, T. Ishiyama, H. Sasaki, M. Ishikawa, M. Saton, A. Suzuki, J. Am. Chem.
Soc. 111 (1989) 314–321.
[23] K. Sonogashira, Y.N. Tohda, Tetrahedron Lett. 16 (1975) 4467–4470.
[24] J.E. Hein, J.C. Tripp, L.B.H. Krasnova, K.B. Sharpless, V.V. Fokin, Angew. Chem. Int.
Ed. 48 (2009) 8018–8021.
16] J.H.M. Lange, C.G. Kruse, Drug Discov. Today 10 (2005) 693–702.
17] (a) P. Lazzari, A. Pau, S. Tambaro, B. Asproni, S. Ruiu, G. Pinna, A. Mastinu, M.M.
Curzu, R. Reali, M.E.H. Bottazzi, G.A. Pinna, G. Murineddu, Cent. Nerv. Syst. Agents
Med. Chem. 12 (2012) 254–276;
(
b) S. Frau, S. Dall’angelo, G.L. Baillie, R.A. Ross, M. Pira, C.-C. Tseng, P. Lazzari, M.
[25] (a) M.G. Cascio, L.A. Gauson, L.A. Stevenson, R.A. Ross, R.G. Pertwee, Br. J.
Pharmacol. 159 (2010) 129–141;
Zanda, J. Fluor. Chem. 152 (2013) 166–172, and references therein.
18] B.K. Srivastava, R. Soni, J.Z. Patel, A. Joharapurkar, N. Sadhwani, S. Kshirsagar, B.
Mishra, V. Takale, S. Gupta, P. Pandya, P. Kapadnis, M. Solanki, H. Patel, P. Mitra,
M.R. Jain, P.R. Patel, Bioorg. Med. Chem. Lett. 19 (2009) 2546–2550.
[
(b) D. Bolognini, B. Costa, S. Maione, F. Comelli, P. Marini, V. Di Marzo, D. Parolaro,
R.A. Ross, L.A. Gauson, M.G. Cascio, R.G. Pertwee, Br. J. Pharmacol. 160 (2010)
677–687.